Protoplasma DOI 10.1007/s00709-015-0842-1

REVIEW ARTICLE

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in plants Shucen Wan 1,3 & Liwen Jiang 2,3

Received: 29 May 2015 / Accepted: 30 May 2015 # Springer-Verlag Wien 2015

Abstract Being a major factory for protein synthesis, assembly, and export, the endoplasmic reticulum (ER) has a precise and robust ER quality control (ERQC) system monitoring its product line. However, when organisms are subjected to environmental stress, whether biotic or abiotic, the levels of misfolded proteins may overwhelm the ERQC system, tilting the balance between the capacity of and demand for ER quality control and resulting in a scenario termed ER stress. Intense or prolonged ER stress may cause damage to the ER as well as to other organelles, or even lead to cell death in extreme cases. To avoid such serious consequences, cells activate self-rescue programs to restore protein homeostasis in the ER, either through the enhancement of protein-folding and degradation competence or by alleviating the demands for such reactions. These are collectively called the unfolded protein response (UPR). Long investigated in mammalian cells and yeasts, the UPR is also of great interest to plant scientists. Among the three branches of UPR discovered in mammals,

Handling Editor: David Robinson * Shucen Wan [email protected] * Liwen Jiang [email protected] 1

Molecular Biotechnology Program, School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China

2

Centre for Cell and Developmental Biology and State Key Laboratory of Agrobiotechnology, School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China

3

School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China

two have been studied in plants with plant homologs existing of the ER-membrane-associated activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1). This review discusses the molecular mechanisms of these two types of UPR in plants, as well as the consequences of insufficient UPR, with a focus on experiments using model plants. Keywords Plant . ER stress . UPR . ATF6 . IRE1

Introduction ER stress The eukaryotic endoplasmic reticulum (ER) membrane system plays a significant role as the gateway to the secretory pathway, into which newly synthesized and correctly folded are loaded for transfer to other organelles. To maintain a healthy cellular environment, the inherent ER quality control (ERQC) machinery, including the ER retention and retrieval pathways, actively supervises protein production and assembly in the ER lumen (Ellgaard and Helenius 2003; Sitia and Braakman 2003). Plant cells, like yeasts and mammalian cells, are also equipped with an ERQC system (Liu and Li 2014) and are therefore capable of dealing with increased amounts of unfolded or misfolded proteins. However, it is possible that when plants are experiencing unexpected stresses, the demands put on the ERQC machinery will not suffice, leaving a considerable volume of misfolded proteins in the ER: a situation designated as ER stress (Howell 2013; Vitale and Boston 2008). In yeasts and mammals, ER stress has been extensively studied, with several hypotheses regarding the causes and consequences of ER stress having been proposed (Schröder and Kaufman 2005a). Their counterparts in plants also promise to be of continuing interest.

S. Wan, L. Jiang

In plant cells, ER stress is typically induced by adverse environmental conditions such as heat, cold, salt, and drought (Bray 2004; Deng et al. 2011; Liu et al. 2007a; Thomashow 1999). Recent studies on plant pathogen infection also successfully link pathogen diseases to stressed ER (Moreno et al. 2012; Sun et al. 2013b; YE et al. 2013; Ye et al. 2012). In addition, certain experimental conditions, e.g., the application of chemicals like tunicamycin (TM) and dithiothreitol (DTT) can also cause ER stress with more explicit working mechanisms. TM interferes with N-linked glycosylation of secreted glycoproteins and impedes their normal folding process (Iwata and Koizumi 2005a; Koizumi et al. 1999). As a reducing agent, DTT inhibits the proper folding of disulfide bonds through the disturbance of the oxidizing environment (Braakman et al. 1992). To restore homeostasis in protein synthesis, stressed plant cells need to reconstruct the balance between protein folding capacity and demand. They do so by the following means: (1) upregulating genes encoding ER chaperones and foldases to accelerate protein folding (Helenius and Aebi 2004; Kamauchi et al. 2005; Martinez and Chrispeels 2003); (2) upregulating components of the ER-associated degradation (ERAD) to hasten misfolded protein eradication (Doblas et al. 2013; Pollier et al. 2013); and (3) diminishing the synthesis of secretory proteins to lighten misfolded protein loads (Chen and Brandizzi 2013; Mishiba et al. 2013). Appropriately handled, short-term ER stress can be restrained and eliminated, recreating a peaceful environment. Otherwise, prolonged ER stress will lead to autophagy, cell death, or even the death of the whole plant (Cai et al. 2014; Levine and Yuan 2005; Williams et al. 2014). UPR Phylogenetically conserved in eukaryotes, unfolded protein response (UPR) refers to a series of cytoprotective signaling pathways initiated by ER-resident stress sensors, who sense ER stress and regulate transcriptional or translational activities to bring protein folding capacity and demand back into alignment (Hetz 2012; Schröder and Kaufman 2005b; Walter and Ron 2011; Welihinda and Kaufman 1996). Under mild, shortterm stress conditions, transcriptional regulations are involved, which upregulate genes encoding ER-resident chaperones and foldases, as well as ERAD components. As introduced previously, such pathways mainly impinge on the existent unfolded proteins inside the ER, fixing the exculpable products, or terminating the futile folding cycles and evacuating misfolded or damaged proteins (Howell 2013; Schröder and Kaufman 2005b; Walter and Ron 2011; Welihinda and Kaufman 1996). On the contrary, chronic stress usually induces translational regulations, which prevent further messenger RNAs (mRNAs) from being translated (Maurel et al. 2014; Schröder and Kaufman 2005b; Walter and Ron 2011).

