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      The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins

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          Abstract

          The endoplasmic reticulum (ER) supports biosynthesis of proteins with diverse transmembrane domain (TMD) lengths and hydrophobicity. Features in transmembrane domains such as charged residues in ion channels are often functionally important, but could pose a challenge during cotranslational membrane insertion and folding. Our systematic proteomic approaches in both yeast and human cells revealed that the ER membrane protein complex (EMC) binds to and promotes the biogenesis of a range of multipass transmembrane proteins, with a particular enrichment for transporters. Proximity-specific ribosome profiling demonstrates that the EMC engages clients cotranslationally and immediately following clusters of TMDs enriched for charged residues. The EMC can remain associated after completion of translation, which both protects clients from premature degradation and allows recruitment of substrate-specific and general chaperones. Thus, the EMC broadly enables the biogenesis of multipass transmembrane proteins containing destabilizing features, thereby mitigating the trade-off between function and stability.

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          Most cited references41

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          1D and 2D annotation enrichment: a statistical method integrating quantitative proteomics with complementary high-throughput data

          Quantitative proteomics now provides abundance ratios for thousands of proteins upon perturbations. These need to be functionally interpreted and correlated to other types of quantitative genome-wide data such as the corresponding transcriptome changes. We describe a new method, 2D annotation enrichment, which compares quantitative data from any two 'omics' types in the context of categorical annotation of the proteins or genes. Suitable genome-wide categories are membership of proteins in biochemical pathways, their annotation with gene ontology terms, sub-cellular localization, the presence of protein domains or the membership in protein complexes. 2D annotation enrichment detects annotation terms whose members show consistent behavior in one or both of the data dimensions. This consistent behavior can be a correlation between the two data types, such as simultaneous up- or down-regulation in both data dimensions, or a lack thereof, such as regulation in one dimension but no change in the other. For the statistical formulation of the test we introduce a two-dimensional generalization of the nonparametric two-sample test. The false discovery rate is stringently controlled by correcting for multiple hypothesis testing. We also describe one-dimensional annotation enrichment, which can be applied to single omics data. The 1D and 2D annotation enrichment algorithms are freely available as part of the Perseus software.
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            RNA interference screen for human genes associated with West Nile virus infection.

            West Nile virus (WNV), and related flaviviruses such as tick-borne encephalitis, Japanese encephalitis, yellow fever and dengue viruses, constitute a significant global human health problem. However, our understanding of the molecular interaction of such flaviviruses with mammalian host cells is limited. WNV encodes only 10 proteins, implying that it may use many cellular proteins for infection. WNV enters the cytoplasm through pH-dependent endocytosis, undergoes cycles of translation and replication, assembles progeny virions in association with endoplasmic reticulum, and exits along the secretory pathway. RNA interference (RNAi) presents a powerful forward genetics approach to dissect virus-host cell interactions. Here we report the identification of 305 host proteins that affect WNV infection, using a human-genome-wide RNAi screen. Functional clustering of the genes revealed a complex dependence of this virus on host cell physiology, requiring a wide variety of molecules and cellular pathways for successful infection. We further demonstrate a requirement for the ubiquitin ligase CBLL1 in WNV internalization, a post-entry role for the endoplasmic-reticulum-associated degradation pathway in viral infection, and the monocarboxylic acid transporter MCT4 as a viral replication resistance factor. By extending this study to dengue virus, we show that flaviviruses have both overlapping and unique interaction strategies with host cells. This study provides a comprehensive molecular portrait of WNV-human cell interactions that forms a model for understanding single plus-stranded RNA virus infection, and reveals potential antiviral targets.
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              Defining human ERAD networks through an integrative mapping strategy

              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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                Author and article information

                Contributors
                Role: Reviewing Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                29 May 2018
                2018
                : 7
                : e37018
                Affiliations
                [1 ]deptDepartment of Cellular and Molecular Pharmacology University of California, San Francisco San FranciscoUnited States
                [2 ]deptDepartment of Proteomics and Signal Transduction Max Planck Institute of Biochemistry MartinsriedGermany
                [3 ]deptDepartment of Biochemistry and Biophysics University of California, San Francisco San FranciscoUnited States
                [4 ]deptDepartment of Biological Sciences University of Pittsburgh PittsburghUnited States
                [5 ]deptDepartment of Pharmaceutical Chemistry University of California, San Francisco San FranciscoUnited States
                [6 ]Chan Zuckerberg Biohub San FranciscoUnited States
                [7 ]Howard Hughes Medical Institute, University of California, San Francisco San FranciscoUnited States
                [8]University of Cambridge United Kingdom
                [9]University of Cambridge United Kingdom
                Author notes
                [‡]

                Department of Molecular Biology, Princeton University, Princeton, United States.

                [§]

                Calico Life Sciences LLC, San Francisco, United States.

                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0001-9846-3051
                http://orcid.org/0000-0001-8365-0436
                https://orcid.org/0000-0002-2653-1702
                https://orcid.org/0000-0003-2231-2577
                https://orcid.org/0000-0002-3166-3435
                http://orcid.org/0000-0003-2445-670X
                Article
                37018
                10.7554/eLife.37018
                5995541
                29809151
                fb4971b6-0329-465c-9912-d41b184f3f02
                © 2018, Shurtleff et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 27 March 2018
                : 26 May 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;
                Award ID: Investigator Program
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM075061
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100005237, Helen Hay Whitney Foundation;
                Award ID: Postdoctoral Fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100001033, Jane Coffin Childs Memorial Fund for Medical Research;
                Award ID: Postdoctoral Fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100007100, Sandler Foundation;
                Award ID: Program for Breakthrough Biomedical Research
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100008925, American Asthma Foundation;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001706, Louis-Jeantet Foundation;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100005984, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004189, Max-Planck-Gesellschaft;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: Gottfried Wilhelm Leibniz Prize MA 1764/2-1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: ERC2012-SyG_318987-ToPAG
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;
                Award ID: Faculty Scholar Grant
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AG041826
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 1DP2GM110772-01
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 8P41GM103481
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 1S10OD16229
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Cell Biology
                Custom metadata
                The ER membrane protein complex promotes the biogenesis of a subset multipass membrane proteins enriched for transporters and other proteins with destabilizing features in transmembrane domains.

                Life sciences
                emc,endoplasmic reticulum,transmembrane,transporter,ion channel,human
                Life sciences
                emc, endoplasmic reticulum, transmembrane, transporter, ion channel, human

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