Acta Biochim Biophys Sin, 2015, 47(8), 571–580 doi: 10.1093/abbs/gmv055 Advance Access Publication Date: 25 June 2015 Review

Review

The receptor proteins: pivotal roles in selective autophagy Zhijie Xu1,2,3, Lifang Yang1,2,3,*, San Xu1,2,3, Zhibao Zhang1,2,3, and Ya Cao1,2,3 1

*Correspondence address. Tel: +86-731-84805448; Fax: +86-731-84470589; E-mail: [email protected] Received 5 January 2015; Accepted 30 March 2015

Abstract Autophagy is a highly regulated and multistep biological process whereby cells under metabolic, proteotoxic, or other stresses remove dysfunctional organelles and/or misfolded/polyubiquitinated proteins by shuttling them via specialized structures called autophagosomes to the lysosome for degradation. Although autophagy is generally considered to be a non-selective process, accumulating evidence suggests that it can also selectively degrade specific target cargoes. These selective targets include proteins, mitochondria, and even invading bacteria. The discovery and characterization of autophagic adapters, such as p62/Sequestosome 1 (SQSTM1) and Neighbor of BRCA1 gene 1 (NBR1), have provided mechanistic insights into selective autophagy. These receptors are all able to act as cargo receptors for the degradation of ubiquitinated substrates. This review mainly summarizes the most up-to-date findings regarding the key receptor proteins that play important roles in regulating selective autophagy. Key words: autophagy, selective, receptor proteins

Introduction The term ‘autophagy’, which is derived from the Greek words ‘auto’ and ‘phagy’ meaning ‘self’ and ‘eating’, was coined by de Duve in 1963 to describe an evolutionarily conserved process of the degradation of a cell’s components through its own lysosomal machinery [1]. Since then, it has been characterized as an adaptive catabolic process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more essential ones. Depending on the route of delivery to the lysosome, three different types of autophagy are defined: microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy [2,3]. Microautophagy participates in the direct engulfment of cytoplasm at the lysosomal surface, whereas CMA translocates unfolded, soluble proteins directly across the limiting

membrane of the lysosome. However, during macroautophagy, or bulk autophagy, intact organelles (such as the endoplasmic reticulum) and portions of the cytosol are sequestered into a double-membrane vesicle, named an autophagosome (AP). Subsequently, the completed AP matures by fusing with an endosome and/or lysosome, therefore forming an autolysosome (AL). This latter step exposes the cargo to lysosomal hydrolases to allow its breakdown, and the resulting macromolecules are transported back into the cytosol through membrane permeases for rescue [4,5]. Although APs can sequester cytosolic material non-specifically, there is proof for selective autophagic degradation of various cellular structures. Selective autophagy is a specific type of autophagy that specifically targets protein aggregates, organelles, and even intracellular pathogens [6–9]. Thus, selective autophagy plays a different role in addressing specific biological or pathological concerns. Although the mechanism of selective autophagy is not well understood, the

© The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. 571

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Cancer Research Institute, Central South University, Changsha 410078, China, 2Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha 410078, China, and 3Key Laboratory of Carcinogenesis, Ministry of Health, Changsha 410078, China

572 molecular basis undoubtedly depends on receptor proteins, such as p62/Sequestosome 1 (SQSTM1), which are able to link autophagy targets to the autophagosomal membranes [10,11]. Here, we summarize the most up-to-date findings regarding how selective autophagy is executed and regulated at the molecular level and how its disruption can lead to disease.