Under extreme situations, when neither regulation of UPR is capable of restoring the homeostasis of proteins, autophagy or even programmed cell death will occur, eliminating the damaged organelles or the entire cell (Hetz 2012; Xu et al. 2005). In metazoa, diverse UPR signaling pathways have been classified into three major branches, involving either an ERmembrane-associated activating transcription factor 6 (ATF6), an inositol-requiring enzyme 1 (IRE1), or a protein kinase RNA-like ER kinase (PERK), respectively (Schröder and Kaufman 2005b). ATF6 resides in the ER membrane under normal conditions (Haze et al. 1999), but under stress is exported from the ER and transported to the Golgi apparatus (Chen et al. 2002). Here, it undergoes proteolysis (Ye et al. 2000), releasing the soluble and functional basic leucine zipper (bZIP), which then relocates to the nucleus and upregulates the synthesis of ER chaperones and foldases to enhance protein folding competence (Kokame et al. 2001; Wang et al. 2000). Similar to ATF6, IRE1 works to increase gene transcription, but through the unconventional splicing of XBP1 mRNA. As a result, the cell will generate more lipids for ER augmentation and components of ERAD for faster clearance of unfolded proteins (Cox et al. 1997; Travers et al. 2000). Additionally, the alternative signaling pathway of IRE1 initiates a reaction called regulated IRE1-dependent decay (RIDD), where the target mRNA of IRE1 splicing becomes rather promiscuous, effectively curtailing further biosynthesis of proteins (Han et al. 2009; Hollien and Weissman 2006; Hollien et al. 2009). Such a pathway mitigating ER stress at the translational level has proved to be efficient regionally. The last pathway in metazoa involving PERK also tempers translational activities, as the kinase phosphorylates and inactivates a translation initiation factor, eIF2a (Cullinan et al. 2003; Harding et al. 1999). Of these three arms, the PERK pathway has not been reported in yeasts nor in plants, whereas the IRE1 pathway is the only one well-conserved in all the eukaryotes (Howell 2013; Ruberti and Brandizzi 2014; Walter and Ron 2011). In other words, the types of UPR recognized in plants are the ATF6 homolog and IRE1 pathways. Figure 1 shows a comparison between the ERQC system in a normal plant cell and these two types of UPR in a stressed plant cell.

Mechanisms of UPR branches in plants The ATF6 homolog pathway The mammalian ER membrane stress transducer ATF6 is a type II ER membrane protein with a single-pass transmembrane domain (TMD), whose N-terminus facing the cytosol is a bZIP, and the C-terminal tail is a large ER-luminal domain interacting with the ER-resident chaperone binding protein BiP/Grp78 (Chen et al. 2002; Haze et al. 1999; Shen et al.

