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• W2978073856 abstract "The clearance of surplus, broken, or dangerous components is key for maintaining cellular homeostasis. The failure to remove protein aggregates, damaged organelles, or intracellular pathogens leads to diseases, including neurodegeneration, cancer, and infectious diseases. Autophagy is the evolutionarily conserved pathway that sequesters cytoplasmic components in specialized vesicles, autophagosomes, which transport the cargo to the degradative compartments (vacuoles or lysosomes). Research during the past few decades has elucidated how autophagosomes engulf their substrates selectively. This type of autophagy involves a growing number of selective autophagy receptors (SARs) (e.g., Atg19 in yeasts, p62/SQSTM1 in mammals), which bind to the cargo and simultaneously engage components of the core autophagic machinery via direct interaction with the ubiquitin-like proteins (UBLs) of the Atg8/LC3/GABARAP family and adaptors, Atg11 (in yeasts) or FIP200 (in mammals). In this Review, we critically discuss the biology of the SARs with special emphasis on their interactions with UBLs. The clearance of surplus, broken, or dangerous components is key for maintaining cellular homeostasis. The failure to remove protein aggregates, damaged organelles, or intracellular pathogens leads to diseases, including neurodegeneration, cancer, and infectious diseases. Autophagy is the evolutionarily conserved pathway that sequesters cytoplasmic components in specialized vesicles, autophagosomes, which transport the cargo to the degradative compartments (vacuoles or lysosomes). Research during the past few decades has elucidated how autophagosomes engulf their substrates selectively. This type of autophagy involves a growing number of selective autophagy receptors (SARs) (e.g., Atg19 in yeasts, p62/SQSTM1 in mammals), which bind to the cargo and simultaneously engage components of the core autophagic machinery via direct interaction with the ubiquitin-like proteins (UBLs) of the Atg8/LC3/GABARAP family and adaptors, Atg11 (in yeasts) or FIP200 (in mammals). In this Review, we critically discuss the biology of the SARs with special emphasis on their interactions with UBLs. Removal of unwanted, damaged, or dangerous components is crucial for normal functioning of the cell. Thus, the failure to clear misfolded and aggregated proteins or damaged mitochondria in model organisms is implicated in the increased production of reactive oxygen species (ROS), DNA mutagenesis, and neoplastic transformation. Unabated proteotoxic and oxidative stress in neurons caused by protein aggregation triggers cell death and neurodegeneration, while the unrestricted proliferation of intracellular bacteria, such as Salmonella, in host cells can result in the spread of the infection throughout the organism. To prevent diseases linked to the accumulation of bulky cytoplasmic cargo, evolution adapted the degradative power of the highly conserved cellular pathway, macroautophagy, which had first emerged as a response to amino acid starvation. Macroautophagy, hereafter referred to as simply autophagy, manifests itself through the formation of specialized, double-membrane vesicles, autophagosomes, which fuse with the vacuole (in fungi and plants) or lysosomes (in higher organisms) for the cargo to become exposed to the resident degradative enzymes, enabling the disassembly of macromolecules and the recycling of their constituents in downstream metabolic reactions. Autophagosomes are capable of engulfing cytoplasmic material of various geometries and sizes, ranging from a protein oligomer (a few nanometers) to a micron-sized protein crystal (indeed, an entire