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• W3017267170 abstract "The Golgi complex regulates production and delivery of proteins and lipids, and is a site of lipid metabolism needed for autophagy, in particular PI(4)P.ATG9A is the sole transmembrane ATG protein and has a crucial role in the formation of the autophagosome, one new role being the delivery of the metabolizing enzymes of PI to the nascent autophagosome.ATG9A trafficking from the Golgi and recycling endosome is controlled by the coat adaptor complexes AP1, AP2, and AP4, and several BAR-domain containing proteins BIF1, SNX18, and recently Arfaptin2.The control of ATG9A delivery to the forming autophagosome allows in situ PI(4)P production for the initiation of phagophore formation. Autophagy is traditionally depicted as a signaling cascade that culminates in the formation of an autophagosome that degrades cellular cargo. However, recent studies have identified myriad pathways and cellular organelles underlying the autophagy process, be it as signaling platforms or through the contribution of proteins and lipids. The Golgi complex is recognized as being a central transport hub in the cell, with a critical role in endocytic trafficking and endoplasmic reticulum (ER) to plasma membrane (PM) transport. However, the Golgi is also an important site of key autophagy regulators, including the protein autophagy-related (ATG)-9A and the lipid, phosphatidylinositol-4-phosphate [PI(4)P]. In this review, we highlight the central function of this organelle in autophagy as a transport hub supplying various components of autophagosome formation. Autophagy is traditionally depicted as a signaling cascade that culminates in the formation of an autophagosome that degrades cellular cargo. However, recent studies have identified myriad pathways and cellular organelles underlying the autophagy process, be it as signaling platforms or through the contribution of proteins and lipids. The Golgi complex is recognized as being a central transport hub in the cell, with a critical role in endocytic trafficking and endoplasmic reticulum (ER) to plasma membrane (PM) transport. However, the Golgi is also an important site of key autophagy regulators, including the protein autophagy-related (ATG)-9A and the lipid, phosphatidylinositol-4-phosphate [PI(4)P]. In this review, we highlight the central function of this organelle in autophagy as a transport hub supplying various components of autophagosome formation. Autophagy is a process whereby cellular material is degraded to procure nutrients or to remove organelles and proteins [1.Mercer T.J. et al.A molecular perspective of mammalian autophagosome biogenesis.J. Biol. Chem. 2018; 293: 5386-5395Crossref PubMed Scopus (158) Google Scholar]. This highly conserved, essential process is mediated by a cohort of proteins called the ATG proteins, which are conserved from yeast to humans. There are many different cues that initiate autophagy, but perhaps the best known is amino acid starvation, which induces autophagy to offset the lack of nutrients. Autophagy can be seen as a complex pathway of membrane formation and reformation, centered on the de novo creation of a double-membraned autophagosome, which will fuse with the lysosome so as to degrade its cargo [1.Mercer T.J. et al.A molecular perspective of mammalian autophagosome biogenesis.J. Biol. Chem. 2018; 293: 5386-5395Crossref PubMed Scopus (158) Google Scholar]. Many aspects of autophagosome formation are by now well understood and, in simplified form, can be viewed as a cascade starting from the mammalian target of rapamycin (mTOR), which activates the Unc-51-like kinase 1 (ULK1) complex, followed by phosphatidylinositol 3-phosphate [PI(3)P] generation at the ER by the phosphatidylinositol 3-kinase catalytic subunit type 3 [PI(3)KC3] complex I. The generation of PI(3)P at the ER leads to the recruitment of autophagy effectors to form the omegasome, the earliest autophagic structure, which grows into the phagophore. One of the effectors that bind PI(3)P is WIPI2B, which has an important role in the lipidation and membrane association of LC3/GABARAPs (e.g., LC3-II; see Glossary), which are essential for