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      Defining human ERAD networks through an integrative mapping strategy

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          SUMMARY

          Proteins that fail to correctly fold or assemble into oligomeric complexes in the endoplasmic reticulum (ER) are degraded by a ubiquitin and proteasome dependent process known as ER-associated degradation (ERAD). Although many individual components of the ERAD system have been identified, how these proteins are organised into a functional network that coordinates recognition, ubiquitination, and dislocation of substrates across the ER membrane is not well understood. We have investigated the functional organisation of the mammalian ERAD system using a systems-level strategy that integrates proteomics, functional genomics, and the transcriptional response to ER stress. This analysis supports an adaptive organisation for the mammalian ERAD machinery and reveals a number of metazoan-specific genes not previously linked to ERAD.

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          Most cited references57

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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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            One step at a time: endoplasmic reticulum-associated degradation.

            Protein folding in the endoplasmic reticulum (ER) is monitored by ER quality control (ERQC) mechanisms. Proteins that pass ERQC criteria traffic to their final destinations through the secretory pathway, whereas non-native and unassembled subunits of multimeric proteins are degraded by the ER-associated degradation (ERAD) pathway. During ERAD, molecular chaperones and associated factors recognize and target substrates for retrotranslocation to the cytoplasm, where they are degraded by the ubiquitin-proteasome machinery. The discovery of diseases that are associated with ERAD substrates highlights the importance of this pathway. Here, we summarize our current understanding of each step during ERAD, with emphasis on the factors that catalyse distinct activities.
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              A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol.

              Elimination of misfolded proteins from the endoplasmic reticulum (ER) by retro-translocation is an important physiological adaptation to ER stress. This process requires recognition of a substrate in the ER lumen and its subsequent movement through the membrane by the cytosolic p97 ATPase. Here we identify a p97-interacting membrane protein complex in the mammalian ER that links these two events. The central component of the complex, Derlin-1, is a homologue of Der1, a yeast protein whose inactivation prevents the elimination of misfolded luminal ER proteins. Derlin-1 associates with different substrates as they move through the membrane, and inactivation of Derlin-1 in C. elegans causes ER stress. Derlin-1 interacts with US11, a virally encoded ER protein that specifically targets MHC class I heavy chains for export from the ER, as well as with VIMP, a novel membrane protein that recruits the p97 ATPase and its cofactor.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature Cell Biology
                1465-7392
                1476-4679
                2 December 2011
                27 November 2011
                01 July 2012
                : 14
                : 1
                : 93-105
                Affiliations
                [1 ]Department of Biology & Bio-X Program, Stanford University, Lorry Lokey Bldg., 337 Campus Drive, Stanford, California 94305, USA
                [2 ]Ludwig Institute for Cancer Research, University of Oxford, ORCRB, Headington, Oxford, OX3 7DQ, UK
                [3 ]SRI International, Menlo Park, California 94025, USA
                [4 ]Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
                Author notes
                Correspondence should be address to R.R.K. Phone: 650-723-7581, FAX: 650-724-4927, kopito@ 123456stanford.edu
                [5]

                current address: Division of Biological Sciences, UC San Diego, La Jolla, California 92093

                [6]

                These authors contributed equally to this work

                Article
                nihpa333655
                10.1038/ncb2383
                3250479
                22119785
                fb07bc2d-d584-453b-921e-ee9c6bb4bfab

                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 Neurological Disorders and Stroke : NINDS
                Award ID: R01 NS042842-09 || NS
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM074874-06 || GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: F32 GM086026-03 || GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: F32 GM086026-02 || GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: F32 GM086026-01 || GM
                Categories
                Article

                Cell biology
                interaction network,er-associated degradation (erad),hrd1,comppass analysis,ubac2,fam8a1,mammalian emc

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