bacterium), revealing the power and the flexibility of this degradative system (reviewed in Dikic and Elazar, 2018Dikic I. Elazar Z. Mechanism and medical implications of mammalian autophagy.Nat. Rev. Mol. Cell Biol. 2018; 19: 349-364Crossref PubMed Scopus (29) Google Scholar and Mizushima et al., 2011Mizushima N. Yoshimori T. Ohsumi Y. The role of Atg proteins in autophagosome formation.Annu. Rev. Cell Dev. Biol. 2011; 27: 107-132Crossref PubMed Scopus (1327) Google Scholar). In yeasts, an autophagosome (∼500 nm in diameter) is produced de novo at a single perivacuolar site, referred to as a phagophore assembly site (PAS). The term “phagophore” denotes a primordial cup-shaped precursor membrane of a poorly characterized origin whose production depends on the concerted action of some 40 autophagy-related (Atg) proteins. The discovery of the Atg genes in the 1990 by Yoshinori Ohsumi was awarded the Nobel Prize in Physiology or Medicine in 2016. The evolutionary adaptation of the autophagosome to tackling specific cargos, called selective autophagy, relies on the use of specialized adaptor proteins that were discovered by Daniel Klionsky at the turn of the 21st century when studying the biosynthetic cytoplasm-to-vacuole targeting (Cvt) pathway (reviewed by Lynch-Day and Klionsky, 2010Lynch-Day M.A. Klionsky D.J. The Cvt pathway as a model for selective autophagy.FEBS Lett. 2010; 584: 1359-1366Crossref PubMed Scopus (175) Google Scholar). This selective autophagy-like pathway transports several vacuolar hydrolases from the place of their synthesis, the cytoplasm, to the vacuole and relies on largely the same set of Atg genes as the starvation-induced autophagy. The prerequisite for the formation of the double-membrane Cvt vesicle is both the oligomerization of the hydrolase precursors and their interaction with specialized adaptor proteins that physically link the Cvt cargo with the core Atg machinery. Because, upon their interaction with the cargo the Cvt adaptors trigger a signaling cascade that culminates in the formation of a selective autophagosome (exemplified here by the Cvt vesicle), we refer to such cargo-binding adaptors as selective autophagy receptors (SARs). One important feature of the SARs is their ability to bind small globular proteins that show remarkable similarity to ubiquitin both in terms of their 3D structure and ability to become reversibly conjugated to their substrates—other proteins and lipids. A number of these ubiquitin-like proteins (UBLs) play roles in the biogenesis of the autophagosome. The research of the past decade has been focused on the elucidation of the mode of binding between the SARs and the UBLs, which has also led to the discovery of a battery of SARs functioning in various selective autophagy pathways, including those ensuring the clinically relevant selective degradation of protein aggregates (aggrephagy), damaged mitochondria (mitophagy), and cytoplasmic pathogens (xenophagy). There are at least 10 SARs known in yeast and >30 in mammalian cells (Figure 1). In this review, we summarize the rapidly developing knowledge on selective autophagy mechanisms, laying emphasis on the role of the interactions between the diverse SARs and the autophagy-related UBLs in the formation of a selective autophagosome. We critically review the emerging mechanisms of cargo linking to the core Atg machinery and suggest a model for the selective autophagosome formation, whose refinement will guide the development of new therapeutic strategies for diseases with high unmet medical need. The molecular mechanisms underlying the formation of an autophagosome were first elucidated in yeasts (reviewed in Dikic and Elazar, 2018Dikic I. Elazar Z. Mechanism and medical implications