Selective Autophagy

p62/SQSTM1 Human p62/SQSTM1 is a multidomain scaffold protein. It comprises an N-terminal Phox and Bem1p domain (PB1, residues 20–102), required for self-oligomerization and binding to other PB1-domain proteins, a ZZ-type zinc finger domain (Zinc, residues 122–167), an LC3-recognition sequence (LRS, residues 335–345), a Keap1-interacting region (KIR, residues 346–359), and a C-terminal region encompassing a UBA domain (residues 391–436) (Fig. 2) [21,22]. Moreover, the Drosophila p62 homolog, refractory to sigma P (Ref(2)P), is also known based on its implicated roles in sigma rhabdovirus multiplication. The protein product encoded by Ref(2)P shows a domain structure similar to human p62 [23]. Interestingly, tobacco Joka2 protein, a hybrid homolog of p62 and NBR1, has two non-identical UBA domains, whereas p62 contains only one UBA domain [24]. p62/SQSTM1 is a selective substrate of autophagy, and aberrant accumulation of p62 has been observed under various pathological conditions. The intracellular level of p62 is tightly regulated by autophagy. Under physiological conditions, the p62 is incorporated into the AP and then degraded. However, under certain pathological conditions, impaired autophagy leads to the accumulation of p62-ubiquitinated protein complexes, ultimately leading to the formation of inclusion bodies that presumably contribute to the segregation of harmful and unnecessary proteins within the cells. The p62 is sorted to autophagic degradation through a mechanism of LC3 interaction and self-oligomerization. Ichimura et al. [25] reported that there are a series of salt bridges and hydrogen bonds between p62 and LC3. The hydrophobic (Trp340–Leu343) and acidic cluster (Asp337– Asp339) of p62 are very important for LC3 binding, and these motifs are conserved across species. Disruption of the p62–LC3 interaction alone is sufficient to impair the degradation of p62, resulting in the formation of ubiquitin- and p62-positive inclusions. In addition to its LC3 interactions, the self-oligomerization of p62 via its PB1 domain is required for its effective degradation by autophagy. When compared with wild-type p62, p62 that has been mutated in the PB1 region undergoes a significantly delayed degradation. There is increasing evidence that p62 can act as a cargo receptor for selective autophagy of ubiquitinated substrates (Fig. 3), which play very different roles in cellular processes, ranging from membrane trafficking to DNA repair [26]. Cell stress and infection promote the formation of ubiquitinated aggregates. These ubiquitinated structures can be recognized by the autophagy receptor, p62, and then targeted for autophagic degradation by interactions of p62 with both ubiquitin chains and LC3. At least, two modifications, ubiquitination and oligomer formation, have been proposed to serve as cis-acting signals to

Figure 1. Different cargo-binding concepts of selective autophagy receptors, which depend on the interaction with ATG8 The gray shapes indicate cargoes, and the light blue shapes indicate selective autophagy receptors.

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Selective autophagy is the targeted recognition and degradation of substrates. A number of specific proteins, the so-called autophagy receptors, play a key role in both the recognition and the delivery of cytoplasmic contents. Autophagy receptors can be grouped on the basis of their specific cargo-binding domains, which cover proteinspecific binding domains, ubiquitin (Ub)-specific binding (UBA) domains, and transmembrane (TM) domains [12]. Once cargoes are bound by the autophagy receptors, their subsequent delivery to the AP membrane is mainly mediated by the interactions among the cargo-specific autophagy receptor protein, autophagy-related protein 8 (ATG8) of the ubiquitin-like (Ubl) family, and membranes (Fig. 1) [13,14]. In mammalian organisms, for example, autophagic clearance of cytosolic ubiquitinated substrates or aggregate-prone proteins is mediated by autophagy cargo adaptors p62 and NBR1 (Neighbor of BRCA1 gene 1), which bind ubiquitinated proteins via their C-terminal ubiquitin-associated (UBA) domains and the mammalian ATG8 homolog, LC3 (microtubule-associated protein 1 light chain 3), via the LIR (LC3-interacting region) motifs [15]. Several possible mechanisms of selective autophagy are as follows. First, p62/SQSTM1 is specifically phosphorylated by casein kinase 2 (CK2) at serine 403 (Ser403) in its UBA domain. Secondly, optineurin (OPTN) is phosphorylated by the protein kinase TANK binding kinase 1 (TBK1) at serine 177 (Ser177), which precedes the hydrophobic core sequence of the microtubule-associated protein 1 light chain 3 (MAP1LC3/LC3) interaction region (LIR) motif (W/YXXL/I). The phosphorylation of p62 and OPTN can enhance their respective ATG8 binding affinities and increase autophagic clearance of ubiquitinated proteins [16,17]. Finally, several other adapters, such as NIX and NDP52, are also implicated in selective autophagy, facilitating cargo-receptor-ATG8 complex assembly [18,19]. In addition, some emerging receptors, such as tectonin β-propeller repeat-containing protein 1 (Tecpr1), may also induce selective autophagy, but may have no association with the ATG8 complex [20]. The fundamental characteristics of each receptor would be described more in detail in the following sections.

