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Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency

After viral entry and reverse transcription, HIV-1 proviruses that fail to integrate are epigenetically silenced, but the underlying mechanism has remained unclear. Using a genome-wide CRISPR/Cas9 knockout screen, we identified the host SMC5/6 complex as essential for this epigenetic silencing. We s...

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Autores principales: Irwan, Ishak D., Bogerd, Hal P., Cullen, Bryan R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9712108/
https://www.ncbi.nlm.nih.gov/pubmed/36376394
http://dx.doi.org/10.1038/s41564-022-01264-z
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author Irwan, Ishak D.
Bogerd, Hal P.
Cullen, Bryan R.
author_facet Irwan, Ishak D.
Bogerd, Hal P.
Cullen, Bryan R.
author_sort Irwan, Ishak D.
collection PubMed
description After viral entry and reverse transcription, HIV-1 proviruses that fail to integrate are epigenetically silenced, but the underlying mechanism has remained unclear. Using a genome-wide CRISPR/Cas9 knockout screen, we identified the host SMC5/6 complex as essential for this epigenetic silencing. We show that SMC5/6 binds to and then SUMOylates unintegrated chromatinized HIV-1 DNA. Inhibition of SUMOylation, either by point mutagenesis of the SMC5/6 component NSMCE2—a SUMO E3 ligase—or using the SUMOylation inhibitor TAK-981, prevents epigenetic silencing, enables transcription from unintegrated HIV-1 DNA and rescues the replication of integrase-deficient HIV-1. Finally, we show that blocking SMC5/6 complex expression, or inhibiting its SUMOylation activity, suppresses the establishment of latent HIV-1 infections in both CD4+ T cell lines and primary human T cells. Collectively, our data show that the SMC5/6 complex plays a direct role in mediating the establishment of HIV-1 latency by epigenetically silencing integration-competent HIV-1 proviruses before integration.
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spelling pubmed-97121082022-12-02 Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency Irwan, Ishak D. Bogerd, Hal P. Cullen, Bryan R. Nat Microbiol Article After viral entry and reverse transcription, HIV-1 proviruses that fail to integrate are epigenetically silenced, but the underlying mechanism has remained unclear. Using a genome-wide CRISPR/Cas9 knockout screen, we identified the host SMC5/6 complex as essential for this epigenetic silencing. We show that SMC5/6 binds to and then SUMOylates unintegrated chromatinized HIV-1 DNA. Inhibition of SUMOylation, either by point mutagenesis of the SMC5/6 component NSMCE2—a SUMO E3 ligase—or using the SUMOylation inhibitor TAK-981, prevents epigenetic silencing, enables transcription from unintegrated HIV-1 DNA and rescues the replication of integrase-deficient HIV-1. Finally, we show that blocking SMC5/6 complex expression, or inhibiting its SUMOylation activity, suppresses the establishment of latent HIV-1 infections in both CD4+ T cell lines and primary human T cells. Collectively, our data show that the SMC5/6 complex plays a direct role in mediating the establishment of HIV-1 latency by epigenetically silencing integration-competent HIV-1 proviruses before integration. Nature Publishing Group UK 2022-11-14 2022 /pmc/articles/PMC9712108/ /pubmed/36376394 http://dx.doi.org/10.1038/s41564-022-01264-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Irwan, Ishak D.
Bogerd, Hal P.
Cullen, Bryan R.
Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency
title Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency
title_full Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency
title_fullStr Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency
title_full_unstemmed Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency
title_short Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency
title_sort epigenetic silencing by the smc5/6 complex mediates hiv-1 latency
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9712108/
https://www.ncbi.nlm.nih.gov/pubmed/36376394
http://dx.doi.org/10.1038/s41564-022-01264-z
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