Phospholipids in Autophagosome Formation and Fusion.

Autophagosomes are double membrane organelles that are formed during a process referred to as macroautophagy. They serve to deliver cytoplasmic material into the lysosome for degradation. Autophagosomes are formed in a de novo manner and are the result of substantial membrane remodeling processes involving numerous protein-lipid interactions. While most studies focus on the proteins involved in autophagosome formation it is obvious that lipids including phospholipids, sphingolipids and sterols play an equally important role. Here we summarize the current knowledge about the role of lipids, especially focusing on phospholipids and their interplay with the autophagic protein machinery during autophagosome formation and fusion.

[1]  Xiang Zhou,et al.  Regulation of Mammalian Autophagy by Class II and III PI 3-Kinases through PI3P Synthesis , 2013, PloS one.

[2]  Jan Steyaert,et al.  Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes , 2015, Science.

[3]  N. Mizushima,et al.  The role of the Atg1/ULK1 complex in autophagy regulation. , 2010, Current opinion in cell biology.

[4]  M. Mari,et al.  Lipid droplets and their component triglycerides and steryl esters regulate autophagosome biogenesis , 2015, The EMBO journal.

[5]  Gareth Griffiths,et al.  Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum , 2008, The Journal of cell biology.

[6]  Shmuel Pietrokovski,et al.  Atg8: an autophagy-related ubiquitin-like protein family , 2011, Genome Biology.

[7]  E. Bertini,et al.  Mutations in the inositol polyphosphate-5-phosphatase E gene link phosphatidyl inositol signaling to the ciliopathies , 2009, Nature Genetics.

[8]  S. Munro,et al.  Membrane Delivery to the Yeast Autophagosome from the Golgi–Endosomal System , 2010, Molecular biology of the cell.

[9]  Michael D. George,et al.  A protein conjugation system essential for autophagy , 1998, Nature.

[10]  T. Noda,et al.  A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation , 2009, Nature Cell Biology.

[11]  T. Noda,et al.  Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. , 2008, Cell structure and function.

[12]  Eeva-Liisa Eskelinen,et al.  3D tomography reveals connections between the phagophore and endoplasmic reticulum , 2009, Autophagy.

[13]  K. Shokat,et al.  Shaping Development of Autophagy Inhibitors with the Structure of the Lipid Kinase Vps34 , 2010, Science.

[14]  G. Meer,et al.  Membrane lipids: where they are and how they behave , 2008, Nature Reviews Molecular Cell Biology.

[15]  T. Tatsuta,et al.  Lipid droplet–mediated ER homeostasis regulates autophagy and cell survival during starvation , 2016, The Journal of cell biology.

[16]  Rie Ichikawa,et al.  Atg9 vesicles are an important membrane source during early steps of autophagosome formation , 2012, The Journal of cell biology.

[17]  Yigong Shi,et al.  Crystal structure and biochemical analyses reveal Beclin 1 as a novel membrane binding protein , 2012, Cell Research.

[18]  Y. Ohsumi,et al.  The Atg18-Atg2 Complex Is Recruited to Autophagic Membranes via Phosphatidylinositol 3-Phosphate and Exerts an Essential Function* , 2008, Journal of Biological Chemistry.

[19]  M. Fernández-Fernández,et al.  3D electron tomography of brain tissue unveils distinct Golgi structures that sequester cytoplasmic contents in neurons , 2017, Journal of Cell Science.

[20]  Peter K. Kim,et al.  Mitochondria Supply Membranes for Autophagosome Biogenesis during Starvation , 2010, Cell.

[21]  Q. Zhong,et al.  Autophagosome targeting and membrane curvature sensing by Barkor/Atg14(L) , 2011, Proceedings of the National Academy of Sciences.

[22]  Takeshi Noda,et al.  A ubiquitin-like system mediates protein lipidation , 2000, Nature.

[23]  Takeshi Noda,et al.  In Vivo and in Vitro Reconstitution of Atg8 Conjugation Essential for Autophagy* , 2004, Journal of Biological Chemistry.