Receptor proteins in selective autophagy

Receptor proteins in selective autophagy

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Figure 2. Schematic depicting the domains of the selective autophagy receptors The UBA domain binds ubiquitylated targets, and the LRS domain binds ATG8 on APs. TM indicates the transmembrane domain. Other domains are well explained in the relevant sections.

promote this process. Riley et al. [27] proposed that the protein oligomerization drives autophagic substrate selection and that the accumulation of poly-Ub chains in autophagy-deficient circumstances is an indirect consequence of the activation of the nuclear E2-related factor 2 (Nrf2)-dependent stress response pathway. Suppression of autophagy is always accompanied by a marked accumulation of p62. Then, p62 interacts with the Nrf2-binding site on Keap1 (Kelch-like ECH-associated protein 1), a Cullin 3-based ubiquitin ligase adapter, causing competitive inhibition of the Nrf2–Keap1 interaction. The binding of p62 to Keap1 further leads to Nrf2 stabilization and increased translocation to the nucleus. Consequently, the Nrf2dependent genes, including the genes directly affecting ubiquitin metabolism, are transcriptionally activated. This cellular process may cause tumorigenesis associated with chronic inflammation, blockade of mitochondrial activity, and genome instability [28]. However, in

the non-small-cell lung cancer cases analyzed by Inoue et al. [29], accumulated p62 does not necessarily result in the stabilization of Nrf2, which implies that other factors accompanying increased p62 may influence Nrf2 stabilization. In addition, in a physiological innate immune response to TLR4 (toll-like receptor 4) re-stimulation, treatment with either Escherichia coli or lipopolysaccharide leads to an increased level of p62, the induction of aggresome-like structure (ALIS) formation, and the autophagic degradation of those structures. Nrf2 activation, mediated by p38 and reactive oxygen species (ROS), contributes to this progress. These findings suggest that p62 plays an essential role in the formation and degradation of ALIS, which might be critical for regulating host innate immunity [30,31]. Furthermore, blood cell recruitment to larval wound sites and cell spreading in mouse macrophages both require ref(2)P, the Drosophila p62 multi-adaptor, suggesting p62-selective autophagy as an additional mechanism

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Receptor proteins in selective autophagy

regulating immune cell function [32]. Although infection can promote the formation of ALIS and other ubiquitinated protein aggregates and cause host immune response, the effector of the Salmonella pathogenicity island-2-encoded type 3 secretion system (T3SS), SseL, can deubiquitinate these aggregates and prevent the recruitment of p62 and LC3, leading to a reduction in autophagic flux during infection and promoting intracellular bacterial replication [33]. It is becoming apparent that not only specific protein aggregates and pathogens but also organelles can be selectively targeted for autophagic degradation via p62. Grasso et al. [34] described a new type of selective autophagy, named zymophagy, which is activated in pancreatic acinar cells during pancreatitis-induced alterations in vesicular transport. Hyperstimulation of cholecystokinin receptors (CCK-R) induces zymophagy to degrade activated zymogen granules, preventing the release of their contents into the cytoplasm and thus averting further trypsinogen activation and cell death. The ubiquitinbinding protein p62 may act as an important cargo receptor in this selective autophagy pathway. When compared with treated wild-type mice, p62 displays a progressive reduction in treated ELAI-VMP1 transgenic mice, in which acinar cells constitutionally express an autophagy-related vacuole membrane protein 1 (VMP1)-EGFP chimera [34]. In addition, Narendra et al. [35] demonstrated that p62 mediates the aggregation of dysfunctional mitochondria through polymerization via its PB1 domain, following the translocation of Parkin, an E3 ubiquitin ligase, from the cytosol to the mitochondria. The endogenous p62 can mediate the aggregation of depolarized mitochondria expressing Parkin. Surprisingly, p62 appears to mediate mitochondrial clumping but not mitophagy [35]. Additionally, p62 is an important adaptor protein for several signaling pathways that regulate important processes including apoptosis, stress response, and cell growth. As autophagy has been characterized as an adaptive catabolic process that plays a normal role in cell growth, development, and homeostasis, these signaling pathways might be involved in the selective autophagy via modulating p62. First, p62 is essential for Ras to trigger nuclear factor-κB (NF-κB) activation through the polyubiquitination of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which promotes cell