autophagy and are the most widely used markers of autophagosomes. Once the phagophore has grown and enclosed its cargo, it closes to form an autophagosome [1.Mercer T.J. et al.A molecular perspective of mammalian autophagosome biogenesis.J. Biol. Chem. 2018; 293: 5386-5395Crossref PubMed Scopus (158) Google Scholar,2.Kabeya Y. et al.LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.EMBO J. 2000; 19: 5720-5728Crossref PubMed Scopus (5433) Google Scholar]. An important player in each step of this process is ATG9A, a transmembrane protein that cycles between the trans-Golgi network (TGN) and the ATG9 compartment [3.Orsi A. et al.Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy.Mol. Biol. Cell. 2012; 23: 1860-1873Crossref PubMed Scopus (367) Google Scholar]. Curiously, although essential at all stages for autophagosome formation, ATG9A does not have a defined function as far as we know [2.Kabeya Y. et al.LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.EMBO J. 2000; 19: 5720-5728Crossref PubMed Scopus (5433) Google Scholar]. Thus, many questions remain about autophagosomal membrane formation and the role of ATG9A. In particular, because it is the only transmembrane core autophagy protein, could ATG9A contribute lipids to help form the autophagosome? In addition, which proteins or lipid species could be trafficked by ATG9A to the expanding autophagosome? In this review, we address these questions from the viewpoint of the Golgi complex, focusing on the role of the Golgi in autophagy. In particular, we discuss the control of autophagosome formation through the cycling of ATG9A vesicles from the TGN, the role of ATG9A in the contribution of PI(4)P, a lipid gaining in importance in autophagy, and how this is regulated from a Golgi perspective. The Golgi complex was first discovered in 1898 as an ‘internal reticular apparatus’, and comprises a series of interconnected, well-organized, sac-like structures [4.Nakano A. Luini A. Passage through the Golgi.Curr. Opin. Cell Biol. 2010; 22: 471-478Crossref PubMed Scopus (72) Google Scholar]. Comprising three distinct subcompartments, the cis-Golgi, medial-Golgi, and trans-Golgi, and a fourth compartment, the TGN (Figure 1), it has been characterized as a trafficking hub of proteins on their way from the ER to the endosomal system or to the PM to be secreted. The correct trafficking of proteins to their destination relies on the tight regulation of retention, selection, and transport via coat proteins, and the maintenance of signaling lipids in the Golgi [5.Glick B.S. Nakano A. Membrane traffic within the Golgi apparatus.Annu. Rev. Cell Dev. Biol. 2009; 25: 113-132Crossref PubMed Scopus (234) Google Scholar]. Additionally, the Golgi is an important site for the post-translational modification of these proteins, especially glycosylation, which requires a host of specialized enzymes, such as glycan-modifying proteins [6.Welch L.G. Munro S. A tale of short tails, through thick and thin: investigating the sorting mechanisms of Golgi enzymes.FEBS Lett. 2019; 593: 2452-2465Crossref PubMed Scopus (38) Google Scholar,7.Mollenhauer H.H. Morre D.J. Perspectives on Golgi apparatus form and function.J. Electron. Microsc. Tech. 1991; 17: 2-14Crossref PubMed Scopus (57) Google Scholar]. As stated earlier, one of the prominent roles of the Golgi complex is the trafficking of proteins from the ER to the endocytic compartments and PM. Newly synthesized proteins destined for the Golgi are sorted into COPII vesicles at ER exit sites [8.Szul T. Sztul E. COPII and COPI traffic at the ER-Golgi interface.Physiology (Bethesda). 2011; 26: 348-364Crossref PubMed Scopus (92) Google Scholar,9.Stephens D.J. De novo formation, fusion and fission of mammalian COPII-coated endoplasmic reticulum exit sites.EMBO Rep. 2003; 4: 210-217Crossref PubMed Scopus (85) Google Scholar] and trafficked to the ER-to-Golgi intermediate compartment (ERGIC; Figure 1). From the ERGIC, which acts as a sorting station, two things can happen: (i) proteins are transported to the cis-Golgi in an anterograde pathway; or (ii) mislocalized proteins are recycled back to the ER in a retrograde pathway through COPI vesicles [8.Szul T. Sztul E. COPII and COPI traffic at the ER-Golgi interface.Physiology (Bethesda). 