ER stress and the UPR in plants

Fig. 1 A comparison between the ERQC system and UPR in plant cells. In the normal situation, the ERQC system monitors the protein folding process either by the following: (1) actively retaining misfolded proteins by ER-resident chaperones and foldases, (2) passively prevent proteins without proper modifications from exiting the ER, (3) specifically retrieving misfolded proteins that accidentally escaped the ER, and (4) selectively degrading proteins trapped in a futile folding cycle by ERAD. Under ER stress, the balance between ERQC capacity and demand is shifted, triggering UPR reactions such as (5) IRE1 unconventional splicing of the XBP1 homolog mRNA, whose translation products will then activate transcription of genes encoding ERAD components for

accelerating protein clearance from the ER; (6) IRE1 unconventional splicing may also induce further biosynthesis of phospholipids for ER enlargement; (7) another function of IRE1 is the random splicing of mRNAs by RIDD to prevent further protein translation; (8) ATF6 homolog pathway. In plant cells, for example, Arabidopsis thaliana, the transcription factor AtbZIP17/28 is released from the ER and transported to the Golgi apparatus for proteolytic cleavage. The cleavage product bZIPs are then relocated to the nucleus, inducing the production of ER chaperones and foldases. (9) Under extreme situations, the cell may also choose a self-destructive pathway through autophagy or programmed cell death (PCD)

2002). Homologs for ATF6 have been identified and studied in various plant cells; for example, Arabidopsis thaliana genes AtbZIP17 (Liu et al. 2007a) and AtbZIP28 (Liu et al. 2007b) encode bZIP transcription factors that share similar functions and mechanisms to those of ATF6. Figure 2 illustrates the signaling pathway of bZIP17/28 in Arabidopsis. In healthy cells, BiP associates with the luminal domain of the bZIP17/ 28, therefore retains the transcription factors within the ER (Srivastava et al. 2013, 2014). Upon ER stress, however, BiP will be surrounded by loads of unfolded proteins, resulting in the release of bZIP17/28 from it and the exit of bZIP17/28 from the ER (Srivastava et al. 2014). Subsequently, bZIP17/28 is transported to the Golgi and cleaved by two subtilisin-like serine proteases, site-1 protease (S1P), and site-2 protease (S2P), which sequentially remove its ER luminal domain and the N-terminal bZIP domain (Liu et al. 2007a, b). The N-terminal domain so liberated becomes a functional bZIP transcription factor and enters the nucleus to induce transcription of stress-related genes (Howell 2013; Liu and Howell 2010; Tajima et al. 2008).

Although ATF6 and bZIP17/28 are functionally similar, differences do exist regarding their intracellular trafficking when exported from the ER. In mammalian cells, it has been reported that ATF6 molecules, without a tight association to BiP, are incorporated into COPII vesicles and actively transferred to the Golgi (Schindler and Schekman 2009; Zanetti et al. 2012). In contrast, how are COPII vesicles involved in the ER to Golgi trafficking of ATF6 homologs in plants are still debatable (daSilva et al. 2004; Hwang and Robinson 2009; Marti et al. 2010; Takeuchi et al. 2000; Yang et al. 2005). Intriguingly, researchers have detected a potential interaction between bZIP28 and Sar1, the GTPase recruited to the ER membrane during the activation step of COPII vesicle formation (Huang et al. 2001; Springer and Schekman 1998; Srivastava et al. 2012, 2014). According to Srivastava et al. (2012), the interaction between Sar1b and bZIP28, especially through its lysine-rich region on the N-terminus, was enhanced upon ER stress in Arabidopsis. Details of this interaction in response to ER stress are unknown,

S. Wan, L. Jiang Fig. 2 Arabidopsis bZIP17/28 signaling pathway. a bZIP17/28 is normally retained in the ER through its association with the ER chaperone BiP. Upon ER stress, BiP is requested by the unfolded proteins and releases the bZIP17/28. b bZIP17/28 exits the ER and is transported to the Golgi apparatus, a process possibly mediated by COPII vesicles. c Embedded into the Golgi membrane, the bZIP17/28 will be subsequently cleaved by S1P and S2P proteases, liberating the Nterminal active transcription factor to the cytosol. d With the exposed nuclear localization signal, freed bZIP17/28 is transported to the nucleus to induce biosynthesis of ER chaperones and foldases

except for the fact that Sar1 and the lysine-rich region of bZIP28 are facing the cytosol while the ER stress signals were derived from the ER lumen. How does the stress transducer process and deliver this signal from the Cterminus to its N-terminal domain remains to be resolved. As the activated transcription factor bZIP28 enters the nucleus, it will induce the transcription of a number of genes, which share a consensus element in their promoters, referred to as ER stress-response element 1 (ERSE1) (Liu and Howell 2010). One of the subelements of the ERSE1 with the sequence of CCACG is specifically recognized by bZIP28 dimers. Genes activated by AtbZIP28 are mainly ER-resident chaperones and foldases that can increase the assembly competence of the ER, so as to ease the ER stress (Liu and Howell 2010; Tajima et al. 2008). In most cases, AtbZIP17 and AtbZIP28 have identical functions and responses. For instance, they both respond to the ER stress agents TM and DTT (Deng et al. 2011; Liu et al. 2007b), as well as certain environmental stresses such as heat stress (Che et al. 2010; Gao et al. 2008; Mittler et al. 2012). However, researchers have discovered differences in the sensitivity to certain environmental stresses. For example, AtbZIP17 is activated under salt stress, and will activate genes like the homeodomain transcription factor ATHB-7, while AtbZIP28 is not involved in this activity (Liu et al. 2007a). Moreover, distinct levels of responses in cells from different tissues have been shown (Tajima et al. 2008). Further studies are needed to gain better understanding on this topic.

