Posttranslationally modified small-peptide signals in plants.

PP65CH14-Matsubayashi

ARI

ANNUAL REVIEWS

8 April 2014

21:29

Further

Annu. Rev. Plant Biol. 2014.65:385-413. Downloaded from www.annualreviews.org by University of Sheffield on 05/28/14. For personal use only.

Click here for quick links to Annual Reviews content online, including: • Other articles in this volume • Top cited articles • Top downloaded articles • Our comprehensive search

Posttranslationally Modified Small-Peptide Signals in Plants Yoshikatsu Matsubayashi National Institute for Basic Biology, Okazaki 444-8585, Japan; email: [email protected]

Annu. Rev. Plant Biol. 2014. 65:385–413

Keywords

The Annual Review of Plant Biology is online at plant.annualreviews.org

posttranslational modification, secreted peptide, proteolytic processing, cell-to-cell communication, plant hormone, receptor kinase

This article’s doi: 10.1146/annurev-arplant-050312-120122 c 2014 by Annual Reviews. Copyright All rights reserved

Abstract Cell-to-cell signaling is essential for many processes in plant growth and development, including coordination of cellular responses to developmental and environmental cues. Cumulative studies have demonstrated that peptide signaling plays a greater-than-anticipated role in such intercellular communication. Some peptides act as signals during plant growth and development, whereas others are involved in defense responses or symbiosis. Peptides secreted as signals often undergo posttranslational modification and proteolytic processing to generate smaller peptides composed of approximately 10 amino acid residues. Such posttranslationally modified small-peptide signals constitute one of the largest groups of secreted peptide signals in plants. The location of the modification group incorporated into the peptides by specific modification enzymes and the peptide chain length defined by the processing enzymes are critical for biological function and receptor interaction. This review covers 20 years of research into posttranslationally modified small-peptide signals in plants.

385


ARI

8 April 2014

21:29

Contents


INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A BRIEF HISTORY OF HOW PEPTIDE SIGNALS WERE IDENTIFIED . . . . . . . Bioassay-Guided Purification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classical Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bioinformatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . STRUCTURAL CHARACTERISTICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . POSTTRANSLATIONAL MODIFICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tyrosine Sulfation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proline Hydroxylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydroxyproline Arabinosylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PROTEOLYTIC PROCESSING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . STRUCTURES AND FUNCTIONS OF POSTTRANSLATIONALLY MODIFIED SMALL-PEPTIDE SIGNALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PSK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CLV3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CLE Family Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TDIF/CLE41/CLE44 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CLE-RS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CLE40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CLE8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CLE45 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HypSys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PSY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CEP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

386 388 388 389 390 390 391 391 391 394 395 396 396 397 399 399 400 400 401 401 401 402 403 403 404 405

INTRODUCTION Recent biochemical, genetic, and bioinformatic analyses have revealed that secreted peptides are important cell-to-cell signaling components that coordinate and specify cellular functions in plants. Over the past decade, the total number of functionally characterized peptide signals has increased severalfold (70, 83, 112) and now exceeds the total number of classical plant hormones. Additionally, peptide signals in plants have proven to be functionally and structurally more diverse than anticipated. Some of these peptides act as signals during plant growth and development, whereas others are involved in defense responses or symbiosis. In general, peptides can be categorized into two major classes—secreted peptides and nonsecreted peptides—according to the properties of the N-terminal leader sequences (Figure 1). Cell-to-cell signaling is mediated largely by the secreted signals, but there is also evidence that nonsecreted peptides directly released from the damaged cells act as cell-to-cell signals in defense responses in plants. In rare cases, nonsecreted peptides encoded by short open reading frames contribute to plant development in a cell-autonomous manner. 386

Matsubayashi


ARI

8 April 2014

21:29

Secreted peptides

Acts intracellularly


Acts extracellularly

Posttranslationally modified small peptides PSK CLV3 CLE HypSys IDA TDIF PSY CEP CLE-RS RGF

Nonsecreted peptides

Cysteine-rich peptides LAT52 SCR/SP11 RALF TPD1 EA1 EPF LURE STOMAGEN EC1

SYSTEMIN AtPep1

ENOD40 ROT4/DVL POLARIS

Figure 1 Categorization of the peptide signals in plants in terms of structure and site of action. This review covers posttranslationally modified small peptides (blue box), but cysteine-rich peptides and nonsecreted peptides are also known to act as signals. For details on individual peptides, see the following references: PSK (69), CLV3 (26), CLE (16), HypSys (102), IDA (6), TDIF (45), PSY (3), CEP (95), CLE-RS (98), RGF (72), LAT52 (84), SCR/SP11 (116, 137), RALF (103), TPD1 (145), EA1 (64), EPF (35), LURE (100), STOMAGEN (54a, 133), EC1 (126), SYSTEMIN (106), AtPep1 (42), ENOD40 (74), ROT4/DVL (86, 141), and POLARIS (12).

From a structural point of view, secreted peptide signals are further divided into two major classes: posttranslationally modified small peptides and cysteine-rich peptides (Figure 2). Posttranslationally modified small peptides are characterized by the small size of mature peptides and the presence of posttranslational modifications (65, 66). By contrast, cysteine-rich peptides are characterized by the presence of an even number of cysteine residues necessary for the formation of intramolecular disulfide bonds. This review focus on posttranslationally modified small peptides, a group that currently accounts for a major fraction of peptide signals in plants. Information regarding cysteine-rich peptides and defense-related nonsecreted peptides has been reviewed elsewhere (38, 63, 83, 111, 119). Posttranslationally modified small peptides have the following characteristics: (a) they are generally less than 20 amino acid residues in length, with a typical length of approximately 10 residues; (b) they are generated by proteolytic processing from larger polypeptide precursors with an N-terminal secretion signal sequence; and (c) they contain at least one posttranslational modification, such as tyrosine sulfation, proline hydroxylation, or hydroxyproline arabinosylation (Table 1). The molecular nature and location of the modification group incorporated by the modification enzymes and the peptide chain length defined by the processing enzymes are critical for biological function and receptor interaction. Because computationally predicting the mature, biologically functional structures of these peptide signals is still difficult, the www.annualreviews.org • Small-Peptide Signaling in Plants

Secretion signal sequence: a short (∼20-amino-acid) peptide present at the N terminus of a newly synthesized peptide destined for the extracellular space

387


ARI

8 April 2014

21:29

Secreted peptide signal gene

Prepropeptide Signal peptide

Propeptide

C C

Posttranslational modification Proteolytic processing

C

C

C C

Disulfide bond formation (Processing)

X X


Mature peptide Posttranslationally modified small peptide

C CC C C C

Cysteine-rich peptide

Figure 2 Structural categorization of secreted peptide signals. Peptides that undergo complex posttranslational modifications followed by proteolytic processing are defined as posttranslationally modified small peptides; peptides that undergo intramolecular disulfide bond formation are defined as cysteine-rich peptides. Adapted from Reference 66, published in The Arabidopsis Book (http://www.thearabidopsisbook.org); copyright c 2011 by the American Society of Plant Biologists.

search for novel peptide signals presents a highly attractive challenge in the postgenomic era.

A BRIEF HISTORY OF HOW PEPTIDE SIGNALS WERE IDENTIFIED Bioassay-Guided Purification The first peptide signal identified in plants was a tomato systemin involved in the defense response, which was reported in 1991 (106). Although tomato systemin is not a secreted peptide and does not contain posttranslational modifications, discovery of this peptide inspired plant biologists to identify other biologically active peptide signals in plants. The fact that tomato systemin was identified through a bioassay-guided purification process also impressed researchers with the effectiveness of using a biochemical approach to dissect the mechanism of cell-to-cell communication. In 1996, a classical purification study led to the identification of phytosulfokine (PSK), which is involved primarily in cell proliferation (69). PSK is the first example of a posttranslationally modified small peptide discovered in plants. A search for systemin-like peptides in other plant species using bioassay-guided purification methods led to the 2001 identification of the hydroxyproline-rich systemin (HypSys) glycopeptide family in tobacco (102). In contrast to tomato systemin, HypSys is a typical posttranslationally modified small secreted peptide. In 2006, further bioassay-guided study identified tracheary element differentiation inhibitory factor (TDIF), a 12-amino-acid peptide that regulates vascular stem cell fate (45). The TDIF sequence shows high similarity to the short conserved domain within the CLAVATA 3 (CLV3)/embryo surrounding region (CLE) family peptides. This finding, together with elucidation of the structure of mature CLV3 (described below) (56, 96), is a reminder of how important the peptide chain length determined by proteolytic processing is for the function of this type of peptide signal. 388

Matsubayashi


ARI

8 April 2014

21:29

Table 1 Structurally and/or physiologically characterized posttranslationally modified small-peptide signals


Peptide

Mature peptide structure

Representative function(s)

Receptor(s)

Reference

PSK

Tyr(SO3 H)-Ile-Tyr(SO3 H)-Thr-Gln

Cellular proliferation and expansion

PSKR1, PSKR2

69

CLV3

Arg-Thr-Val-Hyp-Ser-Gly[Ara3 ]Hyp-Asp-Pro-Leu-His-HisHis

Regulation of the stem cell population in the shoot apical meristem

CLV1, CLV2, CRN/SOL2, RPK2

96

TDIF/CLE41/ CLE44

His-Glu-Val-Hyp-Ser-Gly-Hyp-AsnPro-Ile-Ser-Asn

Regulation of the vascular stem cell population

TDR/PXY

45

CLE-RS2

Arg-Leu-Ser-Hyp-Gly-Gly[Ara3 ]Hyp-Asp-Pro-Gln-His-AsnAsn

Autoregulation of nodulation in leguminous plants

HAR1

99

CLE40

CLE domain oligopeptide (putative)

Controlling stem cell fate in the root meristem

ACR4, CLV1

41

CLE8


Embryo and endosperm development

Unknown

25

CLE45


Pollen tube growth

SKM1, SKM2

20

CLE2

Arg-Leu-Ser-Hyp-Gly-Gly[Ara3 ]Hyp-Asp-Pro-Gln-His-His

Unknown

Binds CLV1

96

CLE9

Arg-Leu-Val-Hyp-Ser-Gly-Hyp-AsnPro-Leu-His-Asn + Ara3 , Ara4 , or Ara6

Unknown

Binds BAM1

122

NtHypSys I

Arg-Gly-Ala-Asn-Leu-Pro-Hyp-HypSer-Hyp-Ala-Ser-Ser-Hyp-HypSer-Lys-Glu + Pentose9

Defense response in Solanaceae plants

Unknown

102

IDA

EPIP domain oligopeptide (putative)

Floral organ abscission and lateral root emergence

HAE, HSL2

6

PSY1

Asp-Tyr(SO3 H)-Gly-Asp-Pro-SerAla-Asn-Pro-Lys-His-Asp-Pro-GlyVal-[Ara3 ]Hyp-Hyp-Ser

Cellular proliferation and expansion

At1g72300?

3

CEP1

Asp-Phe-Arg-Hyp-Thr-Asn-Pro-GlyAsn-Ser-Hyp-Gly-Val-Gly-His

Lateral root development?

Unknown

95

RGF1

Asp-Tyr(SO3 H)-Ser-Asn-Pro-GlyHis-His-Pro-Hyp-Arg-His-Asn

Root stem cell niche maintenance and transit-amplifying cell proliferation

Unknown

72

Sulfated tyrosine residues are indicated as Tyr(SO3 H), hydroxyproline residues are indicated as Hyp, and hydroxyproline residues modified with three residues of arabinose are indicated as [Ara3 ]Hyp.

Classical Genetics Peptide signals have also been identified using classical genetics approaches, although this has been limited to functionally nonredundant peptide genes. CLV3, which is involved in stem cell maintenance in the shoot apical meristem, was identified in 1999 (26), and INFLORESCENCE DEFICIENT IN ABSCISSION (IDA), which regulates organ abscission, was identified in 2003 (6). The mature, functional structure of CLV3 was later elucidated through biochemical analyses (56, 96), but that of IDA remains to be determined. However, no additional peptide signals have been identified through classical genetics since 2003, indicating that all nonredundant peptide genes that produce a discernible phenotype when disrupted by mutation have been fully characterized. www.annualreviews.org • Small-Peptide Signaling in Plants

389


ARI

8 April 2014

21:29

Bioinformatics Stem cell niche: the microenvironment where stem cells are found


Gene redundancy: the presence of additional copies (generally three to five in Arabidopsis) of genes that all play the same role Paralogous genes: functionally redundant genes that are generated from a common ancestral gene by gene duplication

The current trend in peptide signaling research is the use of bioinformatics tools, which have become increasingly useful owing to continued advances in genomics and transcriptomics technologies. Genome-wide searches for homologs of CLV3 led to the 2001 identification of a group of signaling peptides collectively named CLE peptides. CLE peptides possess a conserved 14amino-acid domain (called the CLE domain) at or near their C terminus (16, 92). A unique example of the use of a bioinformatics strategy in parallel with a homology-based approach involves the identification of the cysteine-rich peptide EPIDERMAL PATTERNING FACTOR 1 (EPF1), which regulates stomatal patterning (35). EPF1 was identified in 2007 through an exhaustive overexpression analysis of genes possibly encoding small secreted peptides extracted from the Arabidopsis annotated genome database. An alternative approach employing in silico screening to pick up secreted peptides that share structural characteristics of the precursor polypeptides of other known posttranslationally modified small peptides led to the identification of C-terminally encoded peptide 1 (CEP1), which has been suggested to play a role in lateral root development (95). An approach coupling in silico peptide screening with a practical bioassay contributed to the 2010 identification of the root meristem growth factor (RGF) family of peptides that are required for maintenance of the root stem cell niche. These peptides rescue root meristem defects in a loss-of-function tyrosylprotein sulfotransferase (TPST) mutant (72). Several cysteine-rich peptide signals that act in the reproductive pathway have been identified using a single-cell transcriptomics approach (100, 126). Because these methods elegantly overcome the barrier posed by gene redundancy and/or low abundance of peptides in the tissues, further attention will be devoted to bioinformatics-based in silico approaches in the future.

STRUCTURAL CHARACTERISTICS From a structural point of view, all peptide signals in plants can be divided into four major groups based on whether they are secreted (i.e., whether an N-terminal secretion signal sequence is present) and whether the mode of action is extracellular or intracellular (Figure 1). Posttranslationally modified small peptides and cysteine-rich peptides are categorized as secreted peptides with an extracellular mode of action. Secreted peptides are thought to move in the extracellular space by passive diffusion and play a determining role in the fate of neighboring cells in a noncell-autonomous manner. Nonsecreted peptides are in some cases delivered to the extracellular space, where they act as cell-to-cell signals (42, 106). Some nonsecreted peptides also play roles in regulating cellular function through intracellular signaling (9, 74, 86, 141). Posttranslationally modified small peptides are characterized by (a) the presence of posttranslational modifications that are mediated by specific transferases and (b) their small size (less than 20 amino acids), which is a result of proteolytic processing (Figure 2). These peptides are initially translated as ∼100-amino-acid precursor polypeptides containing an N-terminal secretion signal and are then structurally altered by specific modification and processing enzymes localized in the endoplasmic reticulum or Golgi complex to yield mature, biologically functional peptides. Interestingly, the primary sequences of the majority of their precursor polypeptides have unique structural features (Figure 3). Precursor polypeptides are encoded by multiple paralogous genes that may be generated by gene duplication. The paralogous genes encode secreted polypeptides approximately 70–120 amino acids in length that, with the exception of conserved regions near the C terminus that correspond to the mature peptide domains, exhibit significant sequence diversity. These characteristic domain structures suggest that a number of amino acid substitutions accumulated evolutionarily outside the region of the mature peptide domains, because these regions are digested by proteolytic processing. Additionally, signal peptide precursor polypeptides 390

Matsubayashi


ARI

8 April 2014

21:29

contain few or no cysteine residues, which is in sharp contrast to the presence of multiple cysteine residues (typically six or eight) in cysteine-rich peptides (Figure 2). The cysteine-rich peptides are structurally stabilized by intramolecular disulfide bonds, thus suggesting that disulfide bonds interfere with proteolysis by the processing enzymes. It should be noted that these characteristic structural features of the precursors of posttranslationally modified small-peptide signals enable the prediction of genes encoding novel peptide signal candidates. More specifically, genes encoding families of cysteine-poor secreted peptides with conserved C-terminal domains may also encode posttranslationally modified small-peptide signals. Indeed, CEP1 and RGF were identified in part by in silico screening of peptide families with these characteristics (72, 95).