The p62 may be involved in the selective

survival by reducing ROS levels and c-Jun N-terminal kinase activity. A lack of p62 impairs NF-κB activation in Ras-transformed cells, leading to higher ROS levels and increased cell death. Interestingly, the activator protein-1 enhancer element in nucleotides −1808 to −1732 of the p62 promoter is necessary for Ras to induce p62 activity. Furthermore, p62 is induced by Ras at the mRNA and protein levels through an extracellular regulated protein kinase and protein kinase B (Akt)-dependent pathway [36]. The persistence of p62 is sufficient to alter NF-κB regulation and gene expression, promoting tumorigenesis and progression [37]. Secondly, p62 is a bona fide target gene of the Farnesoid X receptor (FXR). It is possible that FXR regulates the expression of p62 in order to maintain cellular homeostasis, regulate the inflammatory response, and conduct tissue repair. However, the activation of FXR only induces the expression of p62 mRNA and protein in the ileum but not in the liver, which suggests a complex regulation of p62 by FXR in a tissue-specific manner. In addition, p62 also activates caspase-8 to initiate apoptosis [38]. Thirdly, enhancing mechanistic target of rapamycin (serine/threonine kinase) (mTOR) signaling by overexpression of its activator Ras homolog enriched in brain (Rheb) or knockout of the Rheb inhibitor tuberous sclerosis 2 (Tsc2) can increase the p62 dot number [39]. The phenomenon of p62 overexpression is associated with tumors, at least partially due to defective autophagy [37]. Moreover, p62 levels are strongly influenced by basal autophagic activity. To estimate the actual level of the specific autophagy substrate p62, the current detection methods will require improvement. In a comparison of different experimental approaches, Pircs et al. [39] found that the most widely used method, western blot, can detect endogenous p62 levels and distinguish the soluble and aggregated forms. However, western blot is not feasible in studies of genetic mosaic animals. Immunostaining can provide additional information, including the number, size, and intracellular distribution.

NIX In cell biology, mitochondria generate most of the cell’s supply of adenosine triphosphate (ATP), which is used as a source of chemical

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Figure 3. Model of p62 functioning as a cargo receptor for the selective autophagy of ubiquitinated substrates autophagic/lysosomal pathway by sequestering aggregated proteins prior to their inclusion in APs.

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Receptor proteins in selective autophagy

NDP52 NDP52, originally identified as a component of nuclear promyelocytic leukemia bodies, is a main cytosolic protein that binds to myosin VI and is ubiquitously expressed in various tissues and cells. Human NDP52 comprises an N-terminal skeletal muscle and kidney-enriched inositol phosphatase carboxyl homology domain (amino acids 1–127), an intermediate coiled-coil (CC) domain with a leucine zipper sequence (amino acids 134–350), and a C-terminal Lin11, Isl-1, and Mec-3-like domain (amino acids 395–446) that consists of two zinc fingers (Fig. 2). All these domains are conserved in humans, bovines, dogs, and so on [19,43]. Thurston et al. [19] reported that NDP52 functions as a receptor that recognizes ubiquitinated bacteria and restricts their growth in a selective autophagy-dependent manner. NDP52 is a component of a TBK1 signaling complex. It can directly bind to ubiquitinated bacteria and facilitate the assembly of an autophagic membrane that surrounds these invaders. Both the total number of bacteria and the number of ubiquitin-positive bacteria increase in infected cells expressing NDP52-specific siRNA. Moreover, it has been found that NDP52 and LC3 co-localize around cytosolic ubiquitinated bacteria [44]. These results suggest that NDP52 is an autophagy receptor that detects ubiquitin-coated bacteria and directs the bacteria into APs by simultaneously binding LC3. Alternatively, p62 and NDP52 may regulate autophagy through the recruitment of the signaling complexes in which they coordinate. Cemma et al. [45] found that, even though both p62 and NDP52 are recruited to the same bacteria at the same time, they are independent of one another and do not function in the same pathway, which indicates that these two receptors bring unique components necessary to drive ubiquitin-dependent antibacterial autophagy. In addition, the autophagy receptor NDP52 works downstream of TLR adaptors to negatively regulate TLR signaling. NDP52 mediates selective autophagic degradation of TRAF6, an E3 ubiquitin ligase, and Toll/interleukin-1 receptor homology domain-containing

adaptor-inducing interferon (TRIF). This process may lead to the suppression of TLR- and TRAF6-mediated NF-κB activation. However, this effect can be inhibited by the autophagy inhibitor 3-methyladenine. The ubiquitin-editing enzyme A20, also known as TNFAIP3, could also downregulate the activity of NDP52 through the suppression of poly-Ub by TRAF6 [43].