The IRE1 pathway As a primary stress sensor in yeasts, mammals, and plants, IRE1 is a type I ER membrane-spanning protein possessing an ER lumen-facing N-terminus and a C-terminus with enzymatic functions (Kaufman 1999; Koizumi et al. 2001; Shamu and Walter 1996; Tirasophon et al. 1998; Wang et al. 1998). Interestingly, IRE1 is an ER membrane protein with dual functions: as an endoribonuclease, it catalyzes mRNA splicing (Kawahara et al. 1997; Sidrauski and Walter 1997; Tirasophon et al. 1998; Yoshida et al. 2001); as a serine/ threonine protein kinase, IRE1 initiates autophosphorylation, forming oligomers that stably link to adjacent promoters through salt bridges, to improve its binding to nucleotides (Cox et al. 1993; Koizumi et al. 2001; Tirasophon et al. 1998). More importantly, IRE1 has two disparate signaling pathways: a canonical pathway regulating specific mRNA splicing for a transcription factor relevant to various stress genes, and an alternative pathway that randomly cleaves mRNAs to decrease biosynthesis (Walter and Ron 2011). IRE1-bZIP60 mRNA splicing pathway IRE1 normally exists in the ER membrane as an inactive monomer (Fig. 3a), but undergoes conformational changes especially oligomerization under stress conditions (Shamu and Walter 1996). Back-to-back dimerization is critical for the start of mRNA splicing (Lee et al. 2008; Niwa et al. 1999; Zhou et al. 2006), and further oligomerization of IRE1

ER stress and the UPR in plants

Fig. 3 AtIRE1 signaling pathway for AtbZIP60 splicing. a Inactive AtIRE1 monomer is a ER membrane stress sensor associated with BiP. Under stressed conditions, BiP is occupied by loads of unfolded proteins and detaches from the AtIRE1, exposing the luminal domain of AtIRE1 for unfolded proteins. b Unfolded proteins attached to the AtIRE1 serve as ligands to activate AtIRE1 dimerization, generating functional AtIRE1. Further oligomerization will enhance the enzymatic efficiency

of mRNA splicing. c AtIRE1 selectively recognizes and cleaves the unspliced bZIP60 mRNA, resulting in spliced bZIP60s mRNA that can be translated into active bZIP transcription factor. d Translocated to the ER, bZIP60 induces the production of ERAD components to accelerate the clearance of protein loads; it also leads to the expansion of the ER through upregulation of lipid synthesis and ER chaperone synthesis

correlates with the efficiency of splicing (Korennykh et al. 2009; Li et al. 2010; Shamu and Walter 1996). Moreover, through its kinase function, IRE1 conducts autophosphorylation to form front-to-front dimers, which will then oligomerize to a sizable IRE1 cluster (Fig. 3b) (Ali et al. 2011). Bypass of this process will not affect the normal splicing pathways of the IRE1, but the ultimate efficiency may not be achieved as this type of oligomerization will form salt bridges to adjacent promoters so as to improve IRE1nucleotide binding (Korennykh et al. 2009). Several hypotheses have been proposed in regard to the IRE1 stress-sensing process. The most prevailing hypothesis suggests that the release of IRE1 from BiP upon stress is the key to the initiation of configurational changes, and the ensuing binding of unfolded proteins directly to the IRE1 luminal domain triggers sufficient activation (Bertolotti et al. 2000; Gardner and Walter 2011; Hetz 2012; Kimata and Kohno 2011; Walter and Ron 2011). Although recent experimental results showing that IRE1 without the ER luminal part can still be activated has cast doubt on this explanation (Promlek et al. 2011). Future experiments are required to establish a new hypothesis. Plant homologs of IRE1 have been identified in organisms including A. thaliana, Oryza sativa, and Zea mays (Koizumi