of mammalian autophagy.Nat. Rev. Mol. Cell Biol. 2018; 19: 349-364Crossref PubMed Scopus (29) Google Scholar and Mizushima et al., 2011Mizushima N. Yoshimori T. Ohsumi Y. The role of Atg proteins in autophagosome formation.Annu. Rev. Cell Dev. Biol. 2011; 27: 107-132Crossref PubMed Scopus (1327) Google Scholar). Upon amino acid starvation or rapamycin treatment, which inhibit the activity of the master metabolic kinase target of rapamycin complex 1 (TORC1), core Atg proteins assemble at the PAS in a hierarchical fashion, orchestrating the initiation, the nucleation, the elongation, and the closure of the phagophore. The initiating serine/threonine (Ser/Thr) Atg1 kinase complex, consisting of the catalytic subunit Atg1 and the scaffolding proteins Atg13, Atg17, Atg29, and Atg31, assembles at the PAS in an Atg17-dependent manner. Downstream of Atg1 is the phagophore-nucleating class-III phosphoinositide 3-kinase (PI3K) complex I, which consists of the lipid kinase Vps34 and its ancillary subunits Vps34, Vps15, Atg6, Atg14, and Atg38. Atg1 phosphorylates Atg6, which positively regulates the Vps34 activity. The net result of the Vps34 activity is the local production of the phosphatidylinositol-3-phosphate (PI3P), which serves as a docking site for the lipid-binding Atg2/Atg18 complex. Recent data suggest that the components of the Atg2/Atg18 complex participate in the transfer of lipids from the endoplasmic reticulum (ER) to the phagophore (Gómez-Sánchez et al., 2018Gómez-Sánchez R. Rose J. Guimarães R. Mari M. Papinski D. Rieter E. Geerts W.J. Hardenberg R. Kraft C. Ungermann C. Reggiori F. Atg9 establishes Atg2-dependent contact sites between the endoplasmic reticulum and phagophores.J. Cell Biol. 2018; 217: 2743-2763Crossref PubMed Scopus (19) Google Scholar), with Atg2 directly binding to glycerophospholipids (Valverde et al., 2019Valverde D.P. Yu S. Boggavarapu V. Kumar N. Lees J.A. Walz T. Reinisch K.M. Melia T.J. ATG2 transports lipids to promote autophagosome biogenesis.J. Cell Biol. 2019; 218: 1787-1798Crossref PubMed Scopus (5) Google Scholar). The de novo nucleated membrane of the phagophore expands via two complementary mechanisms. In the first of them, a ubiquitin-like conjugation pathway, orchestrated by the enzymatic activities of Atg7 (E1), Atg3 (E2), and Atg5–Atg12:Atg16 (E3), results in the formation of a covalent bond between the C-terminal Gly of the UBL Atg8 (Figure 2) and the amino group of the phosphatidylethanolamine (PE) enriched in the phagophore. The lipidation of Atg8, with its anchoring in the phagophore membrane, drives the fusion of lipid membranes and the elongation of the phagophore. The Atg8-PE reaction can be reversed by the action of the cysteine protease Atg4, which cleaves the amide bond in the Atg8-PE conjugate. Atg4 is also required for the proteolytic maturation of the precursor Atg8. Of note, Atg5 and Atg12, which together with Atg16 mediate the Atg8-PE conjugation reaction, are themselves UBLs (Figure 2). They are covalently bound as a consequence of a ubiquitin-like conjugation reaction mediated by the Atg7 (E1) and Atg10 (E2) enzymes. The second mechanism of the phagophore expansion involves Atg9, which is the only transmembrane protein of the core Atg proteins. Distinct Atg9 vesicles are derived from the Golgi apparatus in a process facilitated by Atg23 and Atg27 and shuttle to the PAS, delivering lipid membrane to the budding phagophore. Atg9 interacts with the Atg1-adaptor proteins Atg11, Atg17, and Atg13; and Atg1 directly phosphorylates Atg9, indicating a role for the Atg1 signaling in the Atg9-mediated membrane dynamics at the PAS. The final step of the autophagosome formation, the closure of the mature phagophore, is poorly understood but is thought to involve components of endosomal sorting complexes required for transport (ESCRT) (Takahashi et al., 2018Takahashi Y. He H. Tang Z. Hattori T. Liu Y. Young M.M. Serfass J.M. Chen L. Gebru M. Chen C. et al.An autophagy assay reveals the ESCRT-III component CHMP2A as a regulator of phagophore closure.Nat. Commun. 