POSTTRANSLATIONAL MODIFICATIONS Posttranslational modifications are known to alter the physicochemical properties of peptides by changing net charge, hydrophilicity, and/or conformation, thereby modulating the binding ability and specificity of peptides for their target receptor proteins. To date, three types of posttranslational modifications have been identified in secreted peptide signals in plants: tyrosine sulfation, proline hydroxylation, and hydroxyproline arabinosylation (65) (Figure 4, Table 2).

Tyrosine Sulfation Tyrosine sulfation is a posttranslational modification occasionally found in peptides and proteins synthesized through the secretory pathway in both plants and animals (77) (Figure 4a). Three tyrosine-sulfated peptide signals—PSK (69), PSY (3), and RGF (72)—have thus far been identified in plants (Table 1). This modification is mediated by TPST, which catalyzes the transfer of a sulfate from 3 -phosphoadenosine 5 -phosphosulfate (PAPS) to the phenolic group of tyrosine (54). Although the tyrosine sulfation motif in peptides is not clear-cut, the minimum requirement for tyrosine sulfation in plants is the presence of an aspartic acid residue N-terminally adjacent to a tyrosine residue. Multiple acidic amino acids near this tyrosine residue significantly enhance sulfation (34). Arabidopsis TPST (AtTPST) was purified and identified as a cis-Golgi-localized 62-kDa transmembrane protein (54). AtTPST is expressed throughout the plant, and the highest levels of expression are observed in the root apical meristem. Surprisingly, AtTPST shows no sequence similarity with animal TPST, even though both enzymes catalyze identical sulfate transfer reactions using the same cosubstrate, PAPS (77). This structural diversity strongly suggests that the AtTPST gene evolved from an ancestral gene distinct from that of animal TPST genes. Plants and animals likely acquired enzymes for tyrosine sulfation independently through convergent evolution. A loss-of-function AtTPST (tpst-1) mutant displays dwarfism, pale green leaves, and early senescence in the aboveground tissues and an extreme short-root phenotype accompanied by loss of maintenance of stem cells and a considerable decrease in meristematic activity (54, 147). As discussed below, these root defects associated with tpst-1 are caused primarily by loss of sulfation on the RGF peptides that are required for maintenance of the root stem cell niche.

Proline Hydroxylation Hydroxyproline residues have been observed in almost all posttranslationally modified smallpeptide signals except for PSK, which has no proline residues (Figure 4b). Proline hydroxylation is mediated by prolyl-4-hydroxylase (P4H), which belongs to a family of 2-oxoglutarate-dependent dioxygenases that require 2-oxoglutarate and O2 as cosubstrates (85). P4H is a transmembrane www.annualreviews.org • Small-Peptide Signaling in Plants

391

392

Matsubayashi

CLE-RS1 CLE-RS2

M---ENASEVQVSMLIAMVFCTLFVTLQARSLHEQYPLVQQNINSLALLHKLGIDPSKHVQIRVDDSNVPLSPGDRLSPGGPDPQHNGKRPPSNHH MAKTTLARVVCIFVLV-IIFSNFFMTLQARNL--Q--IIHKN-N--AV-QNYVFDLSKHMHV-VHK-DG-YQQ-QRLSPGGPDPQHNNAIPPSN--

93 81

99 88 112

------------------------------------MGGNGI RA-L--VGVIASL-GLI-V--F--LLVGI-LANS-APSV--P-S-SE-NVK-TLR--FS-G-K-DVNL-FHV-SKRKVPNGPDPIHNRKAETSRRPP-RV ---------------------------- MRNNH-SLRLQLWFRT-LFTVGVVT-L--LM-IDAF--VLQNN-KEDDKTKEITTAVNMNNSDAK-EIQQELEDGSRND-DLSY-VASKRKVPRGPDPIHNRRAGNSRRPPGRA MLGSSTRSMFFLLVCIGLLADNRYNVSA MRHREFFLKETQAEKAGV-QTEEISKLRS-IGVQ-FKHTLEDQEMLN-KNRRVLEEVN-KD-KIKAE-ETQ-ERKNKTE-D-SFK-SSKRRVRRGSDPIHN-KAQPFS------

CLE25 CLE26 CLE45

TDIF/CLE41 MATSNDQTNTKSSH-SRTL-LL-L-FIFLSLL-LFSSLTIPMTR-H-Q-STSM--VAPFKRVL-LESSVPASSTMDLRP-KASTRRS-R-TS--R-RR-EF-GNDAHEVPSGPNPISNCLE42 ---------MRSPHI--TISLVFL-F-FL-FL-IIQTHQRTIDQTH-QIGSNVQHVS--D--MAVT-S-PEGKRRE-R-FRV--RRP-M-TTWLKGKM--I-GANEHGVPSGPNPISNR TDIF/CLE44 MATTIDQTSIKSLHFHQVIRLI-ITIIFLAFLFLIGP-TSSMNH-HLHESSSKNTMAPSKRFL-LQPSTPSSSTMKMRP-TAHPRRSGTSSSSARKRRREFRA-EAHEVPSGPNPISN-

M-EA-CSRK-R-RRRRAYTTSTTG-Y-A-AVFF-C--GIF-V--FAQFGISSS-A-LFA-PDHYPSLPRKAGHF----HEMASFQ-AP-KATVS-F-TGQR--REEENRDEVYK DDKRLVHTGPNPLHN-MTHVLVRRQGQGKKRR-WDVNMTMCF--F-LFF---F-VFYVS-F-QIVLSSS-A---S-VG-Y-S--R-L-HL-V--ASPPP-P-PPRKA-LR-Y-STAP-FRGPLSRDDIYG DDKRVVHTGPNPLHN---------------------------------------------------------MKIKGLMILASSLLILAFIHQSESASMRSLLMNNGSYEEEEQVLKYDSMGTIANSSAL DSKRVIPTGPNPLHNR---------------------------------------------MKNKNMNPSRPRLLCLIVFLFLVIVLSKASRIHVERRRFSSKPS-GENREFLPSQPTFPVV-DAGEILP D-KRKVKTGSNPLHNKR ML-ILSSR-Y-AMKRDVL-I-IVI-FTVLVLIIISRSSSIQAGRFMTTGRNRNLS-V-ARSLYYKN-HHKV--V-I--TEMSNFNKVRRRSS-R-F-R--R--KTD-GDEE--EEE KRSIPTGPNPLHNKMGN-YYSRR-KSRKHIT-TVALII-L-LL-LLF-----LF-L--YAKAS-SSS-PNIHHHSTH-GSL-KKSGNLDPKLHDLDSNA-ASSRGS-K-Y-TN---YEGG-G-EDVFE DGKRRVFTGPNPLHNR-

CLE16 CLE17 CLE19 CLE20 CLE21 CLE22

103 99 74 83 106 103 81 102 124

-------------------------------------------------MKVLKRDS-ML LLITLY-FL-L-TTS-M--AR-Q-D--P---F-LVGVEKD-VVPAG-TDLKQNKAKPHLPNLFRT-M RRVPTGPNPLHH--ISP--P-QPGSLNYARN ---------MTM-THLNR-L-ILISLLFVSLLLKSSTASSTVVDEGNRTSRNFRYRTHRFVPRFNHHPYHVT-PHRSCDSFI-RPYA-RS-MCIELQ RIHRSSRKQPLLSPPPP--EIDP-RYGVDKRLVPSGPNPLHN-----------------------------MKTNRNRPINILI-VFF--LL-TTARAA-T--R--NWT--N-R--THRTVPKV-QHAYY-AYPHRSCESFS-RPYA-RS-MCIELE RIHRSSR-QPLFSPPPPPTEIDQ-RYGVEKRLVPSGPNPLHN------------------------------------MTKQPKPCSFL-FHISLLSALF-V-F-L-LISF-AFTTS-YK LKSGI-NS--L--GHKR-I-LASN-FDFTPFL-KNKD RTQRQ-R-QS---PSLTVKE-NGFWYNDEERVVPSGPNPLHH------------------MLRISSSSSMAL-KFSQIL-FIVLWLSLF-F-L-LLHHLYSLNFR-RLYSLNAV-EPSL- LKQ-HYRSYRLV-S-RK-V-LSDR-FDFTPFHSRDNS RHN-H-R-SG---EQYDGDEIDP-RYGVEKRRVPSGPNPLHH---------------------------MATTRVSHVLGFL-LWISLLIF-V-SIG-LFG-NFSSK--PINPFPSPVIT LPA-LY--YR-P-G-RR-A-LAVKTFDFTPFL-KDLR RSN-H-R-KAL--PA-GGSEIDP-RYGVEKRLVPSGPNPLHH------------------------------------------------------------------------------MKVWSQRLSF LIVMIFILAGLHSSSAGRKLPSMTTTEEFQRLSFDGKRILSEVTADKKYDRI YGASARLVPKGPNPLHNK------------------

CLE8 CLE9 CLE10 CLE11 CLE12 CLE13 CLE14

74 75 83 80 81 81 86

MAN--LKFLLCL-FLICVSLSRSS-ASRPM------FPNADGIKRG- RMM-IE-AEEVLKA-SM--EKLMERGFNESMRLSPGGPDPRHH-----------MAKLSFTFCFLLFL-L-LSSIAAGSRPL---EGARVG-VKVRGLSPSI--EATSPTVEDDQAAGSH--GKS-P E--RLSPGGPDPQHH---------MAS--LKLWVCLVLLLVLELTSVH-ECRPLVA-EERFSGSSRLKKIRREL-FERLKE-MKGRSEGEETILGNTL-DSKRLSPGGPDPRHH---------MAS--FKLWVCLILLL-LEF-SVH-QCRPLVA-EESPSDSGNIRKIMREL-LKRSEE-LKVRSKDGQTVLG-TL-DSKRLSPGGPDPRHH---------MATLILKQTL-IILLIIFSLQTLSSQARILRSYRAVSMGNMDSQVLLHELGFD-LSK-FKGHNE--RRFLVSS--D--RVSPGGPDPQHH---------MANLILKQSL-IILLIIYSTPILSSQARILRTYRPTTMGDMDSQVLLRELGID-LSK-FKGQDE--RRFLVDS--E--RVSPGGPDPQHH---------MAS---KALL-LFVMLTF-LLVIEMEGRILRV-NSKTKDG-ESNDLLKRLGYN-VSE-LK-RIG--RELSVQN--EVDRFSPGGPDPQHHSYPLSSKPRI

96 80

CLE1 CLE2 CLE3 CLE4 CLE5 CLE6 CLE7

86 87 81 79 77

---MDSKSFLLLLLLFCFLFLHDASDLTQAHAHVQGLSNRKMMMMKMESEWVGANG EAEKAKTKGLGLH-EELRTVPSGPDPLHH-HVNPPRQPRNNFQLP MAAMKYKGSVFIILVI-LL-L-SSSLLAHSSS-TKSFF-W-LGETQ-DTK-A-MKK E-KKIDG-GTANEVEE-RQVPTGSDPLHHKHI-PFTP--------

CLV3, CLE, TDIF, and CLE-RS

------MKTKSEVLIFFFTLVLLLSMASSVILREDGFAP PKPSPTTHEKASTKGDRDGVECKNSDSEEEC-LVKKTVAA-HTDYIYTQDLNLSP MANVSALL-TIALLLCSTLMCT-ARPEPAISISITTAADPCNMEKKIEGKLDDMHMVDENC-GAD-DEDC-LMRRTLVA-HTDYIYTQKKKHP--------MKQSLCLAVLFLILSTSSSAIRRGKEDQEIN PLVSATSVEEDSVNKLMGMEYC-GEG-DEEC-LRRRMMTESHLDYIYTQHHKH-MGKFTTIF-IMALLLCSTLTYA-ARLTPTTTTALSR--EN-SV-KEIEG--DKVE--EESCNGIG-EEEC-LIRRSLVL-HTDYIYTQNHK-PMVKFTTFLCIIALLLCSTLTHASARLNPTSV--YPE--EN-SF-KKLEQ--GEV-----ICEGVG-EEECFLIRRTLVA-HTDYIYTQNHN-P-

86 120 107 99 118 107 80

8 April 2014

CLV3 CLE40

b

PSK

ARI

PSK1 PSK2 PSK3 PSK4 PSK5

a


PP65CH14-Matsubayashi 21:29

HypSys

91 126 82 86 105

116 109 110 141 88 86 102 123 79 143 101

Structural characteristics of the primary amino acid sequences of precursor polypeptides that represent posttranslationally modified small peptides. Shown are the deduced amino acid sequences of (a) PSK; (b) CLV3, CLE, TDIF, and CLE-RS; (c) HypSys; (d ) IDA; (e) PSY; ( f ) CEP; and ( g) RGF, as well as their representative homologs. Domains encoding the mature peptides (if known) are underlined in red. Identical amino acid residues are highlighted in dark blue, and similar amino acid c 2011 by the residues are highlighted in light blue. Adapted from Reference 66, published in The Arabidopsis Book (http://www.thearabidopsisbook.org); copyright American Society of Plant Biologists.