et al. 2001; Li et al. 2012; Noh and Kwon 2002; Okushima et al. 2002), and some of these isoforms take responsibility for nonconventional mRNA splicing (Deng et al. 2011; Hayashi et al. 2012; Li et al. 2012; Lu et al. 2012; Moreno et al. 2012). We will choose A. thaliana as the model organism for further discussions. In the A. thaliana genome, AtIRE1a and AtIRE1b have been identified as genes encoding full-length IRE1 proteins (Koizumi et al. 2001), but only AtIRE1b is responsible for bZIP60 mRNA splicing. Under mild, short-term ER stress, AtIRE1b regulates unconventional mRNA splicing. In Arabidopsis, the target mRNA is AtbZIP60 (Iwata and Koizumi 2005b; Iwata et al. 2008; Nagashima et al. 2011), a homolog to the X-box binding protein 1 (XBP1) in mammals and HAC1 in yeasts (the similarities and differences among these homologs are summarized in Table 1). Unspliced bZIP60 mRNA folds into twin kissing loops, with three consensus bases on each loop (Deng et al. 2011; Oikawa et al. 2010). Functional IRE1 oligomers cut the mRNA in both loops at sites between a guanine (G) and a cytosine (C) residue, removing a 23 bases segment of mRNA that is supposed to encode a single transmembrane domain in the unspliced bZIP60 (Fig. 3c) (Deng et al. 2011). Also, frameshift leads to the activation of another open reading frame (ORF) so that two putative nuclear localization

S. Wan, L. Jiang Table 1

Comparison between IRE1 splicing targets in different organisms

Organisms

Splicing target

Required IRE1 isoform

Configuration of unspliced mRNA

Mammal

XBP1

IRE1a

Twin stem-loop

Plant

AtbZIP60

IRE1b

Yeast

HAC1

IRE1p

Nucleotide bases removed

Length of unspliced protein

Length of spliced protein

Ref.

26

261aa

376aa

(Tirasophon et al. 1998; Yoshida et al. 2001)

Twin stem-loop

23

295aa

258aa

(Deng et al. 2011; Nagashima et al. 2011)

Twin stem-loop

252

230aa

238aa

(Cox and Walter 1996; Kawahara et al. 1998; Mori et al. 1996)

signals are generated downstream from the splice site (Deng et al. 2011; Howell 2013). Thus, the translational product of spliced AtbZIP60 is a soluble transcription factor located to the nucleus. In mammals, spliced XBP1 will upregulate synthesis of lipids and ERAD components, so as to enlarge the ER and accelerate the clearance of unfolded proteins from the ER (Schröder and Kaufman 2005a). Its Arabidopsis homolog AtbZIP60 also has a significant role to play in upregulating genes under ER stress (Fig. 3d). Genes induced by bZIP60 are involved in protein folding (Deng et al. 2011), transport, secretion, and degradation (Iwata et al. 2008). As demonstrated by Sun et al. (2013a), AtbZIP60 recognizes the promoters of the NAC103 transcription factor that activates ER resident chaperones and foldases such as CRT1, CNX, and PDI-5. As a matter of fact, the NAC family (NAM, ATAF1/2, CUC2) contains a large volume of plant-specific transcription factors (Olsen et al. 2005), with at least 117 downstream target genes in Arabidopsis and 151 targets in rice (Nuruzzaman et al. 2010). By upregulating members of the NAC transcription factor family, AtbZIP60 is able to induce extensive gene expression.

the cytosolic exosome. It is believed that such a mechanism is possibly controlled by higher-order oligomerization (Korennykh et al. 2009). RIDD in mammals is directly related to IRE1a and always leads to apoptosis (Chen and Brandizzi 2013). Plant gene expression studies demonstrated that a significant portion of the genes encoding secretory pathway proteins are downregulated following the orders from IRE1a and IRE1b, implying an potential RIDD mechanism in plants (Kamauchi et al. 2005; Martinez and Chrispeels 2003). Furthermore, with the help of transcriptome analyses on Arabidopsis, a recent study has provided significant evidence testifying to the occurrence of plant RIDD upon heat stress or ER stressor TM (Mishiba et al. 2013). It was reported that under intense ER stress, a considerable amount of mRNAs encoding secretory pathway proteins was degraded, in a IRE1-dependent manner, but was irrelevant to bZIP60 splicing (Mishiba et al. 2013). Such a mechanism prevents the entrance of mRNA into the ER, hence reduces the secretory protein translation rate. However, whether RIDD is a cytoprotective strategy or a pro-apoptosis decision in plants remain to be studied. Further research is expected to illustrate the physiological significance of plant RIDD in cell fate determination, as has been shown in mammals (Chen and Brandizzi 2013).