[24]  Takeshi Noda,et al.  The Reversible Modification Regulates the Membrane-Binding State of Apg8/Aut7 Essential for Autophagy and the Cytoplasm to Vacuole Targeting Pathway , 2000, The Journal of cell biology.

[25]  T. Noda,et al.  The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. , 2008, Molecular biology of the cell.

[26]  James H. Hurley,et al.  Architecture of the Atg17 Complex as a Scaffold for Autophagosome Biogenesis , 2012, Cell.

[27]  T. Wollert,et al.  The Atg1–kinase complex tethers Atg9-vesicles to initiate autophagy , 2016, Nature Communications.

[28]  T. Yoshimori,et al.  Autophagosome–lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome , 2016, The EMBO journal.

[29]  T. Yoshimori,et al.  The autophagosome: origins unknown, biogenesis complex , 2013, Nature Reviews Molecular Cell Biology.

[30]  S. Small,et al.  The phospholipase D1 pathway modulates macroautophagy. , 2010, Nature communications.

[31]  Y. Ohsumi,et al.  Physiological pH and Acidic Phospholipids Contribute to Substrate Specificity in Lipidation of Atg8* , 2008, Journal of Biological Chemistry.

[32]  C. Sasakawa,et al.  A Tecpr1-dependent selective autophagy pathway targets bacterial pathogens. , 2011, Cell host & microbe.

[33]  A. Ernst,et al.  Cargo recognition and trafficking in selective autophagy , 2014, Nature Cell Biology.

[34]  Bruno Antonny,et al.  Mechanisms of membrane curvature sensing. , 2011, Annual review of biochemistry.

[35]  Y. Ohsumi,et al.  Atg8, a Ubiquitin-like Protein Required for Autophagosome Formation, Mediates Membrane Tethering and Hemifusion , 2007, Cell.

[36]  T. Proikas-Cezanne,et al.  Control of autophagy initiation by phosphoinositide 3‐phosphatase jumpy , 2009, The EMBO journal.

[37]  Takeshi Noda,et al.  LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing , 2000, The EMBO journal.

[38]  M. Babu,et al.  ER exit sites are physical and functional core autophagosome biogenesis components , 2013, Molecular biology of the cell.

[39]  Mary G. Lin,et al.  Structure and function of the ULK1 complex in autophagy. , 2016, Current opinion in cell biology.

[40]  T. Noda,et al.  Modulation of Local PtdIns3P Levels by the PI Phosphatase MTMR3 Regulates Constitutive Autophagy , 2010, Traffic.

[41]  F. Inagaki,et al.  The Atg12-Atg5 Conjugate Has a Novel E3-like Activity for Protein Lipidation in Autophagy* , 2007, Journal of Biological Chemistry.

[42]  Michael I. Wilson,et al.  WIPI2 Links LC3 Conjugation with PI3P, Autophagosome Formation, and Pathogen Clearance by Recruiting Atg12–5-16L1 , 2014, Molecular cell.

[43]  M. Thumm,et al.  PI3P binding by Atg21 organises Atg8 lipidation , 2015, The EMBO journal.

[44]  K. Shokat,et al.  PIKfyve Regulation of Endosome-Linked Pathways , 2009, Traffic.

[45]  Taki Nishimura,et al.  Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets , 2012, Molecular biology of the cell.

[46]  L. Collinson,et al.  Autophagy initiation by ULK complex assembly on ER tubulovesicular regions marked by ATG9 vesicles , 2016, Nature Communications.

[47]  S. Gygi,et al.  Network organization of the human autophagy system , 2010, Nature.

[48]  T. Yoshimori,et al.  Up-to-date membrane biogenesis in the autophagosome formation. , 2013, Current opinion in cell biology.

[49]  J. Guan,et al.  FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells , 2008, The Journal of cell biology.