Figure 3

75 71 71

---------------------------MVSIRVICYLLVFSVLQVHAKVSNANFNSQAPQMKNSEGLGASNGTQIAKKHAEDVIENRKTLKHVNVKVEANEKNGLEIESKEMVKKRKNKKRLTKTESLTADYSNPGHHPPRHN --------------------------MTNITSSFLCLLILLLFCLSFGYSLHGDKDEVLSVDVGSNAKVMKHLDGDDAMKKAQ--VRGRSGQEFSKETTKMMM--K-KTTKKETNVE-EED-DLVAY-TADYWKPRHHPPKNN --------------------------MTTL-SKILCVLIILLLCFSFRYSLHEDGNQQSSRDFVSTAKAIKYGDVMKKMIRGRK-LMMASGEK-EEAETKMKR-GN-RETERNSSKSVEED-GLVAY-TADYWRAKHHPPKNN ---MRFTIIVIAFLLIIQSLEEEQILVYARKGREACHKSLDYQGDQDSSTLHPKELYDAPRKVRFGRATRAEKEQVTAMNNDSWSFKISGASKHLIVERKLGFHKRSKSSSFKWKPKKKKSSGPFVAFYDDYRGPARHPPRHNL -------------------------------------------------MSSIHVASM-ILLLFLFLH-HSDSRHLDNVHITAS-RFSLVK-DQNVVS-SSTSKEPVKVSRFVPGPLKHHHRRPPLL-FADYPKPSTRPPRHN -----------------------------------------------------------MSCSLRSGLVIVFCFIL-LLLSSNVGCASAARRLRSHKHHHHKVASLDVFNGGERRRALGGVETGEEVVVMDYPQPHRKPPIHNEKS -----------------------------------------MEMKKWSYANLITLALLFLFFIILLLAFQGGSRDDDHQHVHVAIRTKDISMGRKLKSLKPINPTKKNGFEYPDQGSHDVQEREVYVELRDYGQRKYKPPVHN -------------------------MKLIRVTLFLCALAILLLVTPTS-SLQL-KHPYSSPSQGLSKKIVTKMATRKLMIISSEYVMTSTSHEGSSEQLRVTSSGKSKDEEKKLSEEEEEKKALAKYLSMDYRTFRRRRPVHNKALPLDP ----------------------------------------------------------------MAIRVSHKSFLVALLLILFISSPTQARSLR-EVVRNRTLLVVEKSQESRKIRHEGGGSDVDGLMDMDYNSANKKRPIHNR MDMLRSACFYFLLIVFVILSWSLLCDSRHLGHMEKKLSVNLDLLNKDNEEITKLEAPSTNKTNTLLSQSHAVVNHGDNGQINGKKTKEIHRVKRASDKKVSSKRVSRTWKIPKYPKKQPKSDQEHPGFNLDYMQPTTHPPHHN --------------------------------------------------------MHLLKGGVVLIITLILFLITSSIVAIREDPSLIGVDRQIPTGPDPLHNPPQPSPKHHHWIGVEENNIDRSWNYVDYESHHAHSPIHNSPEPAPLYRHLIGV

RGF

RGF1 RGF2 RGF3 RGF4 RGF5 RGF6 RGF7 RGF8 RGF9 RGF10 CLE18/ RGF11

g

MTFVV--RL-L-VCLLLTLTITSSLARNPVSVSGGFENSGFQRSLLMVNVEDYGDPSANPKHDPGVPPSATGQRVVGRG MSFGT--RL-L-LFLILTLPLVTSSSPNTLHVSG-IVKTGTTSRFLMMTIEDYDDPSANTRHDPSVPTNAKADTTP--MGYSSSSRIGLCLFLFFTFALLSS-ARISLSFSEN-EMTVVPERSLMVSTNDYSDPTANGRHDP--PRGGRGRRR----

77 86 95 99 93 103

------------------------MGMSNRSVSTSIFFLALVVLHG-IQDTEERHLKTTSLEIEGIYK-KTEAE-HPS-IVVTYTRRGV-LQKEVIAHPT-----DFRPTNPGNSPGVGHSNGRH-MKLFIITVVTILTISRVFDKTPATTEARKSKKMVGHEHFNEYLDPTFAGHTFGVVKEDFLEVKKLKKIGDENNLKNRFINEFAPTNPEDSLGIGHPRVLNNKFTNDFAPTNPGDSPGIRHPGVVNV-------------------MATIN-VYV-FAF---IFLLTIS-V-G-S--IEGRKLT--KF---TV-T-TSE-EIRAGGSVLSSSPPTEPLESPP-SH-GV-DT--FRPTEPGHSPGIGHSV-HN------------------------------------------MVSRGCSITVLFRFLIVLLVIQVHFENTKAARHAPVVSWSPPEPPKDDFVWYHKINRFKNIEQDAFRPTHQGPSQGIGHKNPPGAP ---------------MESFMGQKKTLYACY-FLMLVFFLGFNCVHGRTLKVDD-KINGGHYDSKTMMALAKHNDMMVDDKAMQFSPPPPP--PPP-SQSGGKDAEDFRPTTPGHSPGIGHSLSHN--

PSY

CEP

CEP1 CEP2 CEP3 CEP4 CEP5

f

PSY1 PSY2 PSY3

---------------MAPCRTMMVLLCFVLFLAASSSCVAAARIGAT-M---EM-----KKNIKR-LTFKNSHIF-GYLPKGVPIPPSAPSKRHNSFVNSLPH------------------MNLSHKTMFMTL-YIVFLLIFGSYNATARIGPIKLSETEIVQTRSRQEIIGGFTFK-GRVF-HSFSKRVLVPPSGPSMRHNSVVNNLKH----MSSRNQRSRITSSFFVSFFTRTILLLLILLLGFCNGARTNTNVFNSKPHKKHNDAVSSS----------TK--QFLGFLPRHFPVPASGPSRKHNDIGLLSWHRSSPMSSRSHRSR---KYQLTR-TIPILVLLLVLLSCCNGART-TNVFNTSSPPKQKDVVSPPHDHVHHQVQDHKSVQFLGSLPRQFPVPTSGPSRKHNEIGLSSTKT---------------MYPTRPHYWRRRLSINRPQAFLLLILCLFFIHHCDASRFSSSSVFYRNPNYDHSNNTVRRGHFLGFLPRHLPVPASAPSRKHNDIGIQALLSP-------MGNKRIKAMMILVVMIMMVFSWRICEADSLRRYSSSSRPQRFFKVRRPNPRNHHHQNQGFNGDDYPPESFSGFLPKTLPIPHSAPSRKHNVYGLQSTNSHRCP

IDA

8 April 2014

e

IDA IDL1 IDL2 IDL3 IDL4 IDL5

ARI

d

NtHypSys MRVLFLIYLILSPFGAEARTLLENHEGLNVGSGYGRGANLPPPSPASSPPSKEVSNSVSPTRTDEKTSENTELVMTTIAQGENINQLFSFPTSADNYYQLASFKKLFISYLLPVSYVWNLIGSSSFDHDLVDIFDSKSDERYWNRKPLSPPSPKPADGQRPLHSY 165

c


PP65CH14-Matsubayashi 21:29

www.annualreviews.org • Small-Peptide Signaling in Plants

393


ARI

8 April 2014

21:29

a

b

c

R1

O

N SO3H R1

O

O OH

O

N

R2

N H

O OH O

HO

HO

O OH

O HO


O

HO R2

R1

R2

O OH

Tyrosine sulfation

Proline hydroxylation

Hydroxyproline arabinosylation

Tyr(SO3H)

Hyp

[Ara3 ]Hyp

Figure 4 Structures resulting from posttranslational modifications found in secreted peptide signals: (a) tyrosine sulfation, (b) proline hydroxylation, and (c) hydroxyproline arabinosylation. R1 and R2 represent peptide chains. Adapted from Reference 66, published in The Arabidopsis Book (http://www.thearabidopsisbook. c 2011 by the American Society of Plant Biologists. org); copyright

protein that localizes in both the endoplasmic reticulum and the Golgi complex. To date, 13 P4H genes have been identified in Arabidopsis (37, 138, 139, 146). Although some sequence motifs have been associated with efficient proline hydroxylation (120), no definitive consensus sequence has been determined for proline hydroxylation of secreted peptide signals in plants. Disruption of several P4H genes results in the blockage of polarized growth in root hairs (139); however, this phenotype is likely caused primarily by dysfunctional cell wall proteins rather than dysfunctional peptide signals.

Hydroxyproline Arabinosylation Hydroxyproline residues in several secreted peptide signals, such as PSY1, CLV3, CLE2, CLE9, and CLE-RS2, are further modified with an O-linked L-arabinose chain (3, 96, 99, 122) (Figure 4c, Table 1). Although no structural assignments have been provided, circumstantial Table 2 Enzymes involved in posttranslational modifications in peptide signals Posttranslational modification

Enzyme

Localization

Tyrosine sulfation

TPST

cis-Golgi

Proline hydroxylation

P4H

Endoplasmic reticulum and Golgi

Hydroxyproline arabinosylation

HPAT

cis-Golgi

394

Matsubayashi

Number of genes in

Phenotypes of loss-of-function

Arabidopsis

mutants

1 13 3

Dwarfism, pale green leaves, early senescence, and short roots Defective growth in root hairs Enhanced hypocotyl elongation, defects in cell wall thickening, early flowering, early senescence, and defective growth of pollen tubes; hypernodulation in leguminous plants



ARI

8 April 2014

21:29

evidence suggests that pentose residues found in HypSys glycopeptides are arabinosides as well (102). This modification is also prominent in a large family of extracellular proteins, the so-called hydroxyproline-rich glycoproteins (51), which include extensins (50), proline-rich proteins (49), and arabinogalactan proteins (19). Biosynthesis of hydroxyproline-bound β-1,2-linked triarabinoside involves two distinct arabinosyltransferases, the first of which is responsible for the formation of a β linkage with the 4 position of hydroxyproline [hydroxyproline O-arabinosyltransferase (HPAT)]. Arabidopsis HPAT was recently purified and identified as a Golgi-localized transmembrane protein belonging to the glycosyltransferase GT8 family (94). Notably, Arabidopsis HPAT family proteins (HPAT1, -2, and -3) show significant similarity to Pisum sativum NOD3 and Medicago truncatula RDN1, whose loss-of-function mutants show hypernodulation phenotypes (114). That NOD3 and RDN1 belong to the HPAT family strongly supports recent findings that hydroxyproline O-arabinosylated CLE peptides induced by rhizobia act as autoregulation signals to suppress excess nodulation (99). Loss-of-function mutations in HPAT genes in Arabidopsis cause pleiotropic phenotypes that include enhanced hypocotyl elongation, defects in cell wall thickening, early flowering, and early senescence. In addition, a double mutation in HPAT1 and HPAT3 significantly impairs the growth of pollen tubes, thereby causing a transmission defect through the male gametophyte. Because hydroxyproline O-arabinosylation is required for both cell wall structural proteins and glycopeptide signals, interpretation of these phenotypes may be complicated. Nonetheless, there is increasing awareness that arabinosylated small-peptide signals play diverse roles in growth, development, and defense in plants (65). Detailed phenotypic analyses of loss-of-function mutants of HPAT genes will provide a more complete picture of how hydroxyproline O-arabinosylated glycoproteins and glycopeptides contribute to plant growth and development. Two other enzymes suggested to be involved in elongation of the arabinose chain in hydroxyproline O-arabinoside biosynthesis are the GT77 family proteins XEG113 (30) and RRA3 (18, 139). Loss-of-function mutants of these enzymes are partially defective in polarized growth of the root hairs (139).

PROTEOLYTIC PROCESSING In animals and yeast, the biosynthesis of small-peptide signals often involves proteolytic processing of precursor polypeptides to produce mature, functional peptides. Comparative analyses of the primary sequences of many animal peptide signals have shown that cleavage of a precursor polypeptide occurs on the C-terminal side of paired basic amino acids, such as lysine-lysine, lysinearginine, arginine-lysine, and arginine-arginine. In animals, this initial cleavage is catalyzed by subtilisin/kexin-like prohormone convertases (28, 107). Terminal basic residues are subsequently removed by carboxypeptidases (28). Proteolytic processing is also a critical step in the biosynthesis of posttranslationally modified small peptides in plants, but several lines of evidence suggest that the processing mechanisms for plant peptides are quite different from those for animal peptides. First, in plants there is no typical paired basic amino acid motif adjacent to the mature peptide domain within the precursor polypeptides (Figure 3). Second, instead of an enzyme that cleaves at paired basic amino acid residues, in vitro experiments involving crude cauliflower plant extracts have detected the activity of a processing enzyme that cleaves at the N-terminal side of a single arginine residue in the CLV3 precursor polypeptide (88, 89). Activity associated with an enzyme that cleaves between methionine and serine residues located two residues upstream of the mature peptide domain of Medicago truncatula CLE36 has also been detected (17). Third, one of the Arabidopsis subtilases, AtSBT1.1, is responsible for the initial processing of PSK4 in vivo (127), but its processing site is located between www.annualreviews.org • Small-Peptide Signaling in Plants

395


ARI

Endoproteolytic: characterized by site-directed proteolytic cleavage of the internal region of a protein


Exoproteolytic: characterized by proteolytic digestion from the terminal residue of a protein

8 April 2014

21:29

leucine and histidine residues located upstream of the mature peptide domain. These observations suggest that initial processing sites do not always directly define the boundary of the mature peptide domain. Proteolytic processing of plant peptide signals presumably involves a complex series of steps, namely initial endoproteolytic cleavage followed by exoproteolytic trimming of the peptides. One possible candidate gene for the latter exoprotease encodes a putative Zn2+ carboxypeptidase, SOL1, which was identified during suppressor screening for the short-root phenotype generated by CLE19 overexpression (8) (see also Note Added in Proof, below). How the final processing site is defined by such an ambiguous proteolysis system in plants is also unclear. One possibility is that the mature peptide domain escapes proteolysis owing to the presence of posttranslational modifications, which often confer resistance to proteolytic digestion. Alternatively, proline residues that are often present in the mature peptide domain might confer resistance to exoprotease digestion. Because of its unusual structure, the proline residue is generally resistant to enzymatic hydrolysis by exopeptidases. CLE peptides contain conserved proline (or hydroxyproline) residues in the 4th, 7th, and 9th positions (Table 1). Proline (or hydroxyproline) residues are also present in RGF family peptides in the 5th, 9th, and 10th positions and in CEP family peptides in the 4th, 7th, and 11th positions.

STRUCTURES AND FUNCTIONS OF POSTTRANSLATIONALLY MODIFIED SMALL-PEPTIDE SIGNALS This section summarizes the structures and functions of currently known posttranslationally modified small-peptide signals (Figure 5).

