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      TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity


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          SAMHD1 possesses multiple functions, but whether cellular factors regulate SAMHD1 expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that SAMHD1 is a restriction factor for EV71. Importantly, we identify TRIM21, an E3 ubiquitin ligase, as a key regulator of SAMHD1, which specifically interacts and degrades SAMHD1 through the proteasomal pathway. However, TRIM21 has no effect on EV71 replication itself. Moreover, we prove that interferon production stimulated by EV71 infection induces increased TRIM21 and SAMHD1 expression, whereas increasing TRIM21 overrides SAMHD1 inhibition of EV71 in cells and in a neonatal mouse model. TRIM21‐mediated degradation of SAMHD1 also affects SAMHD1‐dependent restriction of HIV‐1 and the regulation of interferon production. We further identify the functional domains in TRIM21 required for SAMHD1 binding and the ubiquitination site K622 in SAMHD1 and show that phosphorylation of SAMHD1 at T592 also blocks EV71 restriction. Our findings illuminate how EV71 overcomes SAMHD1 inhibition via the upregulation of TRIM21.


          SAMHD1, a well‐studied HIV‐1 restriction factor, counteracts also the hand‐foot‐and‐mouth disease pathogen EV71. Upon infection, the E3 ligase TRIM21 is up‐regulated in an IFN‐dependent manner to induce SAMHD1 degradation and to relieve virus restriction.

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          Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu.

          Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha, and it consists of protein-based tethers, which we term 'tetherins', that cause retention of fully formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, we identify CD317 (also called BST2 or HM1.24), a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukaemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces and, after endocytosis, in CD317-positive compartments. Vpu co-localized with CD317 and inhibited these effects. Inhibition of Vpu function and consequent mobilization of tetherin's antiviral activity is a potential therapeutic strategy in HIV/AIDS.
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            A Method for the Acute and Rapid Degradation of Endogenous Proteins

            Summary Methods for the targeted disruption of protein function have revolutionized science and greatly expedited the systematic characterization of genes. Two main approaches are currently used to disrupt protein function: DNA knockout and RNA interference, which act at the genome and mRNA level, respectively. A method that directly alters endogenous protein levels is currently not available. Here, we present Trim-Away, a technique to degrade endogenous proteins acutely in mammalian cells without prior modification of the genome or mRNA. Trim-Away harnesses the cellular protein degradation machinery to remove unmodified native proteins within minutes of application. This rapidity minimizes the risk that phenotypes are compensated and that secondary, non-specific defects accumulate over time. Because Trim-Away utilizes antibodies, it can be applied to a wide range of target proteins using off-the-shelf reagents. Trim-Away allows the study of protein function in diverse cell types, including non-dividing primary cells where genome- and RNA-targeting methods are limited.
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              Intracellular antibody-bound pathogens stimulate immune signaling via Fc-receptor TRIM21

              Antibodies can be carried into the cell during pathogen infection where they are detected by the ubiquitously expressed cytosolic antibody receptor TRIM21. Here we show that TRIM21 recognition of intracellular antibodies activates immune signaling. TRIM21 catalyses K63-ubiquitin chain formation, stimulating transcription factor pathways NF-κB, AP-1 and IRF3, IRF5, IRF7. Activation results in proinflammatory cytokine production, modulation of natural killer (NK) stress ligands and the induction of an antiviral state. Intracellular antibody signaling is abrogated by genetic deletion of TRIM21 and is recovered by ectopic TRIM21 expression. Antibody sensing by TRIM21 can be stimulated upon infection by DNA or RNA non-enveloped viruses or intracellular bacteria. The antibody-TRIM21 detection system provides potent, comprehensive innate immune activation, independent of known pattern recognition receptors.

                Author and article information

                EMBO Rep
                EMBO Rep
                EMBO Reports
                John Wiley and Sons Inc. (Hoboken )
                04 December 2019
                07 January 2020
                04 December 2019
                : 21
                : 1 ( doiID: 10.1002/embr.v21.1 )
                : e47528
                [ 1 ] The First Hospital of Jilin University Institute of Virology and AIDS Research Changchun China
                [ 2 ] Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education) Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou China
                Author notes
                [*] [* ]Corresponding author. Tel: +86 431‐88782148; Fax: +86 431‐85654528; E‐mail: zhangwenyan@ 123456jlu.edu.cn
                Author information
                © 2019 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 04 December 2018
                : 09 October 2019
                : 13 November 2019
                Page count
                Figures: 13, Tables: 0, Pages: 18, Words: 13875
                Funded by: NSF | Foundation for Innovative Research Groups of the National Natural Science Foundation of China , open-funder-registry 10.13039/100000001;
                Award ID: 81672004
                Award ID: 31270202
                Award ID: 81701987
                Funded by: JLU | Program for Jilin University Science and Technology Innovative Research Team (Program for JLU Science and Technology Innovative Research Team) , open-funder-registry 10.13039/100009091;
                Award ID: JLUSTIRT, 2017TD‐05
                Funded by: Science and Technology Department of Jilin Province
                Award ID: 20190101003JH
                Funded by: Key Laboratory of Molecular Virology, Jilin Province
                Award ID: 20102209
                Funded by: Youth Foundation of the First Hospital of Jilin University
                Award ID: JDYY82017003
                Funded by: Graduate Innovation Fund of Jilin University
                Funded by: Chinese Ministry of Science and Technology , open-funder-registry 10.13039/501100002855;
                Award ID: 2018ZX10302104‐001‐010
                Custom metadata
                07 January 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.4 mode:remove_FC converted:07.01.2020

                Molecular biology
                ev71 infection,interferon induction,regulation,samhd1 inhibition,ubiquitin–proteasome degradation,immunology,microbiology, virology & host pathogen interaction,post-translational modifications, proteolysis & proteomics


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