2011; 26: 348-364Crossref PubMed Scopus (92) Google Scholar,10.Rocca D.L. et al.Inhibition of Arp2/3-mediated actin polymerization by PICK1 regulates neuronal morphology and AMPA receptor endocytosis.Nat. Cell Biol. 2008; 10: 259-271Crossref PubMed Scopus (176) Google Scholar]. Proteins transported to the cis-Golgi pass through the medial- and trans-Golgi, arriving at the TGN to be sorted by different coat proteins (see later). These proteins are those destined for the endocytic compartment, the lysosome, or PM, where they are incorporated or released into the extracellular space. Although this review does not focus on intra-Golgi trafficking (that which occurs between the cis-, medial-, and trans-Golgi), it does focus on trafficking out of the Golgi via the TGN and its impact on autophagosome formation. The architecture of the Golgi complex itself (ribbon-like versus Golgi stacks) is dependent upon tethers, including GRIP and coiled-coil domain containing 88 kDa (GCC88), and disruption of this ribbon-shaped architecture by loss of GCC88 leads to aberrant nutrient sensing and alteration of autophagy [11.Gosavi P. et al.The Golgi ribbon in mammalian cells negatively regulates autophagy by modulating mTOR activity.J. Cell Sci. 2018; 131jcs211987Crossref PubMed Scopus (22) Google Scholar]. However, this aspect of Golgi biology will not be further covered in this review. A variety of different cargo-containing vesicles form at the Golgi and are targeted to their destination through the binding of a protein coat. Despite the variety of the coats involved in TGN exit, only adaptor protein (AP) complexes (Figure 2) have been firmly connected with autophagy so far. These five AP proteins (AP1–AP5) [12.Tan J.Z.A. Gleeson P.A. Cargo sorting at the trans-Golgi network for shunting into specific transport routes: role of Arf small G proteins and adaptor complexes.Cells. 2019; 8: 531Crossref PubMed Scopus (29) Google Scholar,13.Sanger A. et al.Adaptor protein complexes and disease at a glance.J. Cell Sci. 2019; 132jcs222992Crossref PubMed Scopus (45) Google Scholar] constitute a family of coat proteins that can be incorporated into either clathrin-coated vesicles (AP1 and AP2), or vesicles partially dependent (in the case of AP3) or independent (for AP4 and AP5) of clathrin. One of the first pieces of evidence for a role of TGN vesicular transport towards forming autophagosomes was illustrated by AP1 complex colocalization with LC3-positive structures upon rapamycin treatment, as well as autophagy inhibition in AP1 knockdown cells [14.Guo Y. et al.AP1 is essential for generation of autophagosomes from the trans-Golgi network.J. Cell Sci. 2012; 125: 1706-1715Crossref PubMed Scopus (90) Google Scholar]. Here, we further discuss the role of vesicular exit from the Golgi in relation to autophagy, and focus on the heterotetrameric AP complexes. Besides proteins, lipids, such as PI(4)P, also have a role in maintaining Golgi cis- versus trans- asymmetry and in protein trafficking; PI(4)P is also an important lipid for autophagy [15.Wang H. et al.GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 7015-7020Crossref PubMed Scopus (122) Google Scholar,16.Judith D. et al.ATG9A shapes the forming autophagosome through Arfaptin 2 and phosphatidylinositol 4-kinase IIIbeta.J. Cell Biol. 2019; 218: 1634-1652Crossref PubMed Scopus (89) Google Scholar]. One of the main roles of PI(4)P in the Golgi, primarily at the TGN, is to recruit and target cytoplasmic PI(4)P-binding effector proteins. As an example of its role in Golgi protein sorting, Golgi phosphoprotein 3 (GOLPH3) is able to bind PI(4)P at the trans-Golgi and simultaneously interact with mislocalized Golgi membrane proteins and COPI to sort them for retrograde recycling [17.Wood C.S. et al.Local control of phosphatidylinositol 4-phosphate signaling in the Golgi apparatus by Vps74 and Sac1 phosphoinositide phosphatase.Mol. Biol. Cell. 2012; 23: 2527-2536Crossref PubMed Scopus (49) Google Scholar]. Although important, multiple pathways beyond PI(4)P can lead to vesicular transport from the Golgi (Golgi vesicular transport; e.g., reviewed in [18.Guo