2018; 9: 2855Crossref PubMed Scopus (13) Google Scholar, Zhou et al., 2019Zhou F. Wu Z. Zhao M. Murtazina R. Cai J. Zhang A. Li R. Sun D. Li W. Zhao L. et al.Rab5-dependent autophagosome closure by ESCRT.J. Cell Biol. 2019; 218: 1908-1927Crossref PubMed Scopus (3) Google Scholar). Unlike yeasts, mammalian cells are able to form autophagosomes at multiple locations in parallel (reviewed in Dikic and Elazar, 2018Dikic I. Elazar Z. Mechanism and medical implications of mammalian autophagy.Nat. Rev. Mol. Cell Biol. 2018; 19: 349-364Crossref PubMed Scopus (29) Google Scholar and Mizushima et al., 2011Mizushima N. Yoshimori T. Ohsumi Y. The role of Atg proteins in autophagosome formation.Annu. Rev. Cell Dev. Biol. 2011; 27: 107-132Crossref PubMed Scopus (1327) Google Scholar). In a widely accepted model, during amino acid starvation, phagophores form at double FYVE domain-containing protein 1-positive (DFCP1+) subdomains of the ER, referred to as omegasomes. The mammalian Atg proteins show remarkable functional conservation with those found in yeasts but are greatly expanded in number. The mammalian Atg1 complex is represented by the homologous ULK1 and ULK2 kinases, with the scaffolding subunits ATG13, FIP200 (analogous to the yeast Atg11 and Atg17), and ATG101. The class-III PI3K complex comprises VPS34, VPS15, Beclin-1 (homologous to the yeast Atg6), and ATG14/Beclin1-associated autophagy-related key regulator (Barkor), while ATG2A, ATG2B, and four WD repeat domain phosphoinositide interacting (WIPI) proteins (WIPI1–4) represent the PI3P-binding proteins. The mammalian ubiquitin-like conjugation system is greatly expanded, with six Atg8-like proteins, LC3/γ-aminobutyric acid receptor-associated proteins (GABARAPs; Figure 2), conjugated to the PE by the action of ATG7 (E1), ATG3 (E2), and ATG5-ATG12:ATG16L1 (E3). Four ATG4 proteases (ATG4A-B) with varying specificities process the precursor forms of LC3/GABARAPs. As in yeasts, formation of the mammalian ATG5-ATG12 conjugate depends on the activity of ATG7 (E1) and ATG10 (E2). Mammals also express ATG16L2, which differs from ATG16L1 in its middle coiled-coil domain and cannot support the E3-like function of the ATG5-ATG12:ATG16L2 complex (Ishibashi et al., 2011Ishibashi K. Fujita N. Kanno E. Omori H. Yoshimori T. Itoh T. Fukuda M. Atg16L2, a novel isoform of mammalian Atg16L that is not essential for canonical autophagy despite forming an Atg12–5-16L2 complex.Autophagy. 2011; 7: 1500-1513Crossref PubMed Scopus (0) Google Scholar). Atg9 in mammals is represented by two homologous proteins, ATG9A and ATG9B. Selective autophagosomes are forming in cells under fed conditions, so that the assembly of Atg proteins at the cargo proceeds in the absence of the global TORC1 inhibition. In the biosynthetic Cvt pathway, oligomeric precursors of the resident hydrolases aminopeptidase 1 (Ape1), aspartyl aminopeptidase 4 (Ape4), and α-mannosidase (Ams1) are constitutively wrapped into small (150 nm in diameter) Cvt vesicles (reviewed in Lynch-Day and Klionsky, 2010Lynch-Day M.A. Klionsky D.J. The Cvt pathway as a model for selective autophagy.FEBS Lett. 2010; 584: 1359-1366Crossref PubMed Scopus (175) Google Scholar). Besides the Atg proteins, formation of the Cvt vesicles depends on additional components. The prototypic SAR in yeasts, Atg19 (Shintani et al., 2002Shintani T. Huang W.P. Stromhaug P.E. Klionsky D.J. Mechanism