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      A molecular perspective of mammalian autophagosome biogenesis

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          Abstract

          Autophagy is a highly conserved process and is essential for the maintenance of cellular homeostasis. Autophagy occurs at a basal level in all cells, but it can be up-regulated during stress, starvation, or infection. Misregulation of autophagy has been linked to various disorders, including cancer, neurodegeneration, and immune diseases. Here, we discuss the essential proteins acting in the formation of an autophagosome, with a focus on the ULK and VPS34 kinase complexes, phosphatidylinositol 3-phosphate effector proteins, and the transmembrane autophagy-related protein ATG9. The function and regulation of these and other autophagy-related proteins acting during formation will be addressed, in particular during amino acid starvation.

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          Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum

          Elizabeth L. Axe, Simon A. Walker, Maria Manifava … (2008)
          Autophagy is the engulfment of cytosol and organelles by double-membrane vesicles termed autophagosomes. Autophagosome formation is known to require phosphatidylinositol 3-phosphate (PI(3)P) and occurs near the endoplasmic reticulum (ER), but the exact mechanisms are unknown. We show that double FYVE domain–containing protein 1, a PI(3)P-binding protein with unusual localization on ER and Golgi membranes, translocates in response to amino acid starvation to a punctate compartment partially colocalized with autophagosomal proteins. Translocation is dependent on Vps34 and beclin function. Other PI(3)P-binding probes targeted to the ER show the same starvation-induced translocation that is dependent on PI(3)P formation and recognition. Live imaging experiments show that this punctate compartment forms near Vps34-containing vesicles, is in dynamic equilibrium with the ER, and provides a membrane platform for accumulation of autophagosomal proteins, expansion of autophagosomal membranes, and emergence of fully formed autophagosomes. This PI(3)P-enriched compartment may be involved in autophagosome biogenesis. Its dynamic relationship with the ER is consistent with the idea that the ER may provide important components for autophagosome formation.
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            Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.

            Zhenyu Yue, Shengkan Jin, Chingwen Yang … (2003)
            The biochemical properties of beclin 1 suggest a role in two fundamentally important cell biological pathways: autophagy and apoptosis. We show here that beclin 1-/- mutant mice die early in embryogenesis and beclin 1+/- mutant mice suffer from a high incidence of spontaneous tumors. These tumors continue to express wild-type beclin 1 mRNA and protein, establishing that beclin 1 is a haploinsufficient tumor suppressor gene. Beclin 1-/- embryonic stem cells have a severely altered autophagic response, whereas their apoptotic response to serum withdrawal or UV light is normal. These results demonstrate that beclin 1 is a critical component of mammalian autophagy and establish a role for autophagy in tumor suppression. They both provide a biological explanation for recent evidence implicating beclin 1 in human cancer and suggest that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy.
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              Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy.

              Joungmok Kim, Young Chul Kim, Chong Fang … (2013)
              Autophagy is a stress response protecting cells from unfavorable conditions, such as nutrient starvation. The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates both intracellular vesicle trafficking and autophagy induction. Here, we show that AMPK plays a key role in regulating different Vps34 complexes. AMPK inhibits the nonautophagy Vps34 complex by phosphorylating T163/S165 in Vps34 and therefore suppresses overall PI(3)P production and protects cells from starvation. In parallel, AMPK activates the proautophagy Vps34 complex by phosphorylating S91/S94 in Beclin1 to induce autophagy. Atg14L, an autophagy-essential gene present only in the proautophagy Vps34 complex, inhibits Vps34 phosphorylation but increases Beclin1 phosphorylation by AMPK. As such, Atg14L dictates the differential regulation (either inhibition or activation) of different Vps34 complexes in response to glucose starvation. Our study reveals an intricate molecular regulation of Vps34 complexes by AMPK in nutrient stress response and autophagy. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Biol Chem
                Journal ID (iso-abbrev): J. Biol. Chem
                Journal ID (hwp): jbc
                Journal ID (pmc): jbc
                Journal ID (publisher-id): JBC
                Title: The Journal of Biological Chemistry
                Publisher: American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
                ISSN (Print): 0021-9258
                ISSN (Electronic): 1083-351X
                Publication date (Print): 13 April 2018
                Publication date (Electronic): 25 January 2018
                Publication date PMC-release: 25 January 2018
                Volume: 293
                Issue: 15
                Pages: 5386-5395
                Affiliations
                [1]From the Molecular Cell Biology of Autophagy Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, United Kingdom
                Author notes
                [1 ] To whom correspondence should be addressed. E-mail: sharon.tooze@ 123456crick.ac.uk .

                Edited by George N. DeMartino

                Author information
                https://orcid.org/0000-0002-2182-3116
                Article
                Publisher ID: R117.810366
                DOI: 10.1074/jbc.R117.810366
                PMC ID: 5900756
                PubMed ID: 29371398
                SO-VID: d853f6fc-0f15-4585-b495-87415b4fc946
                Copyright © © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
                License:

                Author's Choice—Final version free via Creative Commons CC-BY license.

                History
                Funding
                Funded by: Francis Crick Institute , open-funder-registry 10.13039/100010438;
                Award ID: FC001187
                Categories
                Subject: Thematic Minireviews

                ScienceOpen disciplines: Biochemistry
                Keywords: autophagy,intracellular trafficking,phosphatidylinositide 3-kinase (pi 3-kinase),post-translational modification,signaling,atg proteins,atg9,ulk1,vps34,wipi2
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: autophagy, intracellular trafficking, phosphatidylinositide 3-kinase (pi 3-kinase), post-translational modification, signaling, atg proteins, atg9, ulk1, vps34, wipi2

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