Y. et al.Protein sorting at the trans-Golgi network.Annu. Rev. Cell Dev. Biol. 2014; 30: 169-206Crossref PubMed Scopus (153) Google Scholar]). Besides its role in the formation of vesicles from the trans-Golgi, PI(4)P is also crucial for the formation of ER–Golgi contact sites (ERTGoCS), which constitute an important lipid transfer site between the ER and the Golgi complex (Figure 1 and Box 1). These contact sites have a role in the regulation of lipid levels in the Golgi complex, necessary to maintain Golgi asymmetry and effector protein binding, as explained earlier, and can regulate other lipid-transporting enzymes (Box 1). Thus, its level is tightly regulated by the interplay between the PI(4) kinases (PI(4)K), most notably PI(4)KIIIβ, and phosphatases (i.e., SAC1), each of which is regulated by a complex feedback loop involving other Golgi-localized lipids and proteins (Box 1).Box 1Overview of PI(4)P Regulation at the GolgiEnzymes residing in the Golgi have a role not only in maintaining its lipid composition, but also in producing and modifying lipids to be transported to the endocytic system. Here, we give an overview of the synthesis and regulation of PI(4)P and some of its effects (Figure I).In mammalian cells, there are four different PI(4)Ks, of which PI(4)KIIα and PI(4)KIIIβ localize to the Golgi complex. These enzymes work by phosphorylating phosphatidylinositol on the 4 position hydroxyl group of the inositol ring. PI(4)KIIIβ is activated by protein kinase D (PKD) at the Golgi by phosphorylation at serine 294 [19.Hausser A. et al.Protein kinase D regulates vesicular transport by phosphorylating and activating phosphatidylinositol-4 kinase IIIβ at the Golgi complex.Nat. Cell Biol. 2005; 7: 880-886Crossref PubMed Scopus (273) Google Scholar], while, in turn, PKD is recruited to the Golgi by binding diacylglycerol (DAG) [20.Futerman A.H. Riezman H. The ins and outs of sphingolipid synthesis.Trends Cell Biol. 2005; 15: 312-318Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar] (Figure IB). By providing a binding site for ceramide transfer protein (CERT), the level of PI(4)P itself indirectly regulates the supply of ceramide from the ER, which, together with phosphatidylcholine (PC), is converted into sphingomyelin and DAG by sphingomyelin synthase (SMS) (Figure IB). To complete the feedback loop, CERT is also a substrate for phosphorylation by PKD, which limits its activity [21.Diaz Anel A.M. Phospholipase C beta3 is a key component in the Gbetagamma/PKCeta/PKD-mediated regulation of trans-Golgi network to plasma membrane transport.Biochem. J. 2007; 406: 157-165Crossref PubMed Scopus (56) Google Scholar]. Thus, the increase in ceramide through CERT leads to more DAG, recruiting PKD, which in turn activates PI(4)KIIIβ and inhibits CERT, leading to an equilibrium (Figure IB).PI(4)P is also regulated through potential transfer and dephosphorylation at so-called ‘ERTGoCS’. ERTGoCS are mediated by the ER docking proteins vesicle-associated membrane protein (VAMP)-associated protein A and B (VAPA and B), which can bind different proteins and tether them to the ER [22.Murphy S.E. Levine T.P. VAP, a versatile access point for the endoplasmic reticulum: review and analysis of FFAT-like motifs in the VAPome.Biochim. Biophys. Acta. 2016; 1861: 952-961Crossref PubMed Scopus (169) Google Scholar] (Figure IA). The aforementioned CERT is such a protein, targeting to the ER through a FFAT motif (two phenylalanines in an acidic tract), which binds VAPA/B, and by a pleckstrin homology (PH) domain, binding PI(4)P at the Golgi, where it transfers ceramide [23.Kawano M. et al.Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a VAMP-associated protein-interacting FFAT motif of CERT.J. Biol. Chem. 2006; 281: 30279-30288Crossref PubMed Scopus (226) Google Scholar].Besides CERT, oxysterol-binding protein 1 (OSBP1), and oxysterol-binding protein-related protein (ORP) 9 and 10 can also bridge the ER and Golgi through a FFAT motif and a PH domain [24.Venditti R. et al.Molecular determinants of ER-Golgi contacts identified through a new FRET-FLIM system.J. Cell Biol. 2019; 218: 1055-1065Crossref PubMed Scopus (59) Google Scholar,25.Mesmin B. et al.A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP.Cell. 2013; 155: 830-843Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar], where they may mediate the exchange of Golgi-localized PI(4)P and ER-synthesized phosphatidylserine (Figure IA).Besides the transfer of lipids, the ER is also able to modulate lipids at the Golgi through SAC1, an ER-resident protein phosphatase. SAC1 is able to dephosphorylate ER-localized PI(4)P in cis and, through an interaction with phosphatidyl-four-phosphate-adaptor-protein-1 (FAPP1), is able to dephosphorylate Golgi-localized PI(4)P in trans [24.Venditti R. et al.Molecular determinants of ER-Golgi contacts identified through a new FRET-FLIM system.J. Cell Biol. 2019; 218: 1055-1065Crossref PubMed Scopus (59) Google Scholar,25.Mesmin B. et al.A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP.Cell. 2013; 155: 830-843Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar] (Figure IA). Thus, ERTGoCS contact sites are important sites of lipid trafficking and modulation between the ER and the Golgi. Enzymes residing in the Golgi have a role not only in maintaining its lipid composition, but also in producing and modifying lipids to be transported to the endocytic system. Here, we give an overview of the synthesis and regulation of PI(4)P and some of its effects (Figure I). In mammalian cells, there are four different PI(4)Ks, of which PI(4)KIIα and PI(4)KIIIβ localize to the Golgi complex. These enzymes work by phosphorylating phosphatidylinositol on the 4 position hydroxyl group of the inositol ring. PI(4)KIIIβ is activated by protein kinase D (PKD) at the Golgi by phosphorylation at serine 294 [19.Hausser A. et al.Protein kinase D regulates vesicular transport by phosphorylating and activating phosphatidylinositol-4 kinase IIIβ at the Golgi complex.Nat. Cell Biol. 2005; 7: 880-886Crossref PubMed Scopus (273) Google Scholar], while, in turn, PKD is recruited to the Golgi by binding diacylglycerol (DAG) [20.Futerman A.H. Riezman H. The ins and outs of sphingolipid synthesis.Trends Cell Biol. 2005; 15: 312-318Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar] (Figure IB). By providing a binding site for ceramide transfer protein (CERT), the level of PI(4)P itself indirectly regulates the supply of ceramide from the ER, which, together with phosphatidylcholine (PC), is converted into sphingomyelin and DAG by sphingomyelin synthase (SMS) (Figure IB). To complete the feedback loop, CERT is also a substrate for phosphorylation by PKD, which limits its activity [21.Diaz Anel A.M. Phospholipase C beta3 is a key component in the Gbetagamma/PKCeta/PKD-mediated regulation of trans-Golgi network to plasma membrane transport.Biochem. J. 2007; 406: 157-165Crossref PubMed Scopus (56) Google Scholar]. Thus, the increase in ceramide through CERT leads to more DAG, recruiting PKD, which in turn activates PI(4)KIIIβ and inhibits CERT, leading to an equilibrium (Figure IB). PI(4)P is also regulated through potential transfer and dephosphorylation at so-called ‘ERTGoCS’. ERTGoCS are mediated by the ER docking proteins vesicle-associated membrane protein (VAMP)-associated protein A and B (VAPA and B), which can bind different proteins and tether them to the ER [22.Murphy S.E. Levine T.P. VAP, a versatile access point for the endoplasmic reticulum: review and analysis of FFAT-like motifs in the VAPome.Biochim. Biophys. Acta. 2016; 1861: 952-961Crossref PubMed Scopus (169) Google Scholar] (Figure IA). The aforementioned CERT is such a protein, targeting to the ER through a FFAT motif (two phenylalanines in an acidic tract), which binds VAPA/B, and by a pleckstrin homology (PH) domain, binding PI(4)P at the Golgi, where it transfers ceramide [23.Kawano M. et al.Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a VAMP-associated protein-interacting FFAT motif of CERT.J. Biol. Chem. 2006; 281: 30279-30288Crossref PubMed Scopus (226) Google Scholar]. Besides CERT, oxysterol-binding protein 1 (OSBP1), and oxysterol-binding protein-related protein (ORP) 9 and 10 can also bridge the ER and Golgi through a FFAT motif and a PH domain [24.Venditti R. et al.Molecular determinants of ER-Golgi contacts identified through a new FRET-FLIM system.J. Cell Biol. 2019; 218: 1055-1065Crossref PubMed Scopus (59) Google Scholar,25.Mesmin B. et al.A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP.Cell. 2013; 155: 830-843Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar], where they may mediate the exchange of Golgi-localized PI(4)P and ER-synthesized phosphatidylserine (Figure IA). Besides the transfer of lipids, the ER is also able to modulate lipids at the Golgi through SAC1, an ER-resident protein phosphatase. SAC1 is able to dephosphorylate ER-localized PI(4)P in cis and, through an interaction with phosphatidyl-four-phosphate-adaptor-protein-1 (FAPP1), is able to dephosphorylate Golgi-localized PI(4)P in trans [24.Venditti R. et al.Molecular determinants of ER-Golgi contacts identified through a new FRET-FLIM system.J. Cell Biol. 2019; 218: 1055-1065Crossref PubMed Scopus (59) Google Scholar,25.Mesmin B. et al.A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP.Cell. 2013; 155: 830-843Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar] (Figure IA). Thus, ERTGoCS contact sites are important sites of lipid trafficking and modulation between the ER and the Golgi. ATG9A is the only conserved transmembrane ATG protein and, in mammalian cells, resides in the TGN, recycling endosome, and endosomal compartments (Figure 2Ai) [3.Orsi A. et al.Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy.Mol. Biol. Cell. 2012; 23: 1860-1873Crossref PubMed Scopus (367) Google Scholar,26.Young A.R.J. et al.Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes.J. Cell Sci. 2006; 119: 3888-3900Crossref PubMed Scopus (597) Google Scholar,27.Webber J.L. Tooze S.A. Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP.EMBO J. 2010; 29: 27-40Crossref PubMed Scopus (191) Google Scholar]. During starvation, ATG9A accumulates in a vesicular compartment called the ATG9 compartment, from where it can be mobilized to interact with the forming and expanding phagophores (Figure 2Aii) [26.Young A.R.J. et al.Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes.J. Cell Sci. 2006; 119: 3888-3900Crossref PubMed Scopus (597) Google Scholar]. Autophagy depends on the regulation of ATG9A trafficking, which is tightly modulated by different protein components. For example, the ULK complex promotes ATG9A trafficking between the TGN and the ATG9A compartment (Figure 2Ai) [26.Young A.R.J. et al.Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes.J. Cell Sci. 2006; 119: 3888-3900Crossref PubMed Scopus (597) Google Scholar,28.Papinski D. et al.Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase.Mol. Cell. 2014; 53: 471-483Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar,29.Reggiori F. et al.The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure.Dev. Cell. 2004; 6: 79-90Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar] and, similarly, p38α MAP kinase-interacting protein (p38IP) positively regulates ATG9A trafficking during amino-acid deprivation [27.Webber J.L. Tooze S.A. Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP.EMBO J. 2010; 29: 27-40Crossref PubMed Scopus (191) Google Scholar]. While not entirely clear why, the distribution of ATG9A in the absence of ULK1 appears to be primarily perinuclear, while perturbation of the p38IP interaction, which activates p38α MAPK, appears to cause the retention of ATG9A in the endosome [26.Young A.R.J. et al.Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes.J. Cell Sci. 2006; 119: 3888-3900Crossref PubMed Scopus (597) Google Scholar,27.Webber J.L. Tooze S.A. Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP.EMBO J. 2010; 29: 27-40Crossref PubMed Scopus (191) Google Scholar]. Recently, AP complexes and BAR-domain containing proteins have also been implicated in the regulation of ATG9A trafficking from the TGN and the endosomal compartments to the site of the nascent autophagosome, as also discussed later and in Figure 2A and Box 2.Box 2BAR-Domain Containing Proteins Involved in AutophagyThe BAR domain protein superfamily has been described as being crucial in several membrane-sculpting events [39.Peter B.J. et al.BAR domains as sensors of membrane curvature: the amphiphysin BAR structure.Science. 