of cargo selection in the cytoplasm to vacuole targeting pathway.Dev. Cell. 2002; 3: 825-837Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar), simultaneously binds the Cvt cargo, the oligomeric Ape1 precursor (prApe1), and two other Atg proteins, Atg11 and Atg8. Atg34 is a homolog of Atg19 and is required for the efficient trafficking of Ams1 to the vacuole under starvation conditions (Suzuki et al., 2010Suzuki K. Kondo C. Morimoto M. Ohsumi Y. Selective transport of alpha-mannosidase by autophagic pathways: identification of a novel receptor, Atg34p.J. Biol. Chem. 2010; 285: 30019-30025Crossref PubMed Scopus (67) Google Scholar). Atg11 is the selective autophagy-specific scaffolding subunit of the apical Atg1 complex (reviewed in Farré and Subramani, 2016Farré J.C. Subramani S. Mechanistic insights into selective autophagy pathways: lessons from yeast.Nat. Rev. Mol. Cell Biol. 2016; 17: 537-552Crossref PubMed Google Scholar). It physically bridges the Cvt cargo:Atg19 and the Atg1 complexes while tethering both of them to the PAS. The interaction of Atg11 with Atg19 is subject to phosphoregulation: Hrr25, a homolog of casein kinase 1δ (CK1δ), phosphorylates Atg19 in the Atg11-binding region (A11BR; Figure 4) and activates the Atg11:Atg19 interaction (Pfaffenwimmer et al., 2014Pfaffenwimmer T. Reiter W. Brach T. Nogellova V. Papinski D. Schuschnig M. Abert C. Ammerer G. Martens S. Kraft C. Hrr25 kinase promotes selective autophagy by phosphorylating the cargo receptor Atg19.EMBO Rep. 2014; 15: 862-870Crossref PubMed Google Scholar, Tanaka et al., 2014Tanaka C. Tan L.J. Mochida K. Kirisako H. Koizumi M. Asai E. Sakoh-Nakatogawa M. Ohsumi Y. Nakatogawa H. Hrr25 triggers selective autophagy-related pathways by phosphorylating receptor proteins.J. Cell Biol. 2014; 207: 91-105Crossref PubMed Scopus (58) Google Scholar). Due to its oligomeric, coiled-coil nature, Atg11 brings together a plethora of proteins. In addition to Atg1 and Atg9, it may interact with Atg8, as proposed by the Vierstra group based on their interaction studies performed in Arabidopsis (Li et al., 2014Li F. Chung T. Vierstra R.D. AUTOPHAGY-RELATED11 plays a critical role in general autophagy- and senescence-induced mitophagy in Arabidopsis.Plant Cell. 2014; 26: 788-807Crossref PubMed Scopus (88) Google Scholar). Elegant in vitro reconstitution experiments demonstrated that the oligomeric Atg11 can activate Atg1 kinase (Kamber et al., 2015Kamber R.A. Shoemaker C.J. Denic V. Receptor-Bound Targets of Selective Autophagy Use a Scaffold Protein to Activate the Atg1 Kinase.Mol. Cell. 2015; 59: 372-381Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar), which could also be confirmed in cells when Atg11 was tethered directly to the cargo (Torggler et al., 2016Torggler R. Papinski D. Brach T. Bas L. Schuschnig M. Pfaffenwimmer T. Rohringer S. Matzhold T. Schweida D. Brezovich A. Kraft C. Two Independent Pathways within Selective Autophagy Converge to Activate Atg1 Kinase at the Vacuole.Mol. Cell. 2016; 64: 221-235Abstract Full Text Full Text PDF PubMed Google Scholar). Given that virtually all known yeast SARs show Atg11 binding, Atg11 emerges as a critical selective autophagy-specific adaptor that allows Atg1 activation in the presence of active TORC1. The identity of the mammalian Atg11 had long been a mystery until Noboru Mizushima and colleagues identified FAK family kinase-interacting protein of 200 kDa (FIP200) as the component of the ULK1 complex (Hara et al., 2008Hara T. Takamura A. Kishi C. Iemura S. Natsume T. Guan J.L. Mizushima N. FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells.J. Cell Biol. 2008; 181: 497-510Crossref PubMed Scopus (527) Google Scholar), and additional studies showed that several mammalian SARs bind FIP200 directly, thereby recruiting the ULK1 complex to the cargo (Fujita et al., 2013Fujita N. Morita E. Itoh T. Tanaka A. Nakaoka M. Osada Y. Umemoto T. Saitoh T. Nakatogawa H. Kobayashi S. et al.Recruitment of the autophagic machinery to endosomes during infection is mediated by ubiquitin.J. Cell Biol. 2013; 203: 115-128Crossref PubMed Scopus (128) Google Scholar, Gammoh et al., 2013Gammoh N. Florey O. Overholtzer M. Jiang X. Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and -independent autophagy.Nat. Struct. Mol. Biol. 2013; 20: 144-149Crossref PubMed Scopus (81) Google Scholar, Nishimura et al., 2013Nishimura T. Kaizuka T. Cadwell K. Sahani M.H. Saitoh T. Akira S. Virgin H.W. Mizushima N. FIP200 regulates targeting of Atg16L1 to the isolation membrane.EMBO Rep. 2013; 14: 284-291Crossref PubMed Scopus (78) Google Scholar, Ravenhill et al., 2019Ravenhill B.J. Boyle K.B. von Muhlinen N. Ellison C.J. Masson G.R. Otten E.G. Foeglein A. Williams R. Randow F. The Cargo Receptor NDP52 Initiates Selective Autophagy by Recruiting the ULK Complex to Cytosol-Invading Bacteria.Mol. Cell. 2019; 74: 320-329.e6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Smith et al., 2018Smith M.D. Harley M.E. Kemp A.J. Wills J. Lee M. Arends M. von Kriegsheim A. Behrends C. Wilkinson S. CCPG1 Is a Non-canonical Autophagy Cargo Receptor Essential for ER-Phagy and Pancreatic ER Proteostasis.Dev. Cell. 2018; 44: 217-232.e11Abstract Full Text Full Text PDF PubMed Google Scholar, Turco et al., 2019Turco E. Witt M. Abert C. Bock-Bierbaum T. Su M.Y. Trapannone R. Sztacho M. Danieli A. Shi X. Zaffagnini G. et al.FIP200 Claw Domain Binding to p62 Promotes Autophagosome Formation at Ubiquitin Condensates.Mol. Cell. 2019; 74: 330-346.e11Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Vargas et al., 2019Vargas J.N.S. Wang C. Bunker E. Hao L. Maric D. Schiavo G. Randow F. Youle R.J. Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy.Mol. Cell. 2019; 74: 347-362.e6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The notorious protein huntingtin, implicated in Huntington disease, was also proposed to act as a mammalian Atg11 homolog, as it binds ULK1, GABARAPs, and the prototypic mammalian SAR p62/SQSTM1 (Ochaba et al., 2014Ochaba J. Lukacsovich T. Csikos G. Zheng S. Margulis J. Salazar L. Mao K. Lau A.L. Yeung S.Y. Humbert S. et al.Potential function for the Huntingtin protein as a scaffold for selective autophagy.Proc. Natl. Acad. Sci. USA. 2014; 111: 16889-16894Crossref PubMed Scopus (99) Google Scholar, Rui et al., 2015Rui Y.N. Xu Z. Patel B. Chen Z. Chen D. Tito A. David G. Sun Y. Stimming E.F. Bellen H.J. et al.Huntingtin functions as a scaffold for selective macroautophagy.Nat. Cell Biol. 2015; 17: 262-275Crossref PubMed Scopus (131) Google Scholar). Loss of huntingtin in Drosophila and mice disrupts autophagy and leads to the accumulation of p62/SQSTM1, a hallmark of defective selective autophagy (Ochaba et al., 2014Ochaba J. Lukacsovich T. Csikos G. Zheng S. Margulis J. Salazar L. Mao K. Lau A.L. Yeung S.Y. Humbert S. et al.Potential function for the Huntingtin protein as a scaffold for selective autophagy.Proc. Natl. Acad. Sci. USA. 2014; 111: 16889-16894Crossref PubMed Scopus (99) Google Scholar). In addition to Atg11, Atg19 (and all other known SARs) interacts with Atg8, which raises the question of whether cargo receptors also engage the phagophore membrane to mediate the selective engulfment of the cargo. Below, we review the emerging roles of UBLs in selective autophagy. The yeast autophagy-related UBL proteins Atg12, Atg5, and Atg8 share with ubiquitin overall structural similarity (Figure 2) and the ability to be conjugated to their respective substrates. Atg12 