IRE1-RIDD pathway Under irreversible ER stress, another IRE1 signaling pathway termed RIDD will be triggered to rapidly degrade diverse mRNAs (Fig. 4) (Chen and Brandizzi 2013; Mishiba et al. 2013; Walter and Ron 2011). Many scientists believe that this is to limit the rate of further protein influx into the ER and subsequent protein synthesis (Mishiba et al. 2013); however, others state that it is to further enhance the intensity of the ER stress and lead to cell death, because it in a way counteracts the upregulation of stress genes (Chen and Brandizzi 2013). This mechanism was first discovered in metazoans (Hollien and Weissman 2006; Hollien et al. 2009), where the splicing targets of IRE1 switch from specific XBP1 mRNAs to diverse mRNAs relevant to the secretory pathway. ERbound mRNAs are first randomly degraded by the RNase function of IRE1, then subjected to exonucleolytic decay by

Comparison between the two types of UPR in plants Selective activation and attenuation of ER stress transducer signaling bZIP17/28 and IRE1 are ER-membrane-associated ER stress sensors with distinct gene structures (Fig. 5), and therefore different operating mechanisms. The initiation of the bZIP17/28 and IRE1 signaling pathways has been extensively studied, with various theories proposed attempting to correlate them. Early research on mammals suggested that the ATF6 pathway would always be activated first (Yoshida et al. 2003). This was then disproved by scientists who discovered that different stress sensors have different sensitivities to different situations of ER stress (DuRose et al. 2006). For example,

ER stress and the UPR in plants Fig. 4 IRE1-RIDD pathway. Under prolonged and intense ER stress, the IRE1 tend to splice mRNA randomly, to restrict nascent protein influx into the ER. This mainly depends on the endoribonuclease functions of the IRE1

IRE1 is sensitive to reducing agents and disturbed ER calcium homeostasis (DuRose et al. 2006; Hetz 2012), while ATF6 homologs tend to be easily activated by ER membrane protein loads (Maiuolo et al. 2011). Generally, distinct sensitivities reflect their peculiar mechanisms of detecting ER stress. On the other hand, the attenuation of these signaling pathways after being activated also differs from each other: The IRE1 response attenuates quickly despite the persistence of the stress, whereas activities of ATF6 homologs decrease relatively slowly (Lin et al. 2007). According to research on IRE1 kinase, IRE1 kinase function is vital to the prompt attenuation of the signaling pathway, without which the stress sensor would be continuously activated even if the ER stress is eliminated (Walter and Ron 2011).

mRNA splicing, and (2) translational suppression, including the IRE1-RIDD and PERK pathways that is missing in plants (Howell 2013; Walter and Ron 2011). There are three major differences between these two categories: (1) transcriptional regulations aim to accelerate protein folding and elimination, while translational suppressions tend to prevent further protein biosynthesis; (2) transcriptional regulations can be activated under mild ER stress, while translational suppressions are evoked under intense or prolonged ER stress; and (3) transcriptional regulations exert a global effect, while translational suppressions are usually restricted to local areas.

Consequences of inadequate UPR

As mentioned before, UPR pathways can be classified into two categories: (1) transcriptional regulation, including the ATF6 homologs pathway and IRE1-depedent unconventional

Even though diverse UPR pathways seem to be vigorous, in extreme circumstances, they may not be capable of restoring ER homeostasis. In this case, as a last resort, plant cells may conduct autophagy to remove the ER to ease the burden of the protein loads within the cell as well as to recycle materials (Howell 2013; Liu and Bassham 2012; Liu et al. 2012).

Fig. 5 Gene structures of AtbZIP17/28 and AtIRE1. a bZIP17/28 is a type II ER membrane protein, with a bZIP molecule on its N-terminal cytosolic tail, and a C-terminal ER luminal domain. b IRE1 is a type I ER membrane protein, with the catalytic RNase and kinase on its C-terminal

cytosolic tail, and a bulky ER luminal domain on its N-terminus. TAD transcriptional activation domain, bZIP basic leucine zipper, PRD proline-rich domain, TMD transmembrane domain, S1P and S2P are two Golgi-resident proteases