PSK PSK is a five-amino-acid sulfated peptide initially identified as a growth-promoting signal involved in the density effect in plant cell cultures (69) (Table 1). Relative growth rates of plant cells in vitro often depend on initial cell population density. Dilution of dispersed mesophyll cells in

Defense response HypSys (Solanaceae plants), PSK

Vascular development

Pollen tube growth

Embryo development

CLE45

CLE8

TDIF

Floral organ abscission IDA

Shoot meristem development CLV3

Cellular proliferation and expansion PSK, PSY

Lateral root development IDA, CEP

Autoregulation of nodulation CLE-RS (leguminous plants)

Root meristem development CLE40, RGF

Figure 5 Summary of the representative functions of posttranslationally modified small-peptide signals. 396

Matsubayashi



ARI

8 April 2014

21:29

excess culture medium significantly inhibits cell division, even if plant hormones and nutrients are supplied, indicating that cell-to-cell communication is involved in cellular proliferation in vitro (69). A similar phenomenon has also been observed for transdifferentiation of mesophyll cells into tracheary elements (71). If dispersed Zinnia mesophyll cells are cultured below a critical cell density, tracheary element formation is greatly suppressed. Additionally, somatic embryo formation from carrot cells in suspension depends on cell density (53). Interestingly, this dependence on population density is alleviated by the addition of a conditioned medium in which cells were previously grown, indicating that cell-to-cell communication is mediated by one or more secreted signals (53, 69, 71). Purification of this secreted signal led to the identification of PSK. In vitro experiments later showed that PSK also promotes tracheary element differentiation of Zinnia mesophyll cells (71, 81), somatic embryogenesis (33, 44, 53), and pollen germination (11). Genetic evidence further indicated that PSK is involved in root and hypocotyl elongation, primarily via control of mature cell size (36, 59, 67, 132), regulation of cellular longevity (67), and Agrobacterium-induced tumor growth (62). In addition to plant growth and development, PSK is involved in plant innate immune responses triggered upon the perception of elicitors released by pathogens. Loss of PSK signaling causes enhanced immune responses upon treatment with elicitors and increases resistance to biotrophic bacterial infection, suggesting that PSK signaling suppresses immune responses to prevent overresponsiveness to bacterial pathogens (43). Loss of PSK signaling also increases resistance to Fusarium oxysporum (117). In contrast, loss of PSK signaling increases susceptibility to necrotrophic fungal infections (80), indicating that PSK is required for resistance to fungal pathogens. The antagonistic effect of PSK on biotrophic and necrotrophic pathogen resistance is thought to be correlated with alterations in salicylate and jasmonate responses owing to changes in PSK level (80). PSK is produced from an approximately 80-amino-acid precursor polypeptide via tyrosine sulfation and proteolytic processing (67, 144) (Figure 3a). In vitro studies have suggested that this proteolytic processing is mediated at least in part by a subtilisin-like serine protease, AtSBT1.1 (127). Genes encoding PSK precursors are widely expressed in a variety of tissues, and their expression is upregulated by wounding or interaction with microorganisms (62, 67). PSK is recognized by the membrane-localized leucine-rich-repeat receptor kinases (LRR-RKs) PSKR1 and PSKR2 (3, 67, 68). PSK interacts directly with the island domain located between the 17th and 18th LRRs of PSKR1 (123). The kinase domain of PSKR1 was suggested to exhibit guanylate cyclase activity (60). An additional PSKR1 homolog in Arabidopsis, At1g72300, is not required for perception of PSK but rather is likely involved in signaling by another sulfated peptide, PSY, which is also capable of stimulating cellular proliferation and expansion (3). The pskr1 pskr2 double mutant shows a weak short-root phenotype, but further mutation in At1g72300 leads to significant enhancement of this phenotype, resulting in pleiotropic growth defects such as short roots, smaller leaves, early senescence, and insufficiency in tissue repair after wounding (3, 67). These results suggest that this LRR-RK family integrates growth-promoting signals mediated by two structurally distinct sulfated peptides, PSK and PSY.

CLV3 CLV3 is a Hyp O-arabinosylated 13-amino-acid glycopeptide that balances stem cell renewal and differentiation in the shoot apical meristem (26, 96) (Table 1). A 12-amino-acid nonglycosylated form of CLV3 is also active, albeit to a lesser degree (56). Plants continuously produce organs from self-renewing shoot apical meristems. Genetic and molecular analyses have shown that a feedback signaling loop between stem cells and the underlying www.annualreviews.org • Small-Peptide Signaling in Plants

397

ARI

8 April 2014

21:29

organizing center strictly balances stem cell renewal and differentiation (27). The clv3 mutant was initially identified by phenotypic screening for mutants with progressive shoot apical meristem enlargement in Arabidopsis. This mutant also exhibits enlarged floral meristems and club-like abnormally shaped siliques. (The name clavata is derived from the Latin word clavatus, meaning “club-like.”) CLV3 encodes a secreted peptide that is specifically expressed in the outermost cell layers of the central zone of the shoot apical meristem (26). CLV3 acts as a negative regulator of stem cell maintenance by repressing WUSCHEL (WUS), which encodes a homeodomain transcription factor that is expressed in the organizing center and promotes the identity of stem cells. Conversely, WUS positively regulates CLV3 expression in the stem cell region. This negative-feedback loop ensures that stem cells are restricted to the center of the shoot apical meristem (5, 115). (For a comprehensive review of the physiological functions and signaling mechanisms of CLV3 in the shoot apical meristem, see Reference 1.) CLV3 encodes a 96-amino-acid secreted polypeptide that is subsequently modified in vivo by proteolytic processing and posttranslational modification (Figure 3b). A 12-amino-acid peptide in which two proline residues are hydroxylated was detected in Arabidopsis calluses overexpressing CLV3 (56). In contrast, the mature CLV3 peptide identified in the culture medium of whole-plant submerged cultures of CLV3-overexpressing Arabidopsis is a 13-amino-acid glycopeptide in which the seventh residue (hydroxyproline) is further modified with three L-arabinose sugars linked via linear β-1,2 linkages (96). When added exogenously to a clv3 mutant, this arabinosylated CLV3 peptide exhibited higher activity in restricting stem cell proliferation than nonarabinosylated forms did. The route of chemical synthesis of arabinosylated CLV3 has been established (121). NMRbased structure calculations revealed that the arabinose chain causes distinct distortion in the C-terminal half of the peptide in a highly directional manner (121). However, hydroxyproline arabinosylation of CLV3 is not always required to restrict stem cell proliferation in vivo, probably owing to the relatively high CLV3 expression level within the central zone in the shoot apical meristem of Arabidopsis (125). The critical importance of arabinosylation of CLV3 family peptides is highlighted by the recent identification of the Lotus japonicus CLE-RS2 glycopeptide, which is involved in autoregulation of nodulation (99) (see the CLE-RS section, below). Both in vitro and in vivo structure–activity relationship analyses of CLV3 have revealed how each amino acid residue contributes to the peptide’s physiological activity (55, 124, 125). Notably, transgenic plants carrying a CLV3 gene with a Gly6 -to-Thr substitution show a dominant-negative phenotype in vivo (124). Three receptor-like kinases [CLV1 (15), CORYNE (also known as SOL2) (76, 82), and RPK2 (52)] along with one LRR receptor-like protein [CLV2 (46)] are involved in CLV3 signaling in Arabidopsis. Direct binding of CLV3 to the CLV1 ectodomain has been confirmed by photoaffinity labeling (93). Arabinosylated CLV3 peptide interacts more strongly with CLV1 than nonarabinosylated forms do (96, 121). The ligand-binding site of CLV1/BAM family receptor kinases is within the LRR6–LRR8 region in the extracellular LRR domain (122). Consistent with this finding, the clv1-4 mutant carries a missense mutation along the inner concave side of LRR6 (15). CLV3 binding triggers CLV1 internalization from the plasma membrane followed by trafficking to the lytic vacuole, where CLV1 is degraded (90). Increased CLV3-binding activity in membranes is also observed when CLV2 is overexpressed (32), but direct interaction between CLV3 and CLV2 has not been reported. The CORYNE protein, which lacks a distinct extracellular domain, interacts with CLV2 via the transmembrane and adjacent juxtamembrane domains to function as a complex (4, 148). RPK2 forms homo-oligomers but does not associate with CLV1 or CLV2 (52).



398

Matsubayashi


ARI

8 April 2014

21:29

Although signaling through CLV3 is the major pathway in both shoot and floral meristems in Arabidopsis, at least three related CLV3-like peptides, including FLORAL ORGAN NUMBER 2 (FON2, also known as FON4) (14, 135), FON2 SPARE 1 (FOS1) (134), and FON2-LIKE CLE PROTEIN 1 (FCP1) (136), are involved in meristem organization in rice. Each peptide contributes differently to restriction of the stem cell population, depending on the type of meristem.


CLE Family Peptides CLE is a large family of secreted peptides that includes CLV3. As mentioned above, these peptides possess a conserved 14-amino-acid CLE domain at or near their C terminus (16, 92) (Figure 3b). In addition to CLV3, in Arabidopsis the CLE family includes 32 peptides, the majority of which are expressed in a variety of tissues (48). In rice, 44 potential CLE peptides have been identified (92). Although functional characterizations of CLE peptides based on gain-of-function analyses have suggested that they may affect numerous developmental processes in plants, only a few CLE peptides have been characterized in depth, such as TDIF in Zinnia (45); CLE8 (25), CLE40 (129), CLE41 (40), CLE44 (40), and CLE45 (20) in Arabidopsis; FON2 (14, 135), FCP1 (136), and FOS1 (134) in rice; and nodulation-related CLEs in legumes (98). Plant-parasitic cyst nematodes are also known to secrete CLE-like effector proteins (140). These proteins act as ligand mimics of plant CLE peptides and are required for successful nematode infection (75). CLE family peptides are often classified into two groups: A type and B type (142). The Atype group includes CLE peptides that affect shoot and root meristem development, whereas the B-type group includes TDIF/CLE41/CLE44, which inhibits xylem vessel differentiation but has no effect on shoot and root meristem development. The A-type CLEs strengthen the effect of the B-type CLEs on procambium proliferation, suggesting possible crosstalk between the two types of CLE peptides (142). Representative CLE peptides in plants are described below.

TDIF/CLE41/CLE44 TDIF is a 12-amino-acid peptide in which two proline residues are hydroxylated (Table 1) (45). It plays important roles in the maintenance of the vascular stem cell population. The plant vascular system is composed of two conducting tissues: xylem and phloem. The vascular meristem, called the procambium, is located between the xylem and phloem and gives rise to both xylem and phloem cells on opposite sides. TDIF was initially identified as an inhibitor of in vitro transdifferentiation of dispersed Zinnia elegans L. mesophyll cells into tracheary elements (the main conductive cells of the xylem) (45). The amino acid sequence of TDIF is identical to the CLE-domain sequences of Arabidopsis CLE41 and CLE44, which belong to a distinct subclade in the Arabidopsis CLE peptide family (Figure 3b). Indeed, the structure of the mature CLE44 peptide was later shown to be identical to that of TDIF (95). Further studies in Arabidopsis revealed that TDIF/CLE41/CLE44 is recognized by TDR/PXY, an LRR-RK expressed in procambial cells (22, 24, 40). Direct binding of TDIF/CLE41/CLE44 to TDR/PXY has also been biochemically confirmed (40). T-DNA insertion lines of the TDR/PXY gene are insensitive to TDIF/CLE41/CLE44 peptides and exhibit formation of xylem vessels adjacent to phloem cells, accompanied by reduced procambial cell proliferation. CLE41 and CLE44 are expressed in the phloem and the neighboring pericycle cells, and TDR/PXY is specifically expressed in the procambium. Thus, TDIF/CLE41/CLE44 secreted from phloem cells is perceived by TDRs located in procambial cells, resulting in enhanced division of procambial cells and suppression of procambial-cell-to-xylem-cell differentiation. www.annualreviews.org • Small-Peptide Signaling in Plants

399


ARI

8 April 2014

21:29

WOX4, a homolog of the shoot stem cell regulator WUS, is involved in the proliferation of procambial stem cells in response to the TDIF/CLE41/CLE44 signal (39). WOX4 is expressed preferentially in procambium cells, which is similar to the expression pattern of TDR/PXY, and WOX4 is upregulated in a TDR-dependent manner upon application of TDIF. Genetic analyses showed that WOX4 is required for promoting the proliferation of procambial stem cells but not for inhibiting procambial cell differentiation into xylem cells. WOX14 also acts redundantly with WOX4 in the regulation of vascular cell division (21).

CLE-RS


CLE-RS peptides are hydroxyproline O-arabinosylated 13-amino-acid glycopeptides that are responsible for autoregulation of nodulation in leguminous plants (99) (Table 1). Many leguminous plants establish a symbiotic association with rhizobia that induces the formation of nodules on roots. Excessive nodule formation is deleterious to the plants, however, because the energy cost outweighs the need for fixed nitrogen. To achieve a balance in this symbiotic relationship, the host plant tightly controls the number of nodules formed via a root-to-shoot-to-root negative-feedback signaling loop, commonly known as autoregulation of nodulation (7, 97). In Lotus japonicus, this autoregulation is triggered by the CLE-RS1 and CLE-RS2 genes, which are induced in the root upon inoculation with rhizobia (98). Similar rhizobia-responsive CLE genes have also been identified in other leguminous species (61, 78, 79, 108). Mature CLE-RS2 was identified as a posttranslationally arabinosylated glycopeptide derived from the CLE domain (99) (Figure 3b, Table 1). Chemically synthesized CLE-RS1 and CLE-RS2 glycopeptides were confirmed to suppress nodulation at concentrations in the nanomolar range. Notably, arabinosylation of the CLE-RS1 and CLE-RS2 glycopeptides is absolutely critical for their function. The activity of the CLE-RS peptides is dependent on HYPERNODULATION ABERRANT ROOT 1 (HAR1), an LRR-RK that is highly similar to Arabidopsis CLV1 (57, 91). Because grafting experiments have shown that HAR1 in the shoot is necessary to control the number of nodules in the root, the corresponding ligands are expected to be transported to the shoot. That CLERS peptides fulfill this criterion is illustrated by the observations that CLE-RS2 glycopeptide produced in the root can be detected in xylem sap collected from the shoot and that CLE-RS2 directly binds HAR1 with high affinity (99). Thus, CLE-RS glycopeptides are the long-sought root-to-shoot mobile signals responsible for the initial step of autoregulation of nodulation.

CLE40 CLE40 was initially identified by in silico searching as sharing homology with CLV3 (41) (Figure 3b). Although the structure of the mature CLE40 peptide remains to be determined, a synthetic CLE-domain peptide with hydroxylated proline has been shown to be potentially active in controlling stem cell fate in the root meristem. CLE40 is expressed in the embryo and differentiated root cells, especially in columellar cells. Loss of CLE40 delays differentiation and allows stem cell proliferation, leading to formation of additional columellar stem cell layers (129). Indeed, CLE40 is involved at least in part in spatially confining the expression of WOX5, which maintains the undifferentiated status of abutting cells (129). In addition, cle40 mutants develop somewhat shorter roots than wild-type plants do, suggesting a role in meristem maintenance in roots. CLE40 acts through the receptor kinase ARABIDOPSIS CRINKLY 4 (ACR4) and through CLV1 (128, 129). CLV1 was first characterized as a receptor involved in controlling the number of stem cells in the shoot apical meristem, but its expression has also been detected in roots. 400

Matsubayashi


ARI

8 April 2014

21:29

Expression of both ACR4 and CLV1 can be detected in the quiescent center and the two cell layers immediately distal to it, and ACR4 and CLV1 loss-of-function mutants display extra layers of columellar stem cells. In addition, CLV1 and ACR4 can form homo- and heteromeric complexes in vivo. Because the synthetic CLE-domain peptide of CLE40 with hydroxylated proline binds to CLV1 in vitro (32), CLV1 and ACR4 could serve as a receptor complex for CLE40 perception. The contribution of CLV1-to-CLE40 signaling in roots is, however, distinct from the contribution to CLV3 signaling in shoots, in that loss of CLV1 enhances sensitivity to externally added CLE40 peptide. Alternative receptors for CLE40 may be present and activated in the absence of CLV1.


CLE8 CLE8 plays roles in embryo and endosperm development in Arabidopsis (25). Although the structure of the mature CLE8 peptide has not been characterized, its closest homolog, CLE9, is a hydroxyproline O-arabinosylated glycopeptide (122) (Figure 3b, Table 1). CLE8 is specifically expressed in the endosperm and in the apical region of young embryos. The cle8 mutant produces abnormally small, defective embryos, whereas transgenic lines overexpressing CLE8 produce slightly larger embryos and seeds. CLE8 promotes the expression of WOX8, which suggests that CLE8-WOX8 could form a signaling module for regulating seed growth and size. The direct target receptor for CLE8 in embryo and endosperm development has not been identified, but a synthetic CLE-domain peptide of CLE8 with hydroxylated proline has been shown to interact with BAM1 (122).