NBR1 NBR1 is a protein commonly found in ubiquitin-positive inclusions in neurodegenerative diseases. Similar to mammalian autophagy receptor p62, NBR1 also contains an N-terminal PB1 domain (residues 5–85), a Zinc domain (residues 215–259), and a C-terminal UBA domain (residues 913–959). In addition, two LRS domains (LRS1, residues 540–636 and LRS2, residues 727–738) have been found in NBR1. But LRS2 does not have the core consensus motif W/YXXL/I, most likely representing a novel type of LC3-interacting sequence (Fig. 2) [46]. The role of NBR1 is mainly dependent on its interaction with ATG8 [47]. Due to the high architectural similarity between NBR1 and p62, both p62 and NBR1 have been reported to act cooperatively to target polyubiquitylated aggregates and whole organelles, including peroxisomes, to be selectively degraded [48,49]. Unexpectedly, Walinda et al. [50] found that NBR1 differs from p62 in its UBA structure and accordingly in its interaction with ubiquitin. These differences result in a much higher affinity of NBR1 for ubiquitin than p62. Moreover, substrate selectivity is partly achieved by NBR1 itself by coincident binding of the J and UBA domains [49]. Using yeast two-hybrid screens, Zhou et al. [51] isolated Arabidopsis thaliana NBR1, the first plant autophagy receptor, a homolog of mammalian NBR1, and reported that NBR1-mediated autophagy targets most likely derived from denatured or otherwise damaged non-native proteins generated under stress conditions. Under stress conditions, NBR1 and CHIP (C-terminus of the Hsc70-interacting protein), a chaperone-associated E3 ubiquitin ligase, mediate two distinct but complementary pathways in anti-proteotoxic and protein’s propensity to aggregate [52].

OPTN OPTN/optineurin is a recently identified autophagy receptor, characterized by its ability to bind ubiquitin via its ubiquitin binding in ABIN (A20 binding and inhibitor of NF-κB) and NEMO (NF-κB essential modulator) (UBAN) domain and ATG8 via its LRS domain (Fig. 2) [53]. A more recent study reported that TBK1 is found to act as an upstream regulator of autophagy by phosphorylating OPTN on Ser177 and enhancing its interaction of LC3, which promotes the selective autophagic clearance of cytosolic Salmonella [17]. The structures show that the negative change induced by phosphorylation is recognized by the side chain of Arg11 and Lys51 in LC3B [54]. Notably, many known autophagy receptors contain conserved serine residues adjacent to their LRS, including NIX and NBR1, indicating that phosphorylation might be a general mechanism of regulation of selective autophagy. In addition, in mitophagy, Wong and Holzbaur [55] used live cell imaging to demonstrate that OPTN is actively recruited to Parkinlabeled ubiquitinated mitochondria and is stabilized by its ubiquitinbinding domain. OPTN binds the AP protein LC3, and this binding induces AP assembly around damaged mitochondria. Depletion of

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energy. However, these organelles also produce cellular ROS, which may result in significant damage to cell structures, especially to the mitochondria themselves. For this reason, it is crucial to eliminate damaged or excess mitochondria to maintain cellular homeostasis. Several lines of evidence support selective autophagy of mitochondria (mitophagy) as the primary mechanism for the elimination of such organelles [40]. NIX/BNIP3L (BCL2/adenovirus E1B 19 kDa interacting protein 3-like), a BH3-only member of the Bcl-2 family, is a mitochondrial outer membrane protein that is indispensable for the degradation of erythrocyte mitochondria [41]. Mitochondrial protein NIX functions as an autophagy receptor, which can bind to LC3 through its LRS domain (amino acids 35–38) (Fig. 2). After treatment with carbonyl cyanide m-chlorophenylhydrazone (CCCP) or rotenone, mitochondrial poisons, NIX can mediate the clearance of damaged mitochondria. However, mutation of the LRS domain has a partial effect on NIX-mediated mitochondrial clearance in vivo, indicating that other properties of NIX also participate in this progress [18]. In NIX−/− mice, erythrocytes in the peripheral blood exhibit significant mitochondrial retention, accompanied by spontaneous caspase activation. However, contrasting results have shown that depolarizing mitochondria with uncoupling chemicals or BH3 mimetics can restore the sequestration of mitochondria into APs, even in NIX−/− erythroid cells [42]. Thus, it will be important to fully understand the role of NIX in mitophagy.