Transcriptional and translational regulations

S. Wan, L. Jiang

Otherwise, plant cells can simply give up self-rescue attempts and go over to programmed cell death (Ruberti and Brandizzi 2014; Williams et al. 2014). Autophagy Autophagy, conserved in all eukaryotes, refers to the bulk degradation of cytoplasmic components, whole organelles or pieces thereof. It involves the formation of double-membrane autophagosomes, which then convey their contents to the lysosomes in metazoans, or the vacuole in yeast and plants. In these lytic organelles, the contents and the inner membrane of the autophagosome are degraded, and recycling of the macromolecules initiated (Bassham 2007; Liu and Bassham 2012; Mehrpour et al. 2010; Yang and Klionsky 2009; Zhuang et al. 2013; Zhuang and Jiang 2014). ER-stress-induced autophagy has been reported in yeasts and mammalian cells (Bernales et al. 2006; Deegan et al. 2013; Ogata et al. 2006), as well as in plants (Liu et al. 2012). The endomembrane system was shown to crosstalk with the autophagic pathway in mediating vacuolar degradation in plants (Gao et al. 2014, 2015; Zhao et al. 2015). ER-stress-induced autophagy is related to IRE1, but is regulated through distinct pathways. In yeasts, autophagosome formation requires a group of autophagy-related proteins (Atg), the most important member of which is a ubiquitinlike protein, Atg8p, whose biosynthesis is triggered by the IRE1 splicing of HAC1 (Yorimitsu et al. 2006). In other words, autophagy in yeasts depends on the RNase activity of the IRE1. On the contrary, autophagy in metazoans relies on the kinase function of IRE1, which activates the c-Jun N-terminal kinase (JNK) pathway and thus induces the formation of autophagosomes (Ogata et al. 2006; Pattingre et al. 2009). Additionally, the PERK-CHOP pathway in mammals can also modulate the formation of autophagosomes as a parallel mechanism (B’chir et al. 2013; Saitsu et al. 2013). ER-stress-related autophagy in plants has been recently studied using the ER stress agents TM and DTT, leading to a conclusion that an IRE1b isoform is critical to the activation of autophagosome generation (Liu et al. 2012). As previously discussed, IRE1b in plants is responsible for bZIP60 mRNA splicing, but its role in autophagy activation is irrelevant to the specific splicing of bZIP60 (Liu et al. 2012). Though the molecular mechanism of IRE1b in autophagy in terms of its precedent regulators and subsequent targets is largely unknown, the fact that bZIP60 splicing by IRE1b is important to autophagy indicates that IRE1b may possess alternative RNase cleavage targets or potential kinase functions which are significant to autophagy initiation (Howell 2013; Liu and Bassham 2012; Liu et al. 2012). Similar to yeast, plants have a set of ATG genes, encoding proteins that are recruited to autophagosomes. Among them, ATG8 is probably the most significant and has been used as an autophagy marker in plants

(Howell 2013; Liu and Bassham 2012). For example, nine isoforms of the ATG8 genes have been discovered in A r a b i d o p s i s , f o r m i n g a u b i q u i t i n - l i k e , AT G 8 – phosphatidylethenolamine (ATG8–PE) conjugating system for autophagosome assembly (Liu and Bassham 2012). According to Liu et al. (2012), after the initiation of the autophagy in plants, portions of the ER become engulfed by the autophagosome, then delivered to and degraded in the vacuole. Unlike autophagy induced by senescence or nutrient deprivation, the substrate of ER-stress-related autophagy is ER itself, which may manipulate ER turnover under ER stress. A further study on salicylic acid (SA)-dependent ER stress and autophagy has revealed that autophagy deficiency may lead to enhanced ER stress, indicating the importance of autophagy (Munch et al. 2014).