CLE45 CLE45 plays roles in promoting pollen tube growth (20). The reproductive stage in flowering plants is vulnerable to ambient temperature fluctuations. Nevertheless, these plants can maintain seed production under certain levels of exposure to temperature change. The stimulatory effect of CLE45 on pollen tube growth was initially discovered through an in vitro pollen tube growth assay using arrays of synthetic CLE peptides (20). CLE45 is preferentially expressed in the stigma in the pistil under normal conditions, but upon a shift in temperature to 30◦ C, CLE45 expression expands to the transmitting tract, suggesting that CLE45 plays a role in promoting pollen tube growth at higher temperatures. In support of this observation, knockdown of CLE45 expression results in reduced seed production at 30◦ C but not at 22◦ C. A synthetic CLE-domain peptide of CLE45 with hydroxylated proline directly binds STERILITY-REGULATING KINASE MEMBER 1 (SKM1). Both SKM1 and its homolog SKM2 are expressed in pollen, and skm1 skm2 double mutants are insensitive to CLE45 in terms of pollen tube growth in vitro. These results strongly suggest that the pollen–pistil interaction via the CLE45-SKM1/SKM2 signaling pathway sustains pollen performance at higher temperatures, leading to successful seed production.

HypSys HypSys is a family of highly glycosylated (likely arabinosylated) oligopeptides that are thought to be involved in defense responses in Solanaceae plants (102). Many higher plants respond to wounds resulting from herbivore grazing by producing defensive proteins such as protease inhibitors in the leaves and stems (31, 109). Interestingly, protease inhibitors often accumulate not only in wounded leaves but also in undamaged leaves far from the damaged sites, indicating that long-distance signal transmission induces a systemic defense response. Initial purification studies identified an www.annualreviews.org • Small-Peptide Signaling in Plants

401

ARI

8 April 2014

21:29

18-amino-acid peptide, systemin, in wounded tomato leaves (106). Systemin later proved to be an integral component of the jasmonic acid signaling pathway that leads to the synthesis of protease inhibitors (110, 131). Although tomato systemin has no typical secretion signal sequence, this peptide is thought to be transported to the extracellular space by wounding, where it functions through a receptor-mediated pathway. The discovery of systemin led to a search for peptide signals involved in systemic defense responses in other plant families. Tobacco plants exhibit a systemic wound response similar to that of tomato plants, but no tomato systemin ortholog has been found in tobacco. Tomato systemin causes alkalinization of the culture medium of tomato cell suspensions by modulating plasma membrane H+ -ATPase activity (113), and factors that have a similar alkalinization effect have also been detected in wounded tobacco plants. A link has been suggested between proton flux across the plasma membrane and the induction of defense genes (113). Further purification studies identified two hydroxyproline-rich glycopeptides modified with multiple pentose residues in wounded tobacco leaves, and these peptides were designated as Nicotiana tabacum hydroxyproline-rich systemins (NtHypSys) I and II (102) (Table 1). Although they have no sequence similarity with tomato systemin, NtHypSys I and II exhibit a trypsin inhibitor-inducing activity similar to that of tomato systemin. Chemically synthesized NtHypSys analogs lacking sugar chains were 10,000 times less active than the native polypeptides, suggesting that the sugar chains (likely arabinose) are important for their activity. NtHypSys I and II are 18 amino acids in length and are produced from a single precursor protein that has a secretion signal sequence at its N terminus (102) (Figure 3c). Purification studies using alkalinization assays revealed that tomato plants produce three novel hydroxyproline-rich glycopeptides (SlHypSys I, II, and III, with lengths of 20, 18, and 15 amino acids, respectively) that trigger the expression of proteinase inhibitor II (104). HypSys glycopeptides have also been isolated from other dicot plants, such as petunia, sweet potato, and black nightshade (10, 101, 105), but these peptides have never been found in monocots. In contrast to the general peptide signals secreted after proteolytic processing, HypSys accumulates as a precursor protein in the cell wall matrix of vascular parenchyma cells (87). Proteinases released upon wounding are hypothesized to produce mature peptides from the precursor in the cell wall matrix.



IDA Although the structure of the mature peptide remains to be characterized, IDA exhibits the characteristics of a posttranslationally modified small-peptide signal and is involved in the abscission process (Figure 3). Abscission is an active process that enables plants to shed unwanted organs. This process requires the formation of an anatomically distinct structure known as the abscission zone, which constitutes the region where organs are detached from the plant body. The Arabidopsis ida mutant, which never sheds its floral organs, was initially identified by screening for mutants with defects in floral abscission (6). The ida mutant retains its floral organs indefinitely owing to a lack of breakdown of the middle lamella between cell layers of the abscission zone at the base of organs to be shed. The IDA gene encodes a 77-amino-acid polypeptide that is expressed in the floral organ abscission zone throughout the floral abscission process (Figure 3d ). IDA belongs to the IDA-LIKE (IDL) family of peptides, designated IDL1–5. Sequence alignments indicate that these peptides contain a highly conserved proline-rich domain near the C terminus, termed the EPIP domain. The locally conserved structure of these peptides is quite similar to the structure of precursor polypeptides of other posttranslationally modified smallpeptide signals (Figure 3). Indeed, at high concentrations, a synthetic 21-amino-acid peptide 402

Matsubayashi



ARI

8 April 2014

21:29

consisting of the EPIP domain within IDA induces early floral abscission in wild-type flowers (130). Genetic evidence suggests that IDA is a ligand for the LRR receptor-like kinases HAESA (HAE) and HAESA-like 2 (HSL2), loss of function of which also causes defective floral organ abscission (13, 47, 130). (Haesa is a Latin word meaning “to adhere to.”) Overexpression of IDA leads to premature floral organ abscission, but not in a hae hsl2 double mutant background. The IDA signal is thought to be perceived by the extracellular LRRs of HAE and HSL2 and transduced via a mitogen-activated protein kinase cascade (13). A screen for mutations that restore floral organ abscission in ida mutants identified the KNOTTED-LIKE HOMEOBOX gene BREVIPEDICELLUS (BP)/KNOTTED-LIKE FROM ARABIDOPSIS THALIANA1 (KNAT1) (118). BP/KNAT1 acts as a negative regulator of the IDA signaling cascade by inhibiting expression of the positive regulators of floral organ separation KNAT2 and KNAT6. The IDA peptide and the HAE and HSL2 receptor-like kinases are also involved in lateral root emergence, which was indicated by specific expression of IDA in cells overlying new lateral root primordia and by significantly lower densities of emerged lateral roots in the ida mutant and a hae hsl2 double mutant (58). Mutation in these genes constrains the passage of the growing lateral root primordia through the overlying layers, resulting in altered shapes of both the lateral root primordia and overlying cells. Thus, the IDA-HAE/HSL2 signaling module has been adapted to function in different root- and shoot-cell separation processes.

PSY PSY1 is an 18-amino-acid secreted glycopeptide containing one sulfated tyrosine residue and an L-arabinose sugar chain (Figure 3e, Table 1). PSY1 was identified by exhaustive analysis of tyrosine-sulfated peptides in Arabidopsis cell culture media on the assumption that posttranslationally modified peptides biosynthesized through a pathway that consumes more energy than other peptide-biosynthesis pathways provide physiological benefits to the plants that are greater than their energy costs (3). PSY1 is expressed in various Arabidopsis tissues and promotes cellular proliferation and expansion at nanomolar concentrations. The expression pattern and physiological activity of PSY1 are similar to those of PSK. Circumstantial evidence suggests that the Arabidopsis PSK receptor homolog At1g72300 is likely involved in PSY signaling (3). Mutations in At1g72300 significantly enhance the phenotype of pskr1 pskr2 double mutants, resulting in pleiotropic growth defects such as severely short roots, smaller leaves, early senescence, and insufficiency in tissue repair after wounding (3, 67). These results suggest that this LRR-RK family peptide integrates growth-promoting signals mediated by two structurally distinct sulfated peptides, PSK and PSY.

CEP CEP1 is a 15-amino-acid peptide that is thought to play roles in lateral root development. A feature common to posttranslationally modified small-peptide signals is that they are encoded by multiple paralogous genes whose primary translated products are approximately 70–110-aminoacid cysteine-poor secreted polypeptides that share short, conserved domains near the C terminus (Figure 3). CEP1 was identified by in silico gene screening on the assumption that peptides that share structural features with known posttranslationally modified small-peptide signals should function as physiologically active signals (95). Indeed, mature CEP1 is a 15-amino-acid peptide with two hydroxyproline residues and is derived from the C-terminal conserved domain of the precursor (Figure 3f, Table 1). CEP1 is expressed mainly in the lateral root primordia, and when www.annualreviews.org • Small-Peptide Signaling in Plants

403


ARI

8 April 2014

21:29

overexpressed or externally applied, it arrests root growth significantly, which indicates that this peptide is a strong novel peptide signal candidate (see also Note Added in Proof, below).

RGF


RGF1 is a 13-amino-acid sulfated peptide required for root stem cell niche maintenance and transit-amplifying cell proliferation (72). RGF was initially identified in a search for sulfated peptides that recover root meristem defects in the mutant of the tyrosine sulfation enzyme. Tyrosine sulfation is a posttranslational modification that occurs in both animal and plant secreted peptides (77). It is mediated by TPST, a type I transmembrane protein localized in cis-Golgi membranes (54). Loss-of-function mutants of AtTPST (tpst-1) show an extreme shortroot phenotype accompanied by loss of maintenance of stem cells and a considerable decrease in meristematic activity (54, 147). Because AtTPST is a single-copy gene, phenotypes of tpst-1 mutants should reflect the deficiency in the biosynthesis of all of the functional tyrosine-sulfated peptides found in Arabidopsis. RGF was initially identified in a search for sulfated peptides that recover root meristem defects of the tpst-1 mutant in combination with in silico screening of genes encoding sulfated peptides and phenotypic rescue using synthetic sulfated peptides (72). The RGF family of genes, initially thought to comprise 9 genes (72) but later found to comprise 11 genes (23), encodes polypeptides with a C-terminal conserved domain. Mature RGF1 is 13 amino acids in length, carries a tyrosine sulfation, and is derived from the C-terminal conserved domain of the precursor polypeptide through proteolytic processing (Figure 3g, Table 1). Chemically synthesized mature RGF1 peptide restored stem cells and the meristematic activity of tpst-1 to levels comparable to those of the wild type when added in the culture medium. The root meristem activity of tpst-1 was also recovered, albeit to varying degrees, by the application of the synthetic sulfated peptides corresponding to the 13-amino-acid conserved domain of the other members of this RGF peptide family. Because the C-terminal sequence of CLE18 is highly similar to RGF1, some researchers refer to the RGF family as a CLE-like family (73). Additionally, because overexpression of RGF family peptides often causes irregular root waving, some other researchers refer to this as a GOLVEN family ( golven is the Dutch word for “waves”) (143). RGF1 is specifically expressed in quiescent center cells and columellar stem cells in the root tip (72). RGF2 and RGF3 are expressed mainly in the innermost layer of central columellar cells. RGF4 shows a diffuse expression pattern in the stem cell region. RGF5 is weakly expressed in quiescent center cells (23). Other RGF peptides are expressed in tissues other than the root meristem (23). Although single loss-of-function mutants of RGFs do not exhibit any obvious phenotypes in roots, rgf1 rgf2 rgf3 triple mutants show a short-root phenotype characterized by a decrease in the number of meristematic cells, indicating that RGFs function redundantly (72). Although RGF receptors remain to be identified, PLETHORA (PLT) transcription factors constitute one group of RGF signaling molecular targets. PLT genes, which are specifically expressed in the root meristem, encode AP2-domain transcription factors that mediate patterning of the root stem cell niche (2). PLT proteins display gradient distributions, with maximal distribution in the stem cell area, and this gradient is essential for maintenance of the root stem cell niche and transit-amplifying cell proliferation (29). In wild-type seedlings, PLT proteins show gradients that extend into the region of transit-amplifying cells or the elongation zone. In contrast, the region of PLT protein expression (especially PLT2 expression) is considerably reduced in tpst-1 mutant and rgf1 rgf2 rgf3 triple-mutant seedlings, with weak expression in the meristematic zone (72). Importantly, externally added RGF1 restores PLT protein expression levels and patterns in tpst-1 without major changes in PLT gene expression levels. Thus, RGF defines PLT expression levels and patterns mainly at the posttranscriptional level, possibly through stabilization of the PLT proteins. 404

Matsubayashi



ARI

8 April 2014

21:29

Root development is often correlated with longitudinal auxin concentration gradients controlled by the PIN auxin efflux facilitator network. However, transcription of RGF1, RGF2, RGF3, and RGF4, which are specifically expressed in the root apex, is not responsive to auxin treatment (72, 147). In addition, the pattern of DR5:GUS (auxin maximum marker) expression in tpst-1 mutants is comparable to that of the wild type, suggesting that auxin concentration gradients are not directly relevant to RGF signaling. One report claims that overexpression of RGF (GOLVEN) modulates the distribution of auxin and impedes auxin gradient formation, thereby altering gravitropism and leading to root waving (143). However, another report pointed out that Arabidopsis mutants with an impaired gravitropic response (e.g., eir1-1 and aux1-7 mutants) normally respond to RGF (CLE-like) peptides by forming wavy roots (73). In addition, the tpst-1 mutant, which is deficient in functional sulfated RGF peptides, develops roots (albeit short ones) in the direction of gravitational pull, which indicates that irregular root waving phenotypes caused by excess RGF peptides are probably not directly dependent on gravitropism. It will be important to unravel how individual cells perceive RGF peptide signals to ensure precise root meristem patterning during root development.

FUTURE DIRECTIONS Modification enzymes mediating tyrosine sulfation (54), proline hydroxylation (146), and hydroxyproline arabinosylation (94) are all conserved in land plants, including mosses and ferns, suggesting that these modifications have physiological significance in plants. In general, because such modifications require cosubstrates, such as the sulfation donor PAPS and the arabinosylation donor UDP-L-arabinose, which are synthesized using ATP, the biosynthesis of posttranslationally modified peptides has a considerably higher energy cost than the biosynthesis of unmodified proteins and peptides. Nevertheless, a number of posttranslationally modified small peptides are evolutionarily conserved, suggesting that these “expensive” modified peptides impart physiological benefits to the plants that are greater than their energy costs. Plants rely largely on passive diffusion through the thick cell wall for local cell-to-cell signaling in the apoplast, but molecular size and diffusion efficiency are inversely proportional: the lower the molecular weight, the faster the rate of diffusion. However, peptide size and structural diversity are also inversely proportional: the shorter the sequence length, the lower the degree of structural diversity. To balance these antithetical requirements, plants might have evolved unique posttranslational modifications that specifically alter the structure of small peptides composed of a limited number of amino acids. A number of genes encoding secreted peptides have been found in the Arabidopsis genome. In the Arabidopsis Information Resource 10 (TAIR10) protein data set, as many as 1,086 genes encode potential secreted peptides (SignalP score > 0.75) between 50 and 150 amino acid residues in length. Given that the Arabidopsis genome encodes more than 600 receptor-like kinases for which corresponding ligands have not yet been identified, a substantial proportion of such secreted peptides are expected to function as ligands for receptor-like kinases. As discussed above (see A Brief History of How Peptide Signals Were Identified), peptide signals were initially identified using classical bioassay-guided purification methods. The feasibility of this approach, however, depends largely on the quality and sensitivity of the bioassay system and the abundance of the peptides in the samples. Indeed, no additional peptide signal has been identified by bioassay-guided purification since 2006. Similarly, no peptide signal has been identified using a classical genetics approach since 2003, indicating that the nonredundant peptide genes that produce a visible phenotype upon mutation have already been fully characterized. Additionally, the fact that genes for peptide signals are too small to be efficiently disrupted www.annualreviews.org • Small-Peptide Signaling in Plants

405


ARI

8 April 2014

21:29

by T-DNA insertion renders conventional reverse genetics approaches difficult as well. Thus, alternative strategies, such as genomics- or transcriptomics-based in silico approaches, preferably coupled with biochemical and molecular biology techniques, offer promise for further research into plant peptide signals.