576 endogenous OPTN or E478G OPTN mutation inhibits LC3 recruitment to mitochondria and inhibits mitochondria degradation, causative for amyotrophic lateral sclerosis (ALS) and glaucoma. With respect to the interplay of OPTN with other ALS-associated autophagy receptors, OPTN is reported to functionally interact with p62. Liu et al. [56] found that tumor-suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN on lysine 193 (Lys193) and promotes its interaction with p62 to form the autophagy receptor complex, thus accelerating autophagic flux. Interestingly, p62 and OPTN have also been observed to localize to separate subdomains on ubiquitinated Salmonella, suggesting that p62 and OPTN may also play distinct roles in selective autophagy. As OPTN and NDP52 are found to be located on common subdomains on ubiquitinated Salmonella, it would provide further insights as to whether these autophagy receptors have similar roles in selective autophagy [17].

Receptor proteins in selective autophagy phagophores. Additionally, Tecpr1 interacts with a yeast ATG18 homolog and phosphatidylinositol 3 phosphate (Ptdlns(3)P)-interacting protein, WIPI2, before collocating to phagophores. When Tecpr1 was knocked down by siRNA in vivo and in vitro, the number of Shigella mutants lacking the icsB gene (ΔicsB) that survived intracellularly increased, whereas the protein aggregate clearance decreased [20]. Although results from Ogawa and Sasakawa [64] indicated that Tecpr1 has no effect on rapamycin- or starvation-induced canonical autophagy, Tecpr1 plays a crucial function in AP maturation and promotes AP–lysosome fusion by associating with both ATG12-ATG5 conjugates and Ptdlns(3)P. The absence of Tecpr1 leads to defective AP maturation marked by GFP-mRFP-LC3 (a tandem monomeric fluorescent RFP-GFP-tagged LC3) [65,66].

Parkin FUN14 Domain Containing 1

Tectonin β-propeller Repeat-containing Protein 1 Tectonin β-propeller repeat-containing protein 1 (Tecpr1) was first identified as DKFZP434B0335, the human ortholog of Yarrowia lipolytica Pex23p, containing dysferlin domains in addition to a tachylectin-like seven-bladed β-propeller and a pleckstrin homology (PH) domain (Fig. 2) [63]. Ogawa and Sasakawa [64] found that Tecpr1 is a cargo receptor involved in selective autophagy that targets the substrates, such as bacteria, depolarized mitochondria, and protein aggregates. Tecpr1 co-localizes with ATG5 at Shigella-containing

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FUN14 domain containing 1 (FUNDC1) is a mitophagy receptor for selectively removing damaged mitochondria in response to hypoxia through its N-terminal characteristic LRS (Y(18)XXL) to specifically interact with ATG8 in mammalian systems. FUNDC1 is found to localize on the mitochondrial outer membrane with three TM domains (Fig. 2). FUNDC1 is conserved in higher eukaryotic organisms and expressed at high levels in most tissues [57]. The activity of FUNDC1-mediated mitophagy is regulated by reversible phosphorylation at the post-translational level. Under normal physiological conditions, FUNDC1-mediated mitophagy is inhibited by its phosphorylation at tyrosine 18 (Tyr18) by Src kinase and Ser13 by CK2. In response to hypoxia stimulation, both Try18 and Ser13 of FUNDC1 are dephosphorylated, resulting in an increase of the co-localization and interaction between FUNDC1 and LC3, leading to the selective incorporation of the mitochondrion as a specific cargo into LC3-bound isolation membrane for subsequent removal of mitochondria by LAMP1-positive ALs [58,59]. Moreover, Chen et al. [59] identified that the mitochondrially localized phosphoglycerate mutase family member 5 (PGAM5) phosphatase could interact and dephosphorylate FUNDC1 at Ser13 upon hypoxia or carbonyl cyanide p-trifluoromethoxyphenylhydrazone treatment. BCL2L1/ Bcl-xL could interact with and inhibit PGAM5 to prevent the dephosphorylation of FUNDC1 [60]. Meanwhile, upon mitophagy induction by hypoxia, unc-51-like autophagy activating kinase 1 (ULK1) could be upregulated and interact with FUNDC1, leading to phosphorylate FUNDC1 at Ser17, which enhances FUNDC1 binding to LC3 [61]. Except for the phosphorylation modification, the changes in FUNDC1 expression levels also affect the FUNDC1-mediated mitophagy. Li et al. [62] demonstrated that microRNA-137 inhibits mitophagy by reducing the expression of mitophagy receptor FUNDC1 and NIX.

