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      RanBP2 regulates the anti-retroviral activity of TRIM5α by SUMOylation at a predicted phosphorylated SUMOylation motif

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          Abstract

          TRIM5α is a cytoplasmic restriction factor that blocks post-entry retroviral infection. Evidence suggests that its antiviral activity can be regulated by SUMO, but how this is achieved remains unknown. Here, we show that TRIM5α forms a complex with RanGAP1, Ubc9, and RanBP2 at the nuclear pore, and that RanBP2 E3 SUMO ligase promotes the SUMOylation of endogenous TRIM5α in the cytoplasm. Loss of RanBP2 blocked SUMOylation of TRIM5α, altered its localization in primary cells, and suppressed the antiviral activity of both rhesus and human orthologs. In cells, human TRIM5α is modified on K84 within a predicted phosphorylated SUMOylation motif (pSUM) and not on K10 as found in vitro. Non-modified TRIM5α lacked antiviral activity, indicating that only SUMOylated TRIM5α acts as a restriction factor. This work illustrates the importance of the nuclear pore in intrinsic antiviral immunity, acting as a hub where virus, SUMO machinery, and restriction factors can meet.

          Abstract

          Ghizlane Maarifi et al. demonstrate that a nuclear pore component, RanBP2, SUMOylates the retroviral restriction factor TRIM5α to promote its antiviral activity. This study suggests an unexpected role of the nuclear pore for regulating anti-viral innate immunity.

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          Most cited references33

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          The nucleoporin RanBP2 has SUMO1 E3 ligase activity.

          Posttranslational modification with SUMO1 regulates protein/protein interactions, localization, and stability. SUMOylation requires the E1 enzyme Aos1/Uba2 and the E2 enzyme Ubc9. A family of E3-like factors, PIAS proteins, was discovered recently. Here we show that the nucleoporin RanBP2/Nup358 also has SUMO1 E3-like activity. RanBP2 directly interacts with the E2 enzyme Ubc9 and strongly enhances SUMO1-transfer from Ubc9 to the SUMO1 target Sp100. The E3-like activity is contained within a 33 kDa domain of RanBP2 that lacks RING finger motifs and does not resemble PIAS family proteins. Our findings place SUMOylation at the cytoplasmic filaments of the NPC and suggest that, at least for some substrates, modification and nuclear import are linked events.
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            SUMO--nonclassical ubiquitin.

            SUMO (small ubiquitin-related modifier) is the best-characterized member of a growing family of ubiquitin-related proteins. It resembles ubiquitin in its structure, its ability to be ligated to other proteins, as well as in the mechanism of ligation. However, in contrast to ubiquitination-often the first step on a one-way road to protein degradation-SUMOlation does not seem to mark proteins for degradation. In fact, SUMO may even function as an antagonist of ubiquitin in the degradation of selected proteins. While most SUMO targets are still at large, available data provide compelling evidence for a role of SUMO in the regulation of protein-protein interactions and/or subcellular localization.
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              An E3-like factor that promotes SUMO conjugation to the yeast septins.

              Covalent attachment of the ubiquitin-related protein SUMO to other proteins participates in many processes including signal transduction, transcriptional regulation, and growth control. We report the characterization of Siz1 as an E3-like factor in the SUMO pathway. Siz1 is required for SUMO attachment to the S. cerevisiae septins in vivo and strongly stimulates septin sumoylation in vitro. Siz1 and the related protein Siz2 promote SUMO conjugation to different substrates at different stages of the cell cycle and, together, are required for most SUMO conjugation in yeast. Siz1, Siz2, and the PIAS (protein inhibitor of activated STAT) proteins form a conserved family defined by an unusual RING-related motif. Our results suggest that this family functions by promoting SUMO conjugation to specific substrates.
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                Author and article information

                Contributors
                nathalie.arhel@irim.cnrs.fr
                Journal
                Commun Biol
                Commun Biol
                Communications Biology
                Nature Publishing Group UK (London )
                2399-3642
                15 November 2018
                15 November 2018
                2018
                : 1
                : 193
                Affiliations
                [1 ]ISNI 0000 0001 2097 0141, GRID grid.121334.6, Institut de Recherche en Infectiologie de Montpellier (IRIM), , Université de Montpellier, CNRS, ; 34090 Montpellier, France
                [2 ]ISNI 0000 0001 2217 0017, GRID grid.7452.4, Saint-Louis Hospital, INSERM, , Paris 7 University, ; 75010 Paris, France
                [3 ]Bioaxial SAS, 75014 Paris, France
                [4 ]ISNI 0000 0001 2308 1657, GRID grid.462844.8, Center for Research in Myology, INSERM, CNRS, , Paris 6 University, ; 75013 Paris, France
                Author information
                http://orcid.org/0000-0001-9793-419X
                http://orcid.org/0000-0001-5309-1725
                Article
                198
                10.1038/s42003-018-0198-0
                6237768
                30456314
                a7406dc9-b51f-46f8-8d11-0bb3f7a591e1
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 March 2018
                : 19 October 2018
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                © The Author(s) 2018

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