SUMMARY POINTS 1. Posttranslationally modified small peptides currently account for a major fraction of secreted peptide signals in plants.


2. Biosynthesis of these peptide signals involves posttranslational modification of several amino acid residues followed by proteolytic processing to produce the mature, biologically functional peptides. 3. Posttranslationally modified small peptides are perceived by membrane-localized receptor kinases and thus serve as signals in a number of processes, ranging from plant growth and development to defense responses and symbiosis.

FUTURE ISSUES 1. In the Arabidopsis Information Resource 10 (TAIR10) protein data set, as many as 1,086 genes encode putative secreted peptides between 50 and 150 amino acid residues in length. Many of the products of these genes have yet to be characterized. 2. To gain further insight into peptide signaling beyond that afforded by the limited bioassay-guided purification and classical genetics approaches, it will be crucial to develop innovative strategies that lead to the identification of still-undiscovered peptide signals. 3. Use of genome and/or transcriptome information will be a key in future searches for novel peptide signals.

NOTE ADDED IN PROOF While this article was at the proof stage, SOL1 was shown to possess enzymatic activity to remove the C-terminal arginine residue of CLE19 proprotein in vitro (137a). Two papers also reported additional characterization of CEP family peptides (16a, 108a).

DISCLOSURE STATEMENT The author is not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS Our research was supported by a grant from the Funding Program for Next Generation WorldLeading Researchers of the Japan Society for the Promotion of Science (no. GS025) and by 406

Matsubayashi


ARI

8 April 2014

21:29

Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (no. 25221105).


LITERATURE CITED 1. Aichinger E, Kornet N, Friedrich T, Laux T. 2012. Plant stem cell niches. Annu. Rev. Plant Biol. 63:615–36 2. Aida M, Beis D, Heidstra R, Willemsen V, Blilou I, et al. 2004. The PLETHORA genes mediate patterning of the Arabidopsis root stem cell niche. Cell 119:109–20 3. Amano Y, Tsubouchi H, Shinohara H, Ogawa M, Matsubayashi Y. 2007. Tyrosine-sulfated glycopeptide involved in cellular proliferation and expansion in Arabidopsis. Proc. Natl. Acad. Sci. USA 104:18333– 38 4. Bleckmann A, Weidtkamp-Peters S, Seidel CA, Simon R. 2010. Stem cell signaling in Arabidopsis requires CRN to localize CLV2 to the plasma membrane. Plant Physiol. 152:166–76 5. Brand U, Fletcher JC, Hobe M, Meyerowitz EM, Simon R. 2000. Dependence of stem cell fate in Arabidopsis on a feedback loop regulated by CLV3 activity. Science 289:617–19 6. Butenko MA, Patterson SE, Grini PE, Stenvik GE, Amundsen SS, et al. 2003. INFLORESCENCE DEFICIENT IN ABSCISSION controls floral organ abscission in Arabidopsis and identifies a novel family of putative ligands in plants. Plant Cell 15:2296–307 7. Caetano-Anollés G, Gresshoff PM. 1991. Plant genetic control of nodulation. Annu. Rev. Microbiol. 45:345–82 8. Casamitjana-Mart´ınez E, Hofhuis HF, Xu J, Liu CM, Heidstra R, Scheres B. 2003. Root-specific CLE19 overexpression and the sol1/2 suppressors implicate a CLV-like pathway in the control of Arabidopsis root meristem maintenance. Curr. Biol. 13:1435–41 9. Casson SA, Chilley PM, Topping JF, Evans IM, Souter MA, Lindsey K. 2002. The POLARIS gene of Arabidopsis encodes a predicted peptide required for correct root growth and leaf vascular patterning. Plant Cell 14:1705–21 10. Chen YC, Siems WF, Pearce G, Ryan CA. 2008. Six peptide wound signals derived from a single precursor protein in Ipomoea batatas leaves activate the expression of the defense gene sporamin. J. Biol. Chem. 283:11469–76 11. Chen YF, Matsubayashi Y, Sakagami Y. 2000. Peptide growth factor phytosulfokine-α contributes to the pollen population effect. Planta 211:752–55 12. Chilley PM, Casson SA, Tarkowski P, Hawkins N, Wang KL, et al. 2006. The POLARIS peptide of Arabidopsis regulates auxin transport and root growth via effects on ethylene signaling. Plant Cell 18:3058–72 13. Cho SK, Larue CT, Chevalier D, Wang H, Jinn TL, et al. 2008. Regulation of floral organ abscission in Arabidopsis thaliana. Proc. Natl. Acad. Sci. USA 105:15629–34 14. Chu H, Qian Q, Liang W, Yin C, Tan H, et al. 2006. The FLORAL ORGAN NUMBER4 gene encoding a putative ortholog of Arabidopsis CLAVATA3 regulates apical meristem size in rice. Plant Physiol. 142:1039–52 15. Clark SE, Williams RW, Meyerowitz EM. 1997. The CLAVATA1 gene encodes a putative receptor kinase that controls shoot and floral meristem size in Arabidopsis. Cell 89:575–85 16. Cock JM, McCormick S. 2001. A large family of genes that share homology with CLAVATA3. Plant Physiol. 126:939–42 16a. Delay C, Imin N, Djordjevic MA. 2013. CEP genes regulate root and shoot development in response to environmental cues and are specific to seed plants. J. Exp. Bot. 64:5383–94 17. Djordjevic MA, Oakes M, Wong CE, Singh M, Bhalla P, et al. 2011. Border sequences of Medicago truncatula CLE36 are specifically cleaved by endoproteases common to the extracellular fluids of Medicago and soybean. J. Exp. Bot. 62:4649–59 18. Egelund J, Obel N, Ulvskov P, Geshi N, Pauly M, et al. 2007. Molecular characterization of two Arabidopsis thaliana glycosyltransferase mutants, rra1 and rra2, which have a reduced residual arabinose content in a polymer tightly associated with the cellulosic wall residue. Plant Mol. Biol. 64:439–51 www.annualreviews.org • Small-Peptide Signaling in Plants

407

ARI

8 April 2014

21:29

19. Ellis M, Egelund J, Schultz CJ, Bacic A. 2010. Arabinogalactan-proteins: key regulators at the cell surface? Plant Physiol. 153:403–19 20. Endo S, Shinohara H, Matsubayashi Y, Fukuda H. 2013. A novel pollen–pistil interaction conferring high temperature tolerance during reproduction via CLE45 signaling. Curr. Biol. 23:1670–76 21. Etchells JP, Provost CM, Mishra L, Turner SR. 2013. WOX4 and WOX14 act downstream of the PXY receptor kinase to regulate plant vascular proliferation independently of any role in vascular organisation. Development 140:2224–34 22. Etchells JP, Turner SR. 2010. The PXY-CLE41 receptor ligand pair defines a multifunctional pathway that controls the rate and orientation of vascular cell division. Development 137:767–74 23. Fernandez A, Drozdzecki A, Hoogewijs K, Nguyen A, Beeckman T, et al. 2013. Transcriptional and functional classification of the GOLVEN/ROOT GROWTH FACTOR/CLE-like signaling peptides reveals their role in lateral root and hair formation. Plant Physiol. 161:954–70 24. Fisher K, Turner S. 2007. PXY, a receptor-like kinase essential for maintaining polarity during plant vascular-tissue development. Curr. Biol. 17:1061–66 25. Fiume E, Fletcher JC. 2012. Regulation of Arabidopsis embryo and endosperm development by the polypeptide signaling molecule CLE8. Plant Cell 24:1000–12 26. Fletcher JC, Brand U, Running MP, Simon R, Meyerowitz EM. 1999. Signaling of cell fate decisions by CLAVATA3 in Arabidopsis shoot meristems. Science 283:1911–14 27. Fletcher JC, Meyerowitz EM. 2000. Cell signaling within the shoot meristem. Curr. Opin. Plant Biol. 3:23–30 28. Fuller RS, Sterne RE, Thorner J. 1988. Enzymes required for yeast prohormone processing. Annu. Rev. Physiol. 50:345–62 29. Galinha C, Hofhuis H, Luijten M, Willemsen V, Blilou I, et al. 2007. PLETHORA proteins as dosedependent master regulators of Arabidopsis root development. Nature 449:1053–57 30. Gille S, Hansel U, Ziemann M, Pauly M. 2009. Identification of plant cell wall mutants by means of a forward chemical genetic approach using hydrolases. Proc. Natl. Acad. Sci. USA 106:14699–704 31. Green TR, Ryan CA. 1972. Wound-induced proteinase inhibitor in plant leaves: a possible defense mechanism against insects. Science 175:776–77 32. Guo Y, Han L, Hymes M, Denver R, Clark SE. 2010. CLAVATA2 forms a distinct CLE-binding receptor complex regulating Arabidopsis stem cell specification. Plant J. 63:889–900 33. Hanai H, Matsuno T, Yamamoto M, Matsubayashi Y, Kobayashi T, et al. 2000. A secreted peptide growth factor, phytosulfokine, acting as a stimulatory factor of carrot somatic embryo formation. Plant Cell Physiol. 41:27–32 34. Hanai H, Nakayama D, Yang H, Matsubayashi Y, Hirota Y, Sakagami Y. 2000. Existence of a plant tyrosylprotein sulfotransferase: novel plant enzyme catalyzing tyrosine O-sulfation of preprophytosulfokine variants in vitro. FEBS Lett. 470:97–101 35. Hara K, Kajita R, Torii KU, Bergmann DC, Kakimoto T. 2007. The secretory peptide gene EPF1 enforces the stomatal one-cell-spacing rule. Genes Dev. 21:1720–25 36. Hartmann J, Stuhrwohldt N, Dahlke RI, Sauter M. 2013. Phytosulfokine control of growth occurs in the epidermis, is likely to be non-cell autonomous and is dependent on brassinosteroids. Plant J. 73:579–90 37. Hieta R, Myllyharju J. 2002. Cloning and characterization of a low molecular weight prolyl 4hydroxylase from Arabidopsis thaliana: effective hydroxylation of proline-rich, collagen-like, and hypoxiainducible transcription factor α-like peptides. J. Biol. Chem. 277:23965–71 38. Higashiyama T. 2010. Peptide signaling in pollen-pistil interactions. Plant Cell Physiol. 51:177–89 39. Hirakawa Y, Kondo Y, Fukuda H. 2010. TDIF peptide signaling regulates vascular stem cell proliferation via the WOX4 homeobox gene in Arabidopsis. Plant Cell 22:2618–29 40. Hirakawa Y, Shinohara H, Kondo Y, Inoue A, Nakanomyo I, et al. 2008. Non-cell-autonomous control of vascular stem cell fate by a CLE peptide/receptor system. Proc. Natl. Acad. Sci. USA 105:15208–13 41. Hobe M, Muller R, Grunewald M, Brand U, Simon R. 2003. Loss of CLE40, a protein functionally equivalent to the stem cell restricting signal CLV3, enhances root waving in Arabidopsis. Dev. Genes Evol. 213:371–81



408

Matsubayashi



ARI

8 April 2014

21:29

42. Huffaker A, Pearce G, Ryan CA. 2006. An endogenous peptide signal in Arabidopsis activates components of the innate immune response. Proc. Natl. Acad. Sci. USA 103:10098–103 43. Igarashi D, Tsuda K, Katagiri F. 2012. The peptide growth factor, phytosulfokine, attenuates patterntriggered immunity. Plant J. 71:194–204 44. Igasaki T, Akashi N, Ujino-Ihara T, Matsubayashi Y, Sakagami Y, Shinohara K. 2003. Phytosulfokine stimulates somatic embryogenesis in Cryptomeria japonica. Plant Cell Physiol. 44:1412–16 45. Ito Y, Nakanomyo I, Motose H, Iwamoto K, Sawa S, et al. 2006. Dodeca-CLE peptides as suppressors of plant stem cell differentiation. Science 313:842–45 46. Jeong S, Trotochaud AE, Clark SE. 1999. The Arabidopsis CLAVATA2 gene encodes a receptor-like protein required for the stability of the CLAVATA1 receptor-like kinase. Plant Cell 11:1925–34 47. Jinn TL, Stone JM, Walker JC. 2000. HAESA, an Arabidopsis leucine-rich repeat receptor kinase, controls floral organ abscission. Genes Dev. 14:108–17 48. Jun J, Fiume E, Roeder AH, Meng L, Sharma VK, et al. 2010. Comprehensive analysis of CLE polypeptide signaling gene expression and overexpression activity in Arabidopsis. Plant Physiol. 154:1721–36 49. Kieliszewski MJ, de Zacks R, Leykam JF, Lamport DT. 1992. A repetitive proline-rich protein from the gymnosperm Douglas fir is a hydroxyproline-rich glycoprotein. Plant Physiol. 98:919–26 50. Kieliszewski MJ, Lamport DT. 1994. Extensin: repetitive motifs, functional sites, post-translational codes, and phylogeny. Plant J. 5:157–72 51. Kieliszewski MJ, Lamport DT, Tan L, Cannon MC. 2010. Hydroxyproline-rich glycoproteins: form and function. Annu. Plant Rev. 41:321–42 52. Kinoshita A, Betsuyaku S, Osakabe Y, Mizuno S, Nagawa S, et al. 2010. RPK2 is an essential receptorlike kinase that transmits the CLV3 signal in Arabidopsis. Development 137:3911–20 53. Kobayashi T, Eun C, Hanai H, Matsubayashi Y, Sakagami Y, Kamada H. 1999. Phytosulphokine-α, a peptidyl plant growth factor, stimulates somatic embryogenesis in carrot. J. Exp. Bot. 50:1123–28 54. Komori R, Amano Y, Ogawa-Ohnishi M, Matsubayashi Y. 2009. Identification of tyrosylprotein sulfotransferase in Arabidopsis. Proc. Natl. Acad. Sci. USA 106:15067–72 54a. Kondo T, Kajita R, Miyazaki A, Hokoyama M, Nakamura-Miura T, et al. 2010. Stomatal density is controlled by a mesophyll-derived signaling molecule. Plant Cell Physiol. 51:1–8 55. Kondo T, Nakamura T, Yokomine K, Sakagami Y. 2008. Dual assay for MCLV3 activity reveals structure-activity relationship of CLE peptides. Biochem. Biophys. Res. Commun. 377:312–16 56. Kondo T, Sawa S, Kinoshita A, Mizuno S, Kakimoto T, et al. 2006. A plant peptide encoded by CLV3 identified by in situ MALDI-TOF MS analysis. Science 313:845–48 57. Krusell L, Madsen LH, Sato S, Aubert G, Genua A, et al. 2002. Shoot control of root development and nodulation is mediated by a receptor-like kinase. Nature 420:422–26 58. Kumpf RP, Shi CL, Larrieu A, Sto IM, Butenko MA, et al. 2013. Floral organ abscission peptide IDA and its HAE/HSL2 receptors control cell separation during lateral root emergence. Proc. Natl. Acad. Sci. USA 110:5235–40 59. Kutschmar A, Rzewuski G, Stuhrwohldt N, Beemster GT, Inze D, Sauter M. 2009. PSK-α promotes root growth in Arabidopsis. New Phytol. 181:820–31 60. Kwezi L, Ruzvidzo O, Wheeler JI, Govender K, Iacuone S, et al. 2011. The phytosulfokine (PSK) receptor is capable of guanylate cyclase activity and enabling cyclic GMP-dependent signaling in plants. J. Biol. Chem. 286:22580–88 61. Lim CW, Lee YW, Hwang CH. 2011. Soybean nodule-enhanced CLE peptides in roots act as signals in GmNARK-mediated nodulation suppression. Plant Cell Physiol. 52:1613–27 62. Loivamäki M, Stuhrwohldt N, Deeken R, Steffens B, Roitsch T, et al. 2010. A role for PSK signaling ¨ in wounding and microbial interactions in Arabidopsis. Physiol. Plant. 139:348–57 63. Marshall E, Costa LM, Gutierrez-Marcos J. 2011. Cysteine-rich peptides (CRPs) mediate diverse aspects of cell-cell communication in plant reproduction and development. J. Exp. Bot. 62:1677–86 64. Márton ML, Cordts S, Broadhvest J, Dresselhaus T. 2005. Micropylar pollen tube guidance by Egg Apparatus 1 of maize. Science 307:573–76 65. Matsubayashi Y. 2011. Post-translational modifications in secreted peptide hormones in plants. Plant Cell Physiol. 52:5–13 www.annualreviews.org • Small-Peptide Signaling in Plants