is synthesized as a mature protein and is constitutively conjoined with Atg5. The Atg12-Atg5 conjugate, in turn, forms a non-covalent complex with Atg16, whereby the N-terminal α- helix and a loop of Atg16 interact with two UBL domains of Atg5 (Matsushita et al., 2007Matsushita M. Suzuki N.N. Obara K. Fujioka Y. Ohsumi Y. Inagaki F. Structure of Atg5.Atg16, a complex essential for autophagy.J. Biol. Chem. 2007; 282: 6763-6772Crossref PubMed Scopus (133) Google Scholar). To perform its E3-like function, Atg12 of the Atg12-Atg5:Atg16 complex interacts with the 100-residue-long flexible region of the Atg8-specific E2 enzyme Atg3 (Metlagel et al., 2013Metlagel Z. Otomo C. Takaesu G. Otomo T. Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG12.Proc. Natl. Acad. Sci. USA. 2013; 110: 18844-18849Crossref PubMed Scopus (29) Google Scholar), while Atg5 binds lipid membranes, thereby defining the position of the Atg8 conjugation (Romanov et al., 2012Romanov J. Walczak M. Ibiricu I. Schüchner S. Ogris E. Kraft C. Martens S. Mechanism and functions of membrane binding by the Atg5-Atg12/Atg16 complex during autophagosome formation.EMBO J. 2012; 31: 4304-4317Crossref PubMed Scopus (169) Google Scholar). Atg12 also interacts with Atg8, leading to high-order molecular scaffolds consisting of Atg12-Atg5:Atg16 and Atg8, which are required for an efficient autophagosome biogenesis (Kaufmann et al., 2014Kaufmann A. Beier V. Franquelim H.G. Wollert T. Molecular mechanism of autophagic membrane-scaffold assembly and disassembly.Cell. 2014; 156: 469-481Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Atg8 in yeasts and its mammalian homologs LC3A (encoded by microtubule-associated proteins 1A/1B light chain 3 [MAP1LC3A]), LC3B (MAP1LC3B and MAP1LC3B2), LC3C (MAP1LC3C), GABARAP (GABARAP), GABARAPL1 (GABARAPL1), and GABARAPL2/Golgi-associated ATPase enhancer of 16 kDa (GATE-16) (GABARAPL2) show no sequence conservation with other UBLs and are unique in that they are attached to the lipid PE. In yeasts, Atg8 is required for both starvation-induced autophagy and the Cvt pathway and contributes to the growth of the autophagosome due to the fusogenic properties of its unique N-terminal α-helical subdomain (Nakatogawa et al., 2007Nakatogawa H. Ichimura Y. Ohsumi Y. Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion.Cell. 2007; 130: 165-178Abstract Full Text Full Text PDF PubMed Scopus (664) Google Scholar, Weidberg et al., 2011Weidberg H. Shpilka T. Shvets E. Abada A. Shimron F. Elazar Z. LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis.Dev. Cell. 2011; 20: 444-454Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar). To perform this role, Atg8 requires PE conjugation, as Atg7 and Atg3 are essential genes in yeast. In mammalian cells, LC3 and GABARAP subfamilies seem to play different roles, with LC3 regulating elongation of the phagophore and GABARAPs required for later stages of autophagosome maturation (Weidberg et al., 2010Weidberg H. Shvets E. Shpilka T. Shimron F. Shinder V. Elazar Z. LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis.EMBO J. 2010; 29: 1792-1802Crossref PubMed Scopus (371) Google Scholar). More recent studies suggested that GABARAPs, and not LC3s, are also required for the ULK1 activation (Joachim et al., 2015Joachim J. Jefferies H.B. Razi M. Frith D. Snijders A.P. Chakravarty P. Judith D. Tooze S.A. Activation of ULK Kinase and Autophagy by GABARAP Trafficking from the Centrosome Is Regulated by WAC and GM130.Mol. Cell. 2015; 60: 899-913Abstract Full Text Full Text PDF PubMed Google Scholar). Mutations in GABARAPs, which make them more LC3-like, impair SAR degradation (Wirth et al., 2019Wirth M. Zhang W. Razi M. Nyoni L. Joshi D. O’Reilly N. Johansen T. Tooze S.A. Mouilleron S. Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins.Nat. Commun. 2019; 10: 2055Crossref PubMed Scopus (0) Google Scholar). However, in mammalian cells lacking ATG7 or ATG3, STX17+ autophagosomes could still form, despite the fact that the LC3/GABARAP proteins were not covalently attached to the phagophore. ATG7- and ATG3-null cells are largely defective in autophagy, as manifested by the delayed degradation of the inner membrane of the autophagosome. However, these data suggest that mammalian cells can, via an unknown mechanism, at least in part compensate for the deficiency in LC3/GABARAP-PE conjugation during the phagophore maturation step (Tsuboyama et al., 2016Tsuboyama K. Koyama-Honda I. Sakamaki Y. Koike M. Morishita H. Mizushima N. The ATG conjugation systems are important for degradation of the inner autophagosomal membrane.Science. 2016; 354: 1036-1041Crossref PubMed Scopus (91) Google Scholar). The concept of the Atg8-interacting motif (AIM) in yeast and the LC3-interacting region (LIR) in mammals (Figures 3 and 4) is founded upon the pioneering work performed by the groups of Terje Johansen (Pankiv et al., 2007Pankiv S. Clausen T.H. Lamark T. Brech A. Bruun J.A. Outzen H. Øvervatn A. Bjørkøy G. Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy.J. Biol. Chem. 2007; 282: 24131-24145Crossref PubMed Scopus (2362) Google Scholar), Masaaki Komatsu (Ichimura et al., 2008Ichimura Y. Kumanomidou T. Sou Y.S. Mizushima T. Ezaki J. Ueno T. Kominami E. Yamane T. Tanaka K. Komatsu M. Structural basis for sorting mechanism of p62 in selective autophagy.J. Biol. Chem. 2008; 283: 22847-22857Crossref PubMed Scopus (453) Google Scholar), and Fuyuhiko Inagaki (Noda et al., 2008Noda N.N. Kumeta H. Nakatogawa H. Satoo K. Adachi W. Ishii J. Fujioka Y. Ohsumi Y. Inagaki F. Structural basis of target recognition by Atg8/LC3 during selective autophagy.Genes Cells. 2008; 13: 1211-1218Crossref PubMed Scopus (233) Google Scholar). Their studies revealed that the AIMs/LIRs are linear unstructured polypeptide sequences (WXXL, where X is any amino acid residue) located at the C terminus of Atg19 or in the middle of p62/SQSTM1. The polypeptides adopt an extended β-stranded conformation and form an intermolecular parallel β-sheet with the β-strand β2 of Atg8/LC3. The side chains of Trp and Leu are located deep inside two hydrophobic pockets (HPs) on Atg8/LC3 surfaces. The hydrophobic pocket 1 (HP1 or W-site) is formed by the N-terminal α-helical extensions of Atg8/LC3 and by hydrophobic residues within the UBL domain, accommodating the Trp. The hydrophobic pocket 2 (HP2 or L-site) is formed solely by residues within the UBL domain and interacts with the Leu. In addition, the negatively charged residues preceding or within the AIM/LIR motifs participate in ionic interactions with the positively charged Lys/Arg residues of Atg8/LC3. HP1 and HP2 together form the so-called LIR docking site (LDS) exploited by the majority of the described SARs.Figure 4Alignment of AIM/LIR, UIM, and A11BR/FIR Sequences in SARsShow full caption(A) Published AIM/LIR sequences were manually aligned according to the general core consensus Θ-X-X- Γ, where Θ is an aromatic (W/F/Y), Γ is a hydrophobic (L/I/V), and X can be any amino acid. Conserved aromatic and aliphatic residues (bold), negati" @default.
• W2978073856 created "2019-10-10" @default.
• W2978073856 creator A5035695744 @default.
• W2978073856 creator A5072603201 @default.
• W2978073856 date "2019-10-01" @default.
• W2978073856 modified "2023-10-11" @default.
• W2978073856 title "A Diversity of Selective Autophagy Receptors Determines the Specificity of the Autophagy Pathway" @default.
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