Parkin (PARK2), located in the cytosol under basal conditions, is an E3 ubiquitin ligase that was originally identified in a mutated form in monogenic forms of Parkinson’s disease. The protein was recently found to translocate specifically to uncoupled impaired mitochondria and to induce their selective elimination by autophagy [67]. Parkin consists of two functionally different domains (Fig. 2): the C-terminal RING-box, which recruits a specific E2 enzyme (UbcH7), and the N-terminal UBA domain, which is required for the recognition of target proteins for ubiquitination before proteasomal degradation. The RING-box region consists of three domains termed RING1, RING2, and IBR (for in-between RING) [68]. A series of cell biological studies have provided strong evidence that the PINK1/Parkin pathway appears to be an important sensor of mitochondrial dysfunction and a mediator of the selective degradation of damaged mitochondria [69–71]. PINK1 is a serine/threonine kinase (PTEN-induced putative kinase 1) and acts as an upstream initiator of Parkin in regulating mitochondrial homeostasis. Upon the loss of mitochondrial membrane potential induced by CCCP [72] or hepatitis C virus infection [73], the accumulation of PINK1 directly phosphorylates Parkin at Ser65 in the UBA domain, which is required for the efficient translocation of Parkin from the cytosol to the mitochondria as an initial step of mitophagy. Following recruitment, Parkin promotes mitochondrial degradation by mitophagy [69]. Recent work by Geisler et al. [70] revealed that PINK1 mutations lead to failures of Parkin translocation and abrogate autophagic elimination of impaired mitochondria. However, Parkin retains some activity in the absence of PINK1, and this residual Parkin activity may be sufficient to support a basal level of mitophagy, which seems to occur at a low rate [74]. Thus, PINK1 may be required for mitophagy only under conditions of extreme stress. Interestingly, as a cellular substrate for the PINK1 kinase, the mitochondrial chaperone, TNF receptorassociated protein 1 (TRAP1), could partially rescue mitochondrial impairment in Parkin mutant flies [75]. The study about the association of PINK1 and translocase of the outer membrane (TOM) showed that when mitochondria re-establish membrane potential, the TOM complex allows the rapid re-import of PINK1 accumulated on the outer mitochondrial membrane, to further deactivate Parkin and to terminate mitophagy [76]. Although Parkin may be important for mitophagy, the molecular mechanisms for regulating Parkin-mediated mitophagy have not been clearly defined. Recent studies reported that p62 may be involved with Parkin-mediated clearance of depolarized mitochondria [35,77]. Cells with siRNA-silenced p62 exhibited dramatically inhibited final clearance of damaged mitochondria [78,79]. Intriguingly, the work from

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Receptor proteins in selective autophagy Okatsu et al. [80] indicates that the deletion of p62 results in a gross loss of mitochondrial perinuclear clustering, but does not hinder mitochondrial degradation. These conflicting observations need further analysis. In addition, studies in mammalian systems have suggested that NIX, p97 (an AAA+ ATPase), proteasome activity, and ATG proteins are also required for Parkin-mediated mitophagy [81–83]. NIX participates in mitophagy by promoting Parkin translocation, whereas p97 and the proteasome are involved in the process by which Parkin prevents the re-fusion of dysfunctional mitochondria. In the initial stage of Parkin-mediated mitophagy, the ATG1/ULK1 complex and ATG9A are independently recruited to depolarized mitochondria, and both are required for further recruitment of downstream ATG proteins.

Cbl

TRIM5α In 2004, the screening of an Rh-cDNA library identified tripartite motif 5α (TRIM5α) as a cellular antiviral factor. TRIM5α is one member of the TRIM family and consists of RING, B-box 2, CC, and SPRY domains (Fig. 2) [97]. The intact B-box 2 domain is required for TRIM5α-mediated antiviral activity. The CC domain of TRIM5α is important for the formation of homo-oligomers, which is also essential for antiviral activity. The SPRY domain recognizes the viral capsid protein. TRIM5α acts as a bona fide selective autophagy receptor [98]. Based on direct sequence-specific recognition, TRIM5α delivered its cognate cytosolic target, a viral capsid protein, for autophagic degradation. As the key motifs interacting with ATG8, LRS1 and LRS2 in TRIM5α are required for its receptor function [99].