409

ARI

8 April 2014

21:29

66. Matsubayashi Y. 2011. Small post-translationally modified peptide signals in Arabidopsis. Arabidopsis Book 9:e0150 67. Matsubayashi Y, Ogawa M, Kihara H, Niwa M, Sakagami Y. 2006. Disruption and overexpression of Arabidopsis phytosulfokine receptor gene affects cellular longevity and potential for growth. Plant Physiol. 142:45–53 68. Matsubayashi Y, Ogawa M, Morita A, Sakagami Y. 2002. An LRR receptor kinase involved in perception of a peptide plant hormone, phytosulfokine. Science 296:1470–72 69. Matsubayashi Y, Sakagami Y. 1996. Phytosulfokine, sulfated peptides that induce the proliferation of single mesophyll cells of Asparagus officinalis L. Proc. Natl. Acad. Sci. USA 93:7623–27 70. Matsubayashi Y, Sakagami Y. 2006. Peptide hormones in plants. Annu. Rev. Plant Biol. 57:649–74 71. Matsubayashi Y, Takagi L, Omura N, Morita A, Sakagami Y. 1999. The endogenous sulfated pentapeptide phytosulfokine-α stimulates tracheary element differentiation of isolated mesophyll cells of zinnia. Plant Physiol. 120:1043–48 72. Matsuzaki Y, Ogawa-Ohnishi M, Mori A, Matsubayashi Y. 2010. Secreted peptide signals required for maintenance of root stem cell niche in Arabidopsis. Science 329:1065–67 73. Meng L, Buchanan BB, Feldman LJ, Luan S. 2012. CLE-like (CLEL) peptides control the pattern of root growth and lateral root development in Arabidopsis. Proc. Natl. Acad. Sci. USA 109:1760–65 74. Minami E, Kouchi H, Cohn JR, Ogawa T, Stacey G. 1996. Expression of the early nodulin, ENOD40, in soybean roots in response to various lipo-chitin signal molecules. Plant J. 10:23–32 75. Mitchum MG, Wang X, Wang J, Davis EL. 2012. Role of nematode peptides and other small molecules in plant parasitism. Annu. Rev. Phytopathol. 50:175–95 76. Miwa H, Betsuyaku S, Iwamoto K, Kinoshita A, Fukuda H, Sawa S. 2008. The receptor-like kinase SOL2 mediates CLE signaling in Arabidopsis. Plant Cell Physiol. 49:1752–57 77. Moore KL. 2003. The biology and enzymology of protein tyrosine O-sulfation. J. Biol. Chem. 278:24243–46 78. Mortier V, Den Herder G, Whitford R, Van de Velde W, Rombauts S, et al. 2010. CLE peptides control Medicago truncatula nodulation locally and systemically. Plant Physiol. 153:222–37 79. Mortier V, Fenta BA, Martens C, Rombauts S, Holsters M, et al. 2011. Search for nodulation-related CLE genes in the genome of Glycine max. J. Exp. Bot. 62:2571–83 80. Mosher S, Seybold H, Rodriguez P, Stahl M, Davies KA, et al. 2013. The tyrosine-sulfated peptide receptors PSKR1 and PSY1R modify the immunity of Arabidopsis to biotrophic and necrotrophic pathogens in an antagonistic manner. Plant J. 73:469–82 81. Motose H, Iwamoto K, Endo S, Demura T, Sakagami Y, et al. 2009. Involvement of phytosulfokine in the attenuation of stress response during the transdifferentiation of zinnia mesophyll cells into tracheary elements. Plant Physiol. 150:437–47 82. Muller R, Bleckmann A, Simon R. 2008. The receptor kinase CORYNE of Arabidopsis transmits the stem cell-limiting signal CLAVATA3 independently of CLAVATA1. Plant Cell 20:934–46 83. Murphy E, Smith S, De Smet I. 2012. Small signaling peptides in Arabidopsis development: how cells communicate over a short distance. Plant Cell 24:3198–217 84. Muschietti J, Dircks L, Vancanneyt G, McCormick S. 1994. LAT52 protein is essential for tomato pollen development: pollen expressing antisense LAT52 RNA hydrates and germinates abnormally and cannot achieve fertilization. Plant J. 6:321–38 85. Myllyharju J. 2003. Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis. Matrix Biol. 22:15– 24 86. Narita NN, Moore S, Horiguchi G, Kubo M, Demura T, et al. 2004. Overexpression of a novel small peptide ROTUNDIFOLIA4 decreases cell proliferation and alters leaf shape in Arabidopsis thaliana. Plant J. 38:699–713 87. Narváez-Vásquez J, Pearce G, Ryan CA. 2005. The plant cell wall matrix harbors a precursor of defense signaling peptides. Proc. Natl. Acad. Sci. USA 102:12974–77 88. Ni J, Clark SE. 2006. Evidence for functional conservation, sufficiency, and proteolytic processing of the CLAVATA3 CLE domain. Plant Physiol. 140:726–33 89. Ni J, Guo Y, Jin H, Hartsell J, Clark SE. 2011. Characterization of a CLE processing activity. Plant Mol. Biol. 75:67–75



410

Matsubayashi



ARI

8 April 2014

21:29

90. Nimchuk ZL, Tarr PT, Ohno C, Qu X, Meyerowitz EM. 2011. Plant stem cell signaling involves ligand-dependent trafficking of the CLAVATA1 receptor kinase. Curr. Biol. 21:345–52 91. Nishimura R, Hayashi M, Wu GJ, Kouchi H, Imaizumi-Anraku H, et al. 2002. HAR1 mediates systemic regulation of symbiotic organ development. Nature 420:426–29 92. Oelkers K, Goffard N, Weiller GF, Gresshoff PM, Mathesius U, Frickey T. 2008. Bioinformatic analysis of the CLE signaling peptide family. BMC Plant Biol. 8:1 93. Ogawa M, Shinohara H, Sakagami Y, Matsubayashi Y. 2008. Arabidopsis CLV3 peptide directly binds CLV1 ectodomain. Science 319:294 94. Ogawa-Ohnishi M, Matsushita W, Matsubayashi Y. 2013. Identification of three hydroxyproline O-arabinosyltransferases in Arabidopsis thaliana. Nat. Chem. Biol. 9:726–30 95. Ohyama K, Ogawa M, Matsubayashi Y. 2008. Identification of a biologically active, small, secreted peptide in Arabidopsis by in silico gene screening, followed by LC-MS-based structure analysis. Plant J. 55:152–60 96. Ohyama K, Shinohara H, Ogawa-Ohnishi M, Matsubayashi Y. 2009. A glycopeptide regulating stem cell fate in Arabidopsis thaliana. Nat. Chem. Biol. 5:578–80 97. Oka-Kira E, Kawaguchi M. 2006. Long-distance signaling to control root nodule number. Curr. Opin. Plant Biol. 9:496–502 98. Okamoto S, Ohnishi E, Sato S, Takahashi H, Nakazono M, et al. 2009. Nod factor/nitrate-induced CLE genes that drive HAR1-mediated systemic regulation of nodulation. Plant Cell Physiol. 50:67–77 99. Okamoto S, Shinohara H, Mori T, Matsubayashi Y, Kawaguchi M. 2013. Root-derived CLE glycopeptides control nodulation by direct binding to HAR1 receptor kinase. Nat. Commun. 4:2191 100. Okuda S, Tsutsui H, Shiina K, Sprunck S, Takeuchi H, et al. 2009. Defensin-like polypeptide LUREs are pollen tube attractants secreted from synergid cells. Nature 458:357–61 101. Pearce G, Bhattacharya R, Chen YC, Barona G, Yamaguchi Y, Ryan CA. 2009. Isolation and characterization of hydroxyproline-rich glycopeptide signals in black nightshade leaves. Plant Physiol. 150:1422–33 102. Pearce G, Moura DS, Stratmann J, Ryan CA. 2001. Production of multiple plant hormones from a single polyprotein precursor. Nature 411:817–20 103. Pearce G, Moura DS, Stratmann J, Ryan CA. 2001. RALF, a 5-kDa ubiquitous polypeptide in plants, arrests root growth and development. Proc. Natl. Acad. Sci. USA 98:12843–47 104. Pearce G, Ryan CA. 2003. Systemic signaling in tomato plants for defense against herbivores: isolation and characterization of three novel defense-signaling glycopeptide hormones coded in a single precursor gene. J. Biol. Chem. 278:30044–50 105. Pearce G, Siems WF, Bhattacharya R, Chen YC, Ryan CA. 2007. Three hydroxyproline-rich glycopeptides derived from a single petunia polyprotein precursor activate defensin I, a pathogen defense response gene. J. Biol. Chem. 282:17777–84 106. Pearce G, Strydom D, Johnson S, Ryan CA. 1991. A polypeptide from tomato leaves induces woundinducible proteinase inhibitor proteins. Science 253:895–97 107. Rehemtulla A, Kaufman RJ. 1992. Protein processing within the secretory pathway. Curr. Opin. Biotechnol. 3:560–65 108. Reid DE, Ferguson BJ, Gresshoff PM. 2011. Inoculation- and nitrate-induced CLE peptides of soybean control NARK-dependent nodule formation. Mol. Plant-Microbe Interact. 24:606–18 108a. Roberts I, Smith S, De Rybel B, Van Den Broeke J, Smet W, et al. 2013. The CEP family in land plants: evolutionary analyses, expression studies, and role in Arabidopsis shoot development. J. Exp. Bot. 64:5371–81 109. Ryan CA. 1990. Proteinase inhibitors in plants: genes for improving defenses against insects and pathogens. Annu. Rev. Phytopathol. 28:425–49 110. Ryan CA. 2000. The systemin signaling pathway: differential activation of plant defensive genes. Biochim. Biophys. Acta 1477:112–21 111. Ryan CA, Huffaker A, Yamaguchi Y. 2007. New insights into innate immunity in Arabidopsis. Cell Microbiol. 9:1902–8 112. Ryan CA, Pearce G, Scheer J, Moura DS. 2002. Polypeptide hormones. Plant Cell 14(Suppl.):S251–64 113. Schaller A, Oecking C. 1999. Modulation of plasma membrane H+ -ATPase activity differentially activates wound and pathogen defense responses in tomato plants. Plant Cell 11:263–72 www.annualreviews.org • Small-Peptide Signaling in Plants

411

ARI

8 April 2014

21:29

114. Schnabel EL, Kassaw TK, Smith LS, Marsh JF, Oldroyd GE, et al. 2011. The ROOT DETERMINED NODULATION1 gene regulates nodule number in roots of Medicago truncatula and defines a highly conserved, uncharacterized plant gene family. Plant Physiol. 157:328–40 115. Schoof H, Lenhard M, Haecker A, Mayer KF, Jurgens G, Laux T. 2000. The stem cell population of ¨ Arabidopsis shoot meristems is maintained by a regulatory loop between the CLAVATA and WUSCHEL genes. Cell 100:635–44 116. Schopfer CR, Nasrallah ME, Nasrallah JB. 1999. The male determinant of self-incompatibility in Brassica. Science 286:1697–700 117. Shen Y, Diener AC. 2013. Arabidopsis thaliana RESISTANCE TO FUSARIUM OXYSPORUM 2 implicates tyrosine-sulfated peptide signaling in susceptibility and resistance to root infection. PLoS Genet. 9:e1003525 118. Shi CL, Stenvik GE, Vie AK, Bones AM, Pautot V, et al. 2011. Arabidopsis class I KNOTTED-like homeobox proteins act downstream in the IDA-HAE/HSL2 floral abscission signaling pathway. Plant Cell 23:2553–67 119. Shimada T, Sugano SS, Hara-Nishimura I. 2011. Positive and negative peptide signals control stomatal density. Cell. Mol. Life Sci. 68:2081–88 120. Shimizu M, Igasaki T, Yamada M, Yuasa K, Hasegawa J, et al. 2005. Experimental determination of proline hydroxylation and hydroxyproline arabinogalactosylation motifs in secretory proteins. Plant J. 42:877–89 121. Shinohara H, Matsubayashi Y. 2013. Chemical synthesis of Arabidopsis CLV3 glycopeptide reveals the impact of hydroxyproline arabinosylation on peptide conformation and activity. Plant Cell Physiol. 54:369–74 122. Shinohara H, Moriyama Y, Ohyama K, Matsubayashi Y. 2012. Biochemical mapping of a ligand-binding domain within Arabidopsis BAM1 reveals diversified ligand recognition mechanisms of plant LRR-RKs. Plant J. 70:845–54 123. Shinohara H, Ogawa M, Sakagami Y, Matsubayashi Y. 2007. Identification of ligand binding site of phytosulfokine receptor by on-column photoaffinity labeling. J. Biol. Chem. 282:124–31 124. Song XF, Guo P, Ren SC, Xu TT, Liu CM. 2013. Antagonistic peptide technology for functional dissection of CLV3/ESR genes in Arabidopsis. Plant Physiol. 161:1076–85 125. Song XF, Yu DL, Xu TT, Ren SC, Guo P, Liu CM. 2012. Contributions of individual amino acid residues to the endogenous CLV3 function in shoot apical meristem maintenance in Arabidopsis. Mol. Plant 5:515–23 126. Sprunck S, Rademacher S, Vogler F, Gheyselinck J, Grossniklaus U, Dresselhaus T. 2012. Egg cell– secreted EC1 triggers sperm cell activation during double fertilization. Science 338:1093–97 127. Srivastava R, Liu JX, Howell SH. 2008. Proteolytic processing of a precursor protein for a growthpromoting peptide by a subtilisin serine protease in Arabidopsis. Plant J. 56:219–27 128. Stahl Y, Grabowski S, Bleckmann A, Kuhnemuth R, Weidtkamp-Peters S, et al. 2013. Moderation of Arabidopsis root stemness by CLAVATA1 and ARABIDOPSIS CRINKLY4 receptor kinase complexes. Curr. Biol. 23:362–71 129. Stahl Y, Wink RH, Ingram GC, Simon R. 2009. A signaling module controlling the stem cell niche in Arabidopsis root meristems. Curr. Biol. 19:909–14 130. Stenvik GE, Tandstad NM, Guo Y, Shi CL, Kristiansen W, et al. 2008. The EPIP peptide of INFLORESCENCE DEFICIENT IN ABSCISSION is sufficient to induce abscission in Arabidopsis through the receptor-like kinases HAESA and HAESA-LIKE2. Plant Cell 20:1805–17 131. Stratmann JW. 2003. Long distance run in the wound response—jasmonic acid is pulling ahead. Trends Plant Sci. 8:247–50 132. Stuhrwohldt N, Dahlke RI, Steffens B, Johnson A, Sauter M. 2011. Phytosulfokine-αcontrols hypocotyl length and cell expansion in Arabidopsis thaliana through phytosulfokine receptor 1. PLoS ONE 6:e21054 133. Sugano SS, Shimada T, Imai Y, Okawa K, Tamai A, et al. 2010. Stomagen positively regulates stomatal density in Arabidopsis. Nature 463:241–44 134. Suzaki T, Ohneda M, Toriba T, Yoshida A, Hirano HY. 2009. FON2 SPARE1 redundantly regulates floral meristem maintenance with FLORAL ORGAN NUMBER2 in rice. PLoS Genet. 5:e1000693



