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      Mechanism of Stx17 recruitment to autophagosomes via IRGM and mammalian Atg8 proteins

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          Abstract

          Mammalian autophagosomes mature into autolysosomes through SNARE-driven processes that include syntaxin 17 (Stx17). Kumar et al. show that Stx17 interacts with mammalian Atg8s and with the small guanosine triphosphatase IRGM and that both IRGM and mAtg8s help recruit Stx17 to autophagosomes.

          Abstract

          Autophagy is a conserved eukaryotic process with metabolic, immune, and general homeostatic functions in mammalian cells. Mammalian autophagosomes fuse with lysosomes in a SNARE-driven process that includes syntaxin 17 (Stx17). How Stx17 translocates to autophagosomes is unknown. In this study, we show that the mechanism of Stx17 recruitment to autophagosomes in human cells entails the small guanosine triphosphatase IRGM. Stx17 directly interacts with IRGM, and efficient Stx17 recruitment to autophagosomes requires IRGM. Both IRGM and Stx17 directly interact with mammalian Atg8 proteins, thus being guided to autophagosomes. We also show that Stx17 is significant in defense against infectious agents and that Stx17–IRGM interaction is targeted by an HIV virulence factor Nef.

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          Most cited references40

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          The role of Atg proteins in autophagosome formation.

          Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.
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            SNAREs--engines for membrane fusion.

            Since the discovery of SNARE proteins in the late 1980s, SNAREs have been recognized as key components of protein complexes that drive membrane fusion. Despite considerable sequence divergence among SNARE proteins, their mechanism seems to be conserved and is adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesis and synaptic transmission. A fascinating picture of these robust nanomachines is emerging.
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              Directed evolution of APEX2 for electron microscopy and proteomics

              APEX is an engineered peroxidase that functions both as an electron microscopy tag, and as a promiscuous labeling enzyme for live-cell proteomics. Because the limited sensitivity of APEX precludes applications requiring low APEX expression, we used yeast display evolution to improve its catalytic efficiency. Our evolved APEX2 is far more active in cells, enabling the superior enrichment of endogenous mitochondrial and endoplasmic reticulum membrane proteins and the use of electron microscopy to resolve the sub-mitochondrial localization of calcium uptake regulatory protein MICU1.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                jcb
                The Journal of Cell Biology
                Rockefeller University Press
                0021-9525
                1540-8140
                5 March 2018
                : 217
                : 3
                : 997-1013
                Affiliations
                [1 ]Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM
                [2 ]Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM
                [3 ]Department of Molecular Cell Biology, Centre for Cancer Biomedicine, University of Oslo and Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway
                [4 ]Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM
                [5 ]Department of Mathematics and Statistics, University of New Mexico, Albuquerque, NM
                Author notes
                Correspondence to Vojo Deretic: vderetic@ 123456salud.unm.edu
                Author information
                http://orcid.org/0000-0002-1062-3143
                http://orcid.org/0000-0001-6549-2788
                http://orcid.org/0000-0002-9939-1923
                http://orcid.org/0000-0002-3520-7605
                http://orcid.org/0000-0002-9150-2676
                http://orcid.org/0000-0002-3624-5208
                Article
                201708039
                10.1083/jcb.201708039
                5839791
                29420192
                76de4e6e-a29e-47b6-8722-7b3d48f40a3c
                © 2018 Kumar et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 06 August 2017
                : 12 November 2017
                : 22 December 2017
                Funding
                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;
                Award ID: EB019589
                Award ID: GM085273
                Award ID: CA118100
                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;
                Award ID: AI042999
                Award ID: AI111935
                Award ID: P20GM121176
                Categories
                Research Articles
                Article
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                Cell biology
                Cell biology

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