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Precision Autophagy Directed by Receptor Regulators – Emerging Examples Within the TRIM Family Tomonori Kimura*, Michael Mandell and Vojo Deretic*

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Precision Autophagy Directed by Receptor Regulators – Emerging Examples Within the TRIM Family Tomonori Kimura*, Michael Mandell and Vojo Deretic* © 2016. Published by The Company of Biologists Ltd | Journal of Cell Science (2016) 129, 881-891 doi:10.1242/jcs.163758 COMMENTARY Precision autophagy directed by receptor regulators – emerging examples within the TRIM family Tomonori Kimura*, Michael Mandell and Vojo Deretic* ABSTRACT A morphologically emblematic event during autophagy is the Selective autophagy entails cooperation between target recognition formation in the cytoplasm of the membranous organelles termed and assembly of the autophagic apparatus. Target recognition is autophagosomes; these are the executors of macro-autophagy conducted by receptors that often recognize tags, such as ubiquitin (hereafter referred to as autophagy) (Mizushima et al., 2011). and galectins, although examples of selective autophagy Autophagosomes are decorated in yeast with Atg8 and in mammals – independent of these tags are emerging. It is less known how with LC3B [one of six mammalian (m)Atg8 paralogs LC3A, MAP1LC3A MAP1LC3B receptors cooperate with the upstream autophagic regulators, beyond LC3B and LC3C (encoded by , and MAP1LC3C the well-characterized association of receptors with Atg8 or its , respectively) and GABARAP, GABARAPL1 and homologs, such as LC3B (encoded by MAP1LC3B), on autophagic GABARAPL2 (Mizushima et al., 2011; Weidberg et al., 2011)]. membranes. The molecular details of the emerging role in autophagy mAtg8 proteins are conjugated at their C-terminus to a lipid, of the family of proteins called TRIMs shed light on the coordination phosphatidylethanolamine (PtdEtn), which in turn mediates between cargo recognition and the assembly and activation of the association with the autophagic membrane (Kabeya et al., 2000). principal autophagy regulators. In their autophagy roles, TRIMs act Many other parts of the core autophagy machinery are well- both as receptors and as platforms (‘receptor regulators’) for the conserved from yeast to humans (Mizushima et al., 2011). In assembly of the core autophagy regulators, such as ULK1 and Beclin 1 mammals, the key autophagy factors (ATG) include ULK1 (one of in their activated state. As autophagic receptors, TRIMs can directly four mammalian paralogs of Atg1) (Chan et al., 2007; Kundu and recognize endogenous or exogenous targets, obviating a need for Thompson, 2008) and Beclin 1 (a paralog of yeast Atg6) (Liang intermediary autophagic tags, such as ubiquitin and galectins. The et al., 1999). These principal autophagy regulators are controlled by ′ receptor and regulatory features embodied within the same entity upstream serine and threonine (Ser/Thr) protein kinases 5 -AMP- allow TRIMs to govern cargo degradation in a highly exact process activated protein kinase (AMPK) and mammalian target of termed ‘precision autophagy’. rapamycin (mTOR) (Egan et al., 2011; Kim et al., 2011, 2013; Russell et al., 2013), as well as E3 ligases and ubiquitylation (Nazio KEY WORDS: Receptor regulators, TRIMs, Autophagy et al., 2013). Lipid kinases, most notably the class III phosphatidylinositol 3-kinase (PI3K) VPS34 (encoded by Introduction PIK3C3; which forms a complex with Beclin 1), co-activate Autophagy is a set of diverse processes, often classified as macro- autophagy by producing phosphatidylinositol 3-phosphate autophagy, micro-autophagy and chaperone-mediated autophagy, [PtdIns(3)P], a step that commits them to participating in which recognize and deliver endogenous cellular constituents or autophagosome formation (Petiot et al., 2000); however, the roles exogenous cargo to lysosomes for degradation (Mizushima et al., of other mono-phosphoinositides such as phosphatidylinositol 5- 2011). Autophagy can occur in bulk as a response to starvation, phosphate have recently been suggested (Vicinanza et al., 2015). whereby portions of the cytoplasm are auto-digested to meet the The protein kinases (ULK1), lipid kinases (Beclin-1–VPS34) and heightened biogenesis and energy needs of the cell (Rabinowitz and the LC3-conjugation system are all physically connected in their White, 2010; Galluzzi et al., 2014). Autophagy plays equally role in controlling autophagy. First, PtdIns(3)P is recognized by important roles in homeostasis, acting as a quality and quantity WD repeat domain phosphoinositide-interacting protein 2 (WIPI2, control process by removing protein aggregates (Rubinsztein et al., the mammalian Atg18), which interacts with ATG16L1 and forms 2012; Birgisdottir et al., 2013) and defunct or surplus organelles part of the LC3–PtdEtn conjugation system (Dooley et al., 2014). (Maejima et al., 2013; Randow and Youle, 2014), as well as Second, ATG16L1 