Conclusions Tollip By a screen in yeast, Lu et al. [88] identified a new class of ubiquitin-ATG8 receptors termed CUET proteins, comprising the ubiquitin-binding CUE-domain protein Cue5 from yeast and its human homolog Tollip (Toll-interacting protein). Tollip is a modular protein, with an N-terminal target of Myb1 (Tom1)-binding domain, a central phospholipid-binding conserved 2 (C2) domain, and a C-terminal coupling of ubiquitin to endoplasmic reticulum degradation (CUE) domain (Fig. 2) [89]. Tollip directly mediates polyQ protein-efficient elimination via the autophagy pathway, leading to reduction cytotoxicity of polyQ proteins derived from human Huntington disease. Interestingly, different from the human ubiquitin-ATG8 receptors p62 and NBR1, ubiquitin recognition by Tollip is mediated through a CUE domain (rather than a UBA domain). In addition, immunoprecipitation of Tollip co-isolates both p62 and NBR1, indicating that Tollip and p62, in fact, sometimes cooperate in autophagy by targeting the same cellular aggregate [90].

Autophagy is a regulated, catabolic pathway responsible for the lysosomal, non-specific degradation of cytoplasmic constituents, such as long-lived proteins and organelles. It is characterized by the formation of a double-membrane vesicle, the AP, which engulfs the cargoes to be degraded and delivers them to lysosomal components. However, recent evidence identifies another specific type of autophagy, which can mediate the selective removal of particular substrates such as protein aggregates, organelles, and even invading microbes in cells. Selectivity can be mediated by the binding of autophagy receptors to membrane-anchored autophagy-specific Ubl proteins. Many unresolved issues remain in this field. A more comprehensive understanding of autophagic cargo receptor pairs is required to understand the autophagic mechanisms that contribute to proteostasis and organelle homeostasis. Moreover, elucidating the integrated molecular mechanisms responsible for this process will provide better insight into the pathogenesis of relevant diseases and further pave the way for therapeutic drug design.

Funding Nuclear Receptor Coactivator 4 Nuclear receptor coactivator 4 (NCOA4) is a transcriptional coregulatory protein that contains a basic helix-loop-helix domain, a PER-ARNT-SIM (PAS) domain, and seven Leu-Xaa-Xaa-Leu-Leu motifs (Fig. 2) [91]. NCOA4 directly interacts with several ligand-activated nuclear transcription factors, including the aryl hydrocarbon receptor

This work was supported by the grants from the National Natural Science Foundation of China (No. 81372182), the China Postdoctoral Science Foundation (No. 2012T50712), the Hunan Provincial Innovation Foundation for Postgraduate (No. 71380100003), and the Fundamental Research Funds for the Central Universities of Central South University (No. 2014zzts065).

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The Cbl protein family is evolutionarily conserved negative regulators of activated tyrosine kinase-coupled receptors. Antigen receptors are prominent targets of negative regulation by the Cbl family members, Cbl and Cbl-b, proteins of which function as ubiquitin ligases. Cbl is composed of an N-terminal tyrosine kinase-binding domain, which mediates binding to specific phosphotyrosine motifs on other activated signaling proteins; a Zn-coordinating RING finger domain that interacts with ubiquitin-conjugating enzymes; a proline-rich region that contains functional SH3 domain-binding sites; and a C-terminal leucine zipper-like region with high homology to UBA domains (Fig. 2) [84,85]. The E3 ubiquitin ligase Cbl acts as an AP cargo receptor for Src, a non-receptor tyrosine kinase [86]. Defective focal adhesion kinase signaling causes sequestration of active Src away from focal adhesions into intracellular puncta that collocate with several ATG proteins, forming the ‘untethered Src’. Active Src is ubiquitylated by its binding partner Cbl. However, this is independent of Cbl E3 ligase activity, but is mediated by the LC3-interacting region [87].

and the androgen receptor (AR), and its overexpression has been reported to activate the transcription of AR-regulated genes [92,93]. However, not all studies have supported the role of NCOA4 in AR function [94]. Recently, Mancias et al. [95] revealed a previously unrecognized role for NCOA4 as an autophagy cargo receptor. Moreover, as NCOA4 mRNA is induced in red blood cells during erythropoiesis, and its expression correlates with genes involved in the heme biosynthesis, NCOA4 may be required for both cellular remodeling and iron availability during differentiation [96]. NCOA4 is highly enriched in APs and associated with ATG8 proteins that recruit cargo receptor complexes into APs. It acts as an autophagy receptor for the autophagic turnover of ferritin (ferritinophagy), which maintains iron homeostasis by delivering ferritin to lysosomes for degradation. Importantly, when NCOA4 expression was downregulated by short hairpin RNAs, ferritin degradation was abrogated in normal and tumor cell lines, leading to a decrease in bioavailable intracellular iron [95].

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