2004; 303: 495-499Crossref PubMed Scopus (1348) Google Scholar]. By virtue of their ability to sense different membrane curvatures, BAR-domain containing proteins tightly orchestrate multiple intracellular trafficking pathways [10.Rocca D.L. et al.Inhibition of Arp2/3-mediated actin polymerization by PICK1 regulates neuronal morphology and AMPA receptor endocytosis.Nat. Cell Biol. 2008; 10: 259-271Crossref PubMed Scopus (176) Google Scholar,40.Jackson T.R. et al.Cytohesins and centaurins: mediators of PI 3-kinase-regulated Arf signaling.Trends Biochem. Sci. 2000; 25: 489-495Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar]. Three BAR-domain containing proteins have been implicated in autophagy.Bif-1Also known as SH3GLB1/endophilin B, Bif-1 belongs to the endophilin protein family characterized by the presence of an N-terminal N-BAR domain and a C-terminal SH3 domain. Initially discovered as a Bax-binding protein [41.Cuddeback S.M. et al.Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax.J. Biol. Chem. 2001; 276: 20559-20565Crossref PubMed Scopus (143) Google Scholar], Bif-1 has been shown to drive membrane curvature and liposome tubulation through the N-BAR domain [42.Farsad K. et al.Generation of high curvature membranes mediated by direct endophilin bilayer interactions.J. Cell Biol. 2001; 155: 193-200Crossref PubMed Scopus (486) Google Scholar]. In vivo, Bif-1 associates with the membrane compartment of different intracellular organelles, such as the Golgi complex or mitochondria, and regulates multiple membrane dynamics events and the formation of vesicles [42.Farsad K. et al.Generation of high curvature membranes mediated by direct endophilin bilayer interactions.J. Cell Biol. 2001; 155: 193-200Crossref PubMed Scopus (486) Google Scholar,43.Takahashi Y. et al.Loss of Bif-1 suppresses Bax/Bak conformational change and mitochondrial apoptosis.Mol. Cell. Biol. 2005; 25: 9369-9382Crossref PubMed Scopus (156) Google Scholar].SNX18Sorting nexin 18 (SNX18) is a member of the sorting nexin protein family characterized by a phox homolog (PX) domain, responsible for the binding of SNXs to PIs. SNX18 belongs to the PX-BAR protein subfamily and is involved in multiple membrane remodeling events of the endocytic system [44.Håberg K. et al.SNX18 is an SNX9 paralog that acts as a membrane tubulator in AP-1-positive endosomal trafficking.J. Cell Sci. 2008; 121: 1495-1505Crossref PubMed Scopus (72) Google Scholar]. In vitro, SNX18 tubulates liposomes through the PX-BAR domain and shows the propensity to bind PI(4,5)P2. In vivo, SNX18 binds dynamin 2 (DNM2) through its SH3 domain and mediates the formation of AP1-positive carriers, promoting DNM2 GTPase activity [44.Håberg K. et al.SNX18 is an SNX9 paralog that acts as a membrane tubulator in AP-1-positive endosomal trafficking.J. Cell Sci. 2008; 121: 1495-1505Crossref PubMed Scopus (72) Google Scholar].ArfaptinsInitially identified as ARF1-binding proteins [45.Kanoh H. et al.Arfaptin 1, a putative cytosolic target protein of ADP-ribosylation factor, is recruited to Golgi membranes.J. Biol. Chem. 1997; 272: 5421-5429Crossref PubMed Scopus (90) Google Scholar], arfaptins localize at the TGN through the interaction with ARF-like 1 (Arl1) [46.Man Z. et al.Arfaptins are localized to the trans-Golgi by interaction with Arl1, but not Arfs.J. Biol. Chem. 2011; 286: 11569-11578Crossref PubMed Scopus (40) Google Scholar]; their binding to PI(4)P is driven by an amphipathic helix that precedes the BAR domain [47.Cruz-Garcia D. et al.Recruitment of arfaptins to the trans-Golgi network by PI(4)P and their involvement in cargo export.EMBO J. 2013; 32: 1717-1729Crossref PubMed Scopus (48) Google Scholar]. Arfaptins have been described as key regulators of several membrane re" @default.
• W3017267170 created "2020-04-24" @default.
• W3017267170 creator A5035288330 @default.
• W3017267170 creator A5052898943 @default.
• W3017267170 creator A5077715520 @default.
• W3017267170 creator A5078557146 @default.
• W3017267170 date "2020-06-01" @default.
• W3017267170 modified "2023-10-12" @default.
• W3017267170 title "The Golgi as an Assembly Line to the Autophagosome" @default.
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