Programmed cell death Beyond autophagy, programmed cell death (PCD) can also occur in plants and is similar to apoptosis in mammalian cells despite the fact that plant cell walls prevent the cells from being degraded by adjacent cells (Lam 2004; van Doorn and Woltering 2005). PCD in plants is also called vacuolar cell death, since vacuolar processing enzymes (VPEs) will ultimately induce the rupture of the tonoplast and the release of vacuolar hydrolytic enzymes, setting off a path of no return (Van Doorn et al. 2011). In mammals, cysteine-dependent aspartate-specific proteases (caspases) are the major enzymes required for apoptosis (Taylor et al. 2008); similarly, several proteases with caspaselike cleavage activity have been identified in plants as PCDrelated enzymes (Cai et al. 2014; Williams et al. 2014). Growing evidence suggest that these proteases are implicated in ER-stress-induced PCD in plants (Costa et al. 2008; Zuppini et al. 2004). One of such experiment involves soybean suspension cells experiencing ER stress caused by cyclopiazonic acid (CPA), where caspase-3-like and caspase-9-like activities are detected during ER stress-induced PCD, promoting DNA fragmentation (Zuppini et al. 2004). Research on soybeans has also revealed that overexpression of asparagine rich proteins (NRPs) would induce the NAC transcription factor GmNAC81, resulting in UPR and increased caspase-1-like and caspase-3-like activities (Costa et al. 2008; Reis and Fontes 2012). According to Hatsugai et al. (2004), caspase1-like activities are conveyed by the plant VPEs that reside in the vacuole and control tonoplast rupture. Further research on such soybean transcription factors has revealed that under TM-induced ER stress, GmNAC30 and GmNAC81 transcript levels were elevated, synergistically activating VPE gene expression (Mendes et al. 2013). Future studies on these PCDrelated enzymes will provide us with a better understanding of plant PCD.

ER stress and the UPR in plants

Switch between autophagy and PCD The connection between autophagy and PCD has long been investigated, generating plenty of evidence that support two contradictory hypotheses—whether autophagy is a prosurvival or a pro-destructive reaction (Hofius et al. 2009, 2011; Williams et al. 2014). In plants, the autophagy-related Bcl-2 family contains both pro-apoptotic proteins like BAX and antiapoptotic proteins like Bcl-2 (Adams and Cory 1998; Gross et al. 1999), which can be differentiated by 1-4 Bcl-2 homology domains (BH domains) (Adams and Cory 1998). Among them, BH3 seems to govern the balance between the pro-survival and pro-death bifurcation of autophagy (Williams et al. 2014). Nevertheless, future experiments on ERstress-induced autophagy and PCD are required to deepen our understanding of the transition from ER-stress-induced autophagy to PCD pathway.

Conclusion and future perspective Under biotic or abiotic stresses, the protein factory function of the ER becomes overloaded with nascent proteins, leading to a baffled ERQC system. To restore ER homeostasis and recreate a harmonious intracellular environment, UPR is launched either to increase the competence of protein folding and protein clearance, or to decrease the protein synthesis rate. In plant cells, two ER stress transducing pathways have been identified and studied involving the ER membrane-bounded stress sensors bZIP17/28 and IRE1. Under mild stress conditions, bZIP17/28 aims to upregulate genes encoding ER-resident chaperones and foldases, whereas IRE1 modulates the specific splicing of bZIP60 to upregulate stress-response genes. Upon prolonged and intense ER stress, the IRE1-RIDD pathway will be initiated to randomly cleave mRNAs attached to the ER membrane, reducing their influx and preventing further protein synthesis. If all these UPR pathways are incapable of stabling and eliminating the ER stress, autophagy or programmed cell death may result. Compared to other organisms, the complexity of the UPR systems in plants are adequate but moderate, as the PERKCHOP pathway of mammalian cells is missing in plants. Whether the PERK branch exists in plants is in itself an interesting topic. Additionally, there are still some missing details regarding the molecular mechanisms of UPR in plants, such as the signal transfer from the ER lumen to the cytosolic side of the bZIP17/28 stress sensor. Other topics worth investigating involve cell fate determination upon ER stress. For instance, how does the IRE1 know when to switch from unconventional splicing to RIDD? What defines the turning point that determines whether cells switch on the autophagy or even PCD pathway? Through a better knowledge of UPR, it is conceivable that innovative plant biotechnology platforms can be

invented to protect plants, especially crop plants, from adverse environmental problems. ER is the starting point of the endomembrane system containing several other functionally distinct organelles including Golgi apparatus, trans-Golgi network (TGN), prevacuolar compartment (PVC) or multivesicular body (MVB), and vacuole in plant cells, our recent studies indicate that both ER stress and UPR may play roles in regulating the function and turnover of these organelles in plants, and it will be of interest in future research to study the crosstalk between the endomembrane system and the autophagic pathways in plants (Gao et al. 2015; Zhao et al. 2015). Acknowledgments This review article is developed from Literature Review of a Final Year Project of MBT Program of School of Life Sciences. Research in our Laboratory has been supported by grants from the Research Grants Council of Hong Kong (CUHK466613, CUHK2/CRF/ 11G, C4011-14R, and AoE/M-05/12) and NSFC (31470294). Conflicts of interest The author’s declare that they have no competing interests.

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