Cargando…
SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells
SAMHD1 is a cellular triphosphohydrolase (dNTPase) proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting the supply of the dNTP substrates. Yet, phosphorylation of T592 downregulates SAMHD1 antiviral activity, but not its dNTPase function, implying that additional m...
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319325/ https://www.ncbi.nlm.nih.gov/pubmed/34321470 http://dx.doi.org/10.1038/s41467-021-24802-5 |
_version_ | 1783730422274850816 |
---|---|
author | Martinat, Charlotte Cormier, Arthur Tobaly-Tapiero, Joëlle Palmic, Noé Casartelli, Nicoletta Mahboubi, Bijan Coggins, Si’Ana A. Buchrieser, Julian Persaud, Mirjana Diaz-Griffero, Felipe Espert, Lucile Bossis, Guillaume Lesage, Pascale Schwartz, Olivier Kim, Baek Margottin-Goguet, Florence Saïb, Ali Zamborlini, Alessia |
author_facet | Martinat, Charlotte Cormier, Arthur Tobaly-Tapiero, Joëlle Palmic, Noé Casartelli, Nicoletta Mahboubi, Bijan Coggins, Si’Ana A. Buchrieser, Julian Persaud, Mirjana Diaz-Griffero, Felipe Espert, Lucile Bossis, Guillaume Lesage, Pascale Schwartz, Olivier Kim, Baek Margottin-Goguet, Florence Saïb, Ali Zamborlini, Alessia |
author_sort | Martinat, Charlotte |
collection | PubMed |
description | SAMHD1 is a cellular triphosphohydrolase (dNTPase) proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting the supply of the dNTP substrates. Yet, phosphorylation of T592 downregulates SAMHD1 antiviral activity, but not its dNTPase function, implying that additional mechanisms contribute to viral restriction. Here, we show that SAMHD1 is SUMOylated on residue K595, a modification that relies on the presence of a proximal SUMO-interacting motif (SIM). Loss of K595 SUMOylation suppresses the restriction activity of SAMHD1, even in the context of the constitutively active phospho-ablative T592A mutant but has no impact on dNTP depletion. Conversely, the artificial fusion of SUMO2 to a non-SUMOylatable inactive SAMHD1 variant restores its antiviral function, a phenotype that is reversed by the phosphomimetic T(592)E mutation. Collectively, our observations clearly establish that lack of T592 phosphorylation cannot fully account for the restriction activity of SAMHD1. We find that SUMOylation of K595 is required to stimulate a dNTPase-independent antiviral activity in non-cycling immune cells, an effect that is antagonized by cyclin/CDK-dependent phosphorylation of T592 in cycling cells. |
format | Online Article Text |
id | pubmed-8319325 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-83193252021-08-03 SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells Martinat, Charlotte Cormier, Arthur Tobaly-Tapiero, Joëlle Palmic, Noé Casartelli, Nicoletta Mahboubi, Bijan Coggins, Si’Ana A. Buchrieser, Julian Persaud, Mirjana Diaz-Griffero, Felipe Espert, Lucile Bossis, Guillaume Lesage, Pascale Schwartz, Olivier Kim, Baek Margottin-Goguet, Florence Saïb, Ali Zamborlini, Alessia Nat Commun Article SAMHD1 is a cellular triphosphohydrolase (dNTPase) proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting the supply of the dNTP substrates. Yet, phosphorylation of T592 downregulates SAMHD1 antiviral activity, but not its dNTPase function, implying that additional mechanisms contribute to viral restriction. Here, we show that SAMHD1 is SUMOylated on residue K595, a modification that relies on the presence of a proximal SUMO-interacting motif (SIM). Loss of K595 SUMOylation suppresses the restriction activity of SAMHD1, even in the context of the constitutively active phospho-ablative T592A mutant but has no impact on dNTP depletion. Conversely, the artificial fusion of SUMO2 to a non-SUMOylatable inactive SAMHD1 variant restores its antiviral function, a phenotype that is reversed by the phosphomimetic T(592)E mutation. Collectively, our observations clearly establish that lack of T592 phosphorylation cannot fully account for the restriction activity of SAMHD1. We find that SUMOylation of K595 is required to stimulate a dNTPase-independent antiviral activity in non-cycling immune cells, an effect that is antagonized by cyclin/CDK-dependent phosphorylation of T592 in cycling cells. Nature Publishing Group UK 2021-07-28 /pmc/articles/PMC8319325/ /pubmed/34321470 http://dx.doi.org/10.1038/s41467-021-24802-5 Text en © The Author(s) 2021 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 Martinat, Charlotte Cormier, Arthur Tobaly-Tapiero, Joëlle Palmic, Noé Casartelli, Nicoletta Mahboubi, Bijan Coggins, Si’Ana A. Buchrieser, Julian Persaud, Mirjana Diaz-Griffero, Felipe Espert, Lucile Bossis, Guillaume Lesage, Pascale Schwartz, Olivier Kim, Baek Margottin-Goguet, Florence Saïb, Ali Zamborlini, Alessia SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells |
title | SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells |
title_full | SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells |
title_fullStr | SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells |
title_full_unstemmed | SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells |
title_short | SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells |
title_sort | sumoylation of samhd1 at lysine 595 is required for hiv-1 restriction in non-cycling cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319325/ https://www.ncbi.nlm.nih.gov/pubmed/34321470 http://dx.doi.org/10.1038/s41467-021-24802-5 |
work_keys_str_mv | AT martinatcharlotte sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT cormierarthur sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT tobalytapierojoelle sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT palmicnoe sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT casartellinicoletta sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT mahboubibijan sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT cogginssianaa sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT buchrieserjulian sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT persaudmirjana sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT diazgrifferofelipe sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT espertlucile sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT bossisguillaume sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT lesagepascale sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT schwartzolivier sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT kimbaek sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT margottingoguetflorence sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT saibali sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells AT zamborlinialessia sumoylationofsamhd1atlysine595isrequiredforhiv1restrictioninnoncyclingcells |