associates with FIP200 (also known as invading microbes and endogenous and exogenous inflammatory RB1CC1), a component of the ULK1 complex system (Fujita agonists (Deretic et al., 2015). The degradation targets for et al., 2013; Gammoh et al., 2013; Nishimura et al., 2013; Dooley autophagy are not limited to cargo of the cytoplasmic origin, as et al., 2014). Autophagy is further coupled to the lysosomal systems. autophagy can also target nuclear components (Dou et al., 2015). This occurs through the effects on autophagy of members of the key The selectivity of autophagy (Fig. 1) has been a topic of continuing regulator of lysosomal biogenesis ‘microphthalmia/transcription interest; it has been established that a number of receptors can guide factor E’ (MiT/TFE) family (including transcription factor EB; autophagic machinery to targets, which are often earmarked for TFEB) (Settembre et al., 2011; Perera et al., 2015) and through autophagy with ubiquitin or galectins tags (Randow and Youle, SNAREs (Itakura et al., 2012), which enable the maturation of 2014; Stolz et al., 2014). autophagosomes into the autolysosome. Thus, all parts of the autophagy system are interconnected, thereby enabling spatial and temporal regulation of autophagy. Department of Molecular Genetics and Microbiology, University of New Mexico The homing of the autophagy machinery to intended targets Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA. through receptors is an area of intense study (Birgisdottir et al., *Authors for correspondence ([email protected]; [email protected]) 2013; Rogov et al., 2014; Khaminets et al., 2015). Frequently, Journal of Cell Science 881 COMMENTARY Journal of Cell Science (2016) 129, 881-891 doi:10.1242/jcs.163758 A Precision autophagy B Selective autophagy C Nonselective (bulk) group of mammalian proteins, additional receptors fit the SLR autophagy criteria. For instance, RPN10, an Arabidopsis receptor that mediates autophagic degradation of proteasome, binds to ubiquitin tags and Atg8s through its ubiquitin-interacting motif (UIM) domains ULK1 (Marshall et al., 2015). Furthermore, Toll-interacting protein Beclin 1 (TOLLIP) in mammals and Cue5 in yeast fit SLR criteria; Cue5 directly binds both to ubiquitin and to Atg8, whereas TOLLIP Direct target recognition Generic tag-based No known selectivity directly binds to ubiquitin and, in cellular extracts, to LC3 (Lu et al., Assembly of autophagy selectivity 2014). regulators and effectors Key The TRIM protein family Autophagic ULK1 Autophagy TRIMs were first recognized as a family (Reymond et al., 2001) Target or cargo LIR organelles Beclin 1 regulators based on their common tri-partite domain organization, typically Ubiquitin or galectin tag Receptor Receptor mAtg8s comprising an N-terminal RING domain, one or two B-box regulator domains and a coiled-coil domain, although they also have additional features, including a variety of C-terminal domains, Fig. 1. Precision autophagy. (A) Precision autophagy is a receptor-regulator- based form of autophagy. A receptor-regulator protein (such as members of inclusive of SPRY domains (Fig. 2A,B; Table S1). TRIMs are the TRIM family) has the ability to recognize targets directly, often without tags conserved in metazoans, and the number of genes encoding them such as ubiquitin or galectins, and assembles regulators and effectors of escalates in higher organisms (Sardiello et al., 2008; Boudinot et al., autophagy to mediate precision (highly selective) autophagy. (B) Conventional 2011); 82 TRIM genes (excluding the pseudogenes) have been selective autophagy is mediated by autophagic receptors that recognize identified in humans (Table S1). targets through generic tags, such as ubiquitin or galectins, while also binding TRIMs are involved in a variety of seemingly disparate cellular mammalian (m)Atg8 proteins that connect them to autophagic membranes. (C) Nonselective (bulk) autophagy sequesters mixtures of cytoplasmic processes (Table S1); these include cell survival and death components, including cytosol. (Grignani et al., 1993), cell cycle and differentiation (Wang et al., 1998), metabolic states (Skurat et al., 2002), cell membrane repair (Cai et al., 2009), synaptic vesicle exocytosis (Li et al., 2001), targets exhibit ubiquitin or galectin marks, although this does not senescence (Pearson et al., 2000), stem cell pluripotency (Sato et al., appear to be an absolute requirement (Khaminets et al., 2015). 2012) and erythrocyte differentiation (Blaybel et al., 2008; Barde Furthermore, the number of proteinaceous, membranous and et al., 2013), as well as the control of viral, bacterial and fungal complex targets for selective autophagy is rapidly increasing. This infections (Nisole et al., 2005; Rakebrandt et al., 2014; Cao et al., raises an important question: are the number of receptors and the 2015). These and additional roles are linked to a variety of health principles
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