[50]  Henri G. Franquelim,et al.  Molecular Mechanism of Autophagic Membrane-Scaffold Assembly and Disassembly , 2014, Cell.

[51]  Yasushi Hiraoka,et al.  Autophagosomes form at ER–mitochondria contact sites , 2013, Nature.

[52]  Daniel J. Klionsky,et al.  Autophagy fights disease through cellular self-digestion , 2008, Nature.

[53]  N. Mizushima,et al.  Ultrastructural analysis of autophagosome organization using mammalian autophagy-deficient cells , 2014, Journal of Cell Science.

[54]  Daniel J. Klionsky,et al.  An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis , 2010, The Journal of cell biology.

[55]  D. Rubinsztein,et al.  Plasma membrane contributes to the formation of pre-autophagosomal structures , 2010, Nature Cell Biology.

[56]  Y. Ohsumi,et al.  Yeast and mammalian autophagosomes exhibit distinct phosphatidylinositol 3-phosphate asymmetries , 2014, Nature Communications.

[57]  S. Tooze,et al.  Recycling endosomes contribute to autophagosome formation , 2012, Autophagy.

[58]  M. Komatsu,et al.  Phosphatidylserine in Addition to Phosphatidylethanolamine Is an in Vitro Target of the Mammalian Atg8 Modifiers, LC3, GABARAP, and GATE-16* , 2006, Journal of Biological Chemistry.

[59]  C. Kraft,et al.  Mechanism and functions of membrane binding by the Atg5–Atg12/Atg16 complex during autophagosome formation , 2012, The EMBO journal.

[60]  G. Bjørkøy,et al.  FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end–directed vesicle transport , 2010, The Journal of cell biology.

[61]  S. Martens,et al.  Mechanisms of Selective Autophagy , 2016, Journal of molecular biology.

[62]  D. Klionsky,et al.  Phosphatidylinositol-3-Phosphate Clearance Plays a Key Role in Autophagosome Completion , 2012, Current Biology.

[63]  B. Levine,et al.  GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion , 2015, Proceedings of the National Academy of Sciences.

[64]  Patricia Grob,et al.  Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex , 2014, eLife.

[65]  C. Kraft,et al.  Mechanisms and regulation of autophagosome formation. , 2012, Current opinion in cell biology.

[66]  T. Miyatsuka,et al.  Golgi membrane‐associated degradation pathway in yeast and mammals , 2016, The EMBO journal.

[67]  Y. Ohsumi,et al.  Fine mapping of autophagy-related proteins during autophagosome formation in Saccharomyces cerevisiae , 2013, Journal of Cell Science.

[68]  T. Natsume,et al.  Atg101, a novel mammalian autophagy protein interacting with Atg13 , 2009, Autophagy.

[69]  Zvulun Elazar,et al.  LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. , 2011, Developmental cell.

[70]  J. Bewersdorf,et al.  Lipidation of the LC3/GABARAP family of autophagy proteins relies upon a membrane curvature-sensing domain in Atg3 , 2014, Nature Cell Biology.

[71]  T. Noda,et al.  Regulation of membrane biogenesis in autophagy via PI3P dynamics. , 2010, Seminars in cell & developmental biology.

[72]  J. Hurley,et al.  A HORMA domain in Atg13 mediates PI 3-kinase recruitment in autophagy , 2013, Proceedings of the National Academy of Sciences.

[73]  S. Vanni,et al.  A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment , 2014, Nature Communications.

[74]  M. Thumm,et al.  Structural and functional characterization of the two phosphoinositide binding sites of PROPPINs, a β-propeller protein family , 2012, Proceedings of the National Academy of Sciences.

[75]  Xuejun Jiang,et al.  SNARE Proteins Are Required for Macroautophagy , 2011, Cell.

[76]  S. Emr,et al.  A novel protein kinase homolog essential for protein sorting to the yeast lysosome-like vacuole , 1991, Cell.

[77]  P. Wang,et al.  Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy. , 2015, Molecular cell.