412

Matsubayashi



ARI

8 April 2014

21:29

135. Suzaki T, Toriba T, Fujimoto M, Tsutsumi N, Kitano H, Hirano HY. 2006. Conservation and diversification of meristem maintenance mechanism in Oryza sativa: function of the FLORAL ORGAN NUMBER2 gene. Plant Cell Physiol. 47:1591–602 136. Suzaki T, Yoshida A, Hirano HY. 2008. Functional diversification of CLAVATA3-related CLE proteins in meristem maintenance in rice. Plant Cell 20:2049–58 137. Takayama S, Shiba H, Iwano M, Shimosato H, Che FS, et al. 2000. The pollen determinant of selfincompatibility in Brassica campestris. Proc. Natl. Acad. Sci. USA 97:1920–25 137a. Tamaki T, Betsuyaku S, Fujiwara M, Fukao Y, Fukuda H, et al. 2013. SUPPRESSOR OF LLP1 1-mediated C-terminal processing is critical for CLE19 peptide activity. Plant J. 76:970–81 138. Tiainen P, Myllyharju J, Koivunen P. 2005. Characterization of a second Arabidopsis thaliana prolyl 4-hydroxylase with distinct substrate specificity. J. Biol. Chem. 280:1142–48 139. Velasquez SM, Ricardi MM, Dorosz JG, Fernandez PV, Nadra AD, et al. 2011. O-glycosylated cell wall proteins are essential in root hair growth. Science 332:1401–3 140. Wang X, Mitchum MG, Gao B, Li C, Diab H, et al. 2005. A parasitism gene from a plant-parasitic nematode with function similar to CLAVATA3/ESR (CLE) of Arabidopsis thaliana. Mol. Plant Pathol. 6:187–91 141. Wen J, Lease KA, Walker JC. 2004. DVL, a novel class of small polypeptides: overexpression alters Arabidopsis development. Plant J. 37:668–77 142. Whitford R, Fernandez A, De Groodt R, Ortega E, Hilson P. 2008. Plant CLE peptides from two distinct functional classes synergistically induce division of vascular cells. Proc. Natl. Acad. Sci. USA 105:18625–30 143. Whitford R, Fernandez A, Tejos R, Pérez AC, Kleine-Vehn J, et al. 2012. GOLVEN secretory peptides regulate auxin carrier turnover during plant gravitropic responses. Dev. Cell 22:678–85 144. Yang H, Matsubayashi Y, Nakamura K, Sakagami Y. 1999. Oryza sativa PSK gene encodes a precursor of phytosulfokine-α, a sulfated peptide growth factor found in plants. Proc. Natl. Acad. Sci. USA 96:13560– 65 145. Yang SL, Xie LF, Mao HZ, Puah CS, Yang WC, et al. 2003. TAPETUM DETERMINANT1 is required for cell specialization in the Arabidopsis anther. Plant Cell 15:2792–804 146. Yuasa K, Toyooka K, Fukuda H, Matsuoka K. 2005. Membrane-anchored prolyl hydroxylase with an export signal from the endoplasmic reticulum. Plant J. 41:81–94 147. Zhou W, Wei L, Xu J, Zhai Q, Jiang H, et al. 2010. Arabidopsis tyrosylprotein sulfotransferase acts in the auxin/PLETHORA pathway in regulating postembryonic maintenance of the root stem cell niche. Plant Cell 22:3692–709 148. Zhu Y, Wang Y, Li R, Song X, Wang Q, et al. 2010. Analysis of interactions among the CLAVATA3 receptors reveals a direct interaction between CLAVATA2 and CORYNE in Arabidopsis. Plant J. 61:223– 33

www.annualreviews.org • Small-Peptide Signaling in Plants

413

PP65-FrontMatter

ARI

8 April 2014

Annual Review of Plant Biology Volume 65, 2014

23:6

Contents


Our Eclectic Adventures in the Slower Eras of Photosynthesis: From New England Down Under to Biosphere 2 and Beyond Barry Osmond p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Sucrose Metabolism: Gateway to Diverse Carbon Use and Sugar Signaling Yong-Ling Ruan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p33 The Cell Biology of Cellulose Synthesis Heather E. McFarlane, Anett Döring, and Staffan Persson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p69 Phosphate Nutrition: Improving Low-Phosphate Tolerance in Crops Damar Lizbeth López-Arredondo, Marco Antonio Leyva-González, Sandra Isabel González-Morales, José López-Bucio, and Luis Herrera-Estrella p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p95 Iron Cofactor Assembly in Plants Janneke Balk and Theresia A. Schaedler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 125 Cyanogenic Glycosides: Synthesis, Physiology, and Phenotypic Plasticity Roslyn M. Gleadow and Birger Lindberg Møller p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 155 Engineering Complex Metabolic Pathways in Plants Gemma Farré, Dieter Blancquaert, Teresa Capell, Dominique Van Der Straeten, Paul Christou, and Changfu Zhu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 187 Triterpene Biosynthesis in Plants Ramesha Thimmappa, Katrin Geisler, Thomas Louveau, Paul O’Maille, and Anne Osbourn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 225 To Gibberellins and Beyond! Surveying the Evolution of (Di)Terpenoid Metabolism Jiachen Zi, Sibongile Mafu, and Reuben J. Peters p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 259 Regulation and Dynamics of the Light-Harvesting System Jean-David Rochaix p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 287 Gene Expression Regulation in Photomorphogenesis from the Perspective of the Central Dogma Shu-Hsing Wu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 311 viii

PP65-FrontMatter

ARI

8 April 2014

23:6

Light Regulation of Plant Defense Carlos L. Ballaré p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 335 Heterotrimeric G Protein–Coupled Signaling in Plants Daisuke Urano and Alan M. Jones p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 365 Posttranslationally Modified Small-Peptide Signals in Plants Yoshikatsu Matsubayashi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 385 Pentatricopeptide Repeat Proteins in Plants Alice Barkan and Ian Small p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 415


Division and Dynamic Morphology of Plastids Katherine W. Osteryoung and Kevin A. Pyke p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 443 The Diversity, Biogenesis, and Activities of Endogenous Silencing Small RNAs in Arabidopsis Nicolas G. Bologna and Olivier Voinnet p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 473 The Contributions of Transposable Elements to the Structure, Function, and Evolution of Plant Genomes Jeffrey L. Bennetzen and Hao Wang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 505 Natural Variations and Genome-Wide Association Studies in Crop Plants Xuehui Huang and Bin Han p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 531 Molecular Control of Grass Inflorescence Development Dabing Zhang and Zheng Yuan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 553 Male Sterility and Fertility Restoration in Crops Letian Chen and Yao-Guang Liu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 579 Molecular Control of Cell Specification and Cell Differentiation During Procambial Development Kaori Miyashima Furuta, Eva Hellmann, and Ykä Helariutta p p p p p p p p p p p p p p p p p p p p p p p p p p 607 Adventitious Roots and Lateral Roots: Similarities and Differences Catherine Bellini, Daniel I. Pacurar, and Irene Perrone p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 639 Nonstructural Carbon in Woody Plants Michael C. Dietze, Anna Sala, Mariah S. Carbone, Claudia I. Czimczik, Joshua A. Mantooth, Andrew D. Richardson, and Rodrigo Vargas p p p p p p p p p p p p p p p p p p p 667 Plant Interactions with Multiple Insect Herbivores: From Community to Genes Jeltje M. Stam, Anneke Kroes, Yehua Li, Rieta Gols, Joop J.A. van Loon, Erik H. Poelman, and Marcel Dicke p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 689 Genetic Engineering and Breeding of Drought-Resistant Crops Honghong Hu and Lizhong Xiong p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 715

Contents

ix

PP65-FrontMatter

ARI

8 April 2014

23:6

Plant Molecular Pharming for the Treatment of Chronic and Infectious Diseases Eva Stoger, Rainer Fischer, Maurice Moloney, and Julian K.-C. Ma p p p p p p p p p p p p p p p p p p p 743 Genetically Engineered Crops: From Idea to Product Jose Rafael Prado, Gerrit Segers, Toni Voelker, Dave Carson, Raymond Dobert, Jonathan Phillips, Kevin Cook, Camilo Cornejo, Josh Monken, Laura Grapes, Tracey Reynolds, and Susan Martino-Catt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 769 Errata


An online log of corrections to Annual Review of Plant Biology articles may be found at http://www.annualreviews.org/errata/arplant

x

Contents

Annual Reviews It’s about time. Your time. It’s time well spent.

New From Annual Reviews:

Annual Review of Statistics and Its Application Volume 1 • Online January 2014 • http://statistics.annualreviews.org

Editor: Stephen E. Fienberg, Carnegie Mellon University


Associate Editors: Nancy Reid, University of Toronto Stephen M. Stigler, University of Chicago The Annual Review of Statistics and Its Application aims to inform statisticians and quantitative methodologists, as well as all scientists and users of statistics about major methodological advances and the computational tools that allow for their implementation. It will include developments in the field of statistics, including theoretical statistical underpinnings of new methodology, as well as developments in specific application domains such as biostatistics and bioinformatics, economics, machine learning, psychology, sociology, and aspects of the physical sciences.

Complimentary online access to the first volume will be available until January 2015. table of contents:

• What Is Statistics? Stephen E. Fienberg • A Systematic Statistical Approach to Evaluating Evidence from Observational Studies, David Madigan, Paul E. Stang, Jesse A. Berlin, Martijn Schuemie, J. Marc Overhage, Marc A. Suchard, Bill Dumouchel, Abraham G. Hartzema, Patrick B. Ryan

• High-Dimensional Statistics with a View Toward Applications in Biology, Peter Bühlmann, Markus Kalisch, Lukas Meier • Next-Generation Statistical Genetics: Modeling, Penalization, and Optimization in High-Dimensional Data, Kenneth Lange, Jeanette C. Papp, Janet S. Sinsheimer, Eric M. Sobel

• The Role of Statistics in the Discovery of a Higgs Boson, David A. van Dyk

• Breaking Bad: Two Decades of Life-Course Data Analysis in Criminology, Developmental Psychology, and Beyond, Elena A. Erosheva, Ross L. Matsueda, Donatello Telesca

• Brain Imaging Analysis, F. DuBois Bowman

• Event History Analysis, Niels Keiding

• Statistics and Climate, Peter Guttorp

• Statistical Evaluation of Forensic DNA Profile Evidence, Christopher D. Steele, David J. Balding

• Climate Simulators and Climate Projections, Jonathan Rougier, Michael Goldstein • Probabilistic Forecasting, Tilmann Gneiting, Matthias Katzfuss • Bayesian Computational Tools, Christian P. Robert • Bayesian Computation Via Markov Chain Monte Carlo, Radu V. Craiu, Jeffrey S. Rosenthal • Build, Compute, Critique, Repeat: Data Analysis with Latent Variable Models, David M. Blei • Structured Regularizers for High-Dimensional Problems: Statistical and Computational Issues, Martin J. Wainwright

• Using League Table Rankings in Public Policy Formation: Statistical Issues, Harvey Goldstein • Statistical Ecology, Ruth King • Estimating the Number of Species in Microbial Diversity Studies, John Bunge, Amy Willis, Fiona Walsh • Dynamic Treatment Regimes, Bibhas Chakraborty, Susan A. Murphy • Statistics and Related Topics in Single-Molecule Biophysics, Hong Qian, S.C. Kou • Statistics and Quantitative Risk Management for Banking and Insurance, Paul Embrechts, Marius Hofert

Access this and all other Annual Reviews journals via your institution at www.annualreviews.org.

Annual Reviews | Connect With Our Experts Tel: 800.523.8635 (us/can) | Tel: 650.493.4400 | Fax: 650.424.0910 | Email: [email protected]

Stereotyped antibody responses target posttranslationally modified gluten in celiac disease.

Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes.

Spatial distribution of posttranslationally modified tubulins in polarized cells of developing Artemia.

Chemical methods for the proteome-wide identification of posttranslationally modified proteins.

Studying weak and dynamic interactions of posttranslationally modified proteins using expressed protein ligation.

C-terminomics: Targeted analysis of natural and posttranslationally modified protein and peptide C-termini.

Modified OMP algorithm for exponentially decaying signals.

Measuring spatial and temporal Ca2+ signals in Arabidopsis plants.

Carotenoid oxidation products as stress signals in plants.

Molecular signals in the interactions between plants and microbes.

Airborne signals from salt-stressed Arabidopsis plants trigger salinity tolerance in neighboring plants.

Genetically modified plants: public and scientific perceptions.

steroid receptor family, is rapidly modified posttranslationally.

The importance of lipid modified proteins in plants.

Electrical signals in prayer plants (marantaceae)? Insights into the trigger mechanism of the explosive style movement.

Extracellular signals and receptor-like kinases regulating ROP GTPases in plants.

Bacterial LuxR solos have evolved to respond to different molecules including signals from plants.

Signals fly when kinases meet Rho-of-plants (ROP) small G-proteins.

Genetic basis and detection of unintended effects in genetically modified crop plants.

A modified storage protein is synthesized, processed, and degraded in the seeds of transgenic plants.

Denoising and compression of intracortical signals with a modified MDL criterion.

A Modified Differential Coherent Bit Synchronization Algorithm for BeiDou Weak Signals with Large Frequency Deviation.

Trees to treehoppers: genetic variation in host plants contributes to variation in the mating signals of a plant-feeding insect.

The calmodulin fused kinase novel gene family is the major system in plants converting Ca2+ signals to protein phosphorylation responses.