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      Network organization of the human autophagy system

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      1 , 1 , 2 , 1
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          Abstract

          Autophagy, the process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome/vacuole for degradation, provides a primary route for turnover of stable and defective cellular proteins. Defects in this system are linked with numerous human diseases. While conserved protein kinase, lipid kinase, and ubiquitin-like (UBL) protein conjugation sub-networks controlling autophagosome formation and cargo recruitment have been defined, our understanding of the global organization of this system is limited. Here, we report a proteomic analysis of the autophagy interaction network (AIN) in human cells under conditions of ongoing (basal) autophagy, revealing a network of 751 interactions among 4 09 candidate interacting proteins with extensive connectivity among sub-networks. Many new AIN components have roles in vesicle trafficking, protein or lipid phosphorylation, and protein ubiquitination, and affect autophagosome number or flux when depleted by RNAi. The six ATG8 orthologs in humans (MAP1LC3/GABARAP proteins) interact with a cohort of 67 proteins, with extensive binding partner overlap between family members, and frequent involvement of a conserved surface on ATG8 proteins known to interact with LC3-interacting regions (LIR) in partner proteins. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for mechanistic analysis of this critical protein homeostasis pathway.

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          Most cited references27

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          Dynamics and diversity in autophagy mechanisms: lessons from yeast.

          Autophagy is a fundamental function of eukaryotic cells and is well conserved from yeast to humans. The most remarkable feature of autophagy is the synthesis of double membrane-bound compartments that sequester materials to be degraded in lytic compartments, a process that seems to be mechanistically distinct from conventional membrane traffic. The discovery of autophagy in yeast and the genetic tractability of this organism have allowed us to identify genes that are responsible for this process, which has led to the explosive growth of this research field seen today. Analyses of autophagy-related (Atg) proteins have unveiled dynamic and diverse aspects of mechanisms that underlie membrane formation during autophagy.
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            Defining the human deubiquitinating enzyme interaction landscape.

            Deubiquitinating enzymes (Dubs) function to remove covalently attached ubiquitin from proteins, thereby controlling substrate activity and/or abundance. For most Dubs, their functions, targets, and regulation are poorly understood. To systematically investigate Dub function, we initiated a global proteomic analysis of Dubs and their associated protein complexes. This was accomplished through the development of a software platform called CompPASS, which uses unbiased metrics to assign confidence measurements to interactions from parallel nonreciprocal proteomic data sets. We identified 774 candidate interacting proteins associated with 75 Dubs. Using Gene Ontology, interactome topology classification, subcellular localization, and functional studies, we link Dubs to diverse processes, including protein turnover, transcription, RNA processing, DNA damage, and endoplasmic reticulum-associated degradation. This work provides the first glimpse into the Dub interaction landscape, places previously unstudied Dubs within putative biological pathways, and identifies previously unknown interactions and protein complexes involved in this increasingly important arm of the ubiquitin-proteasome pathway.
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              Nix is a selective autophagy receptor for mitochondrial clearance.

              Autophagy is the cellular homeostatic pathway that delivers large cytosolic materials for degradation in the lysosome. Recent evidence indicates that autophagy mediates selective removal of protein aggregates, organelles and microbes in cells. Yet, the specificity in targeting a particular substrate to the autophagy pathway remains poorly understood. Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins, ubiquitin-like modifiers that are required for the growth of autophagosomal membranes. In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. Thus, Nix functions as an autophagy receptor, which mediates mitochondrial clearance after mitochondrial damage and during erythrocyte differentiation.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                2 June 2010
                20 June 2010
                1 July 2010
                1 January 2011
                : 466
                : 7302
                : 68-76
                Affiliations
                [1 ]Department of Pathology, Harvard Medical School, Boston MA 02115
                [2 ]Department of Cell Biology, Harvard Medical School, Boston MA 02115
                Author notes

                Author contributions. C.B. and M.E.S. performed experiments, analyzed data, and co-wrote the paper. S.P.G. provided proteomic infrastructure support and interpreted data. J.W.H. directed the research, interpreted data, and wrote the paper.

                Address correspondence to: wade_harper@ 123456hms.harvard.edu
                Article
                nihpa208952
                10.1038/nature09204
                2901998
                20562859
                d0f0dad8-57f8-48c9-967e-bbf20fce1adb

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Institute on Aging : NIA
                Award ID: R01 GM070565-05S1 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Institute on Aging : NIA
                Award ID: R01 GM054137-15 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Institute on Aging : NIA
                Award ID: R01 GM054137-14S1 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Institute on Aging : NIA
                Award ID: R01 GM054137-14 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Institute on Aging : NIA
                Award ID: R01 AG011085-18 ||AG
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Institute on Aging : NIA
                Award ID: R01 AG011085 ||AG
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