SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells

Charlotte Martinat, Arthur Cormier, Joëlle Tobaly-Tapiero, Noé Palmic, Nicoletta Casartelli, Bijan Mahboubi, Si’Ana A. Coggins, Julian Buchrieser, Mirjana Persaud, Felipe Diaz-Griffero, Lucile Espert, Guillaume Bossis, Pascale Lesage, Olivier Schwartz, Baek Kim, Florence Margottin-Goguet, Ali Saïb and Alessia Zamborlini ()
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Charlotte Martinat: INSERM U944, CNRS UMR 7212, Genomes & Cell Biology of Disease Unit, Institut de Recherche Saint-Louis, Université de Paris, Hôpital Saint-Louis
Arthur Cormier: INSERM U944, CNRS UMR 7212, Genomes & Cell Biology of Disease Unit, Institut de Recherche Saint-Louis, Université de Paris, Hôpital Saint-Louis
Joëlle Tobaly-Tapiero: INSERM U944, CNRS UMR 7212, Genomes & Cell Biology of Disease Unit, Institut de Recherche Saint-Louis, Université de Paris, Hôpital Saint-Louis
Noé Palmic: INSERM U944, CNRS UMR 7212, Genomes & Cell Biology of Disease Unit, Institut de Recherche Saint-Louis, Université de Paris, Hôpital Saint-Louis
Nicoletta Casartelli: Institut Pasteur, Virus and Immunity Unit, CNRS-UMR3569
Bijan Mahboubi: Emory School of Medicine
Si’Ana A. Coggins: Emory School of Medicine
Julian Buchrieser: Institut Pasteur, Virus and Immunity Unit, CNRS-UMR3569
Mirjana Persaud: Albert Einstein College of Medicine, Microbiology and Immunology
Felipe Diaz-Griffero: Albert Einstein College of Medicine, Microbiology and Immunology
Lucile Espert: IRIM, University of Montpellier, UMR 9004 CNRS
Guillaume Bossis: IGMM, Univ Montpellier, CNRS
Pascale Lesage: INSERM U944, CNRS UMR 7212, Genomes & Cell Biology of Disease Unit, Institut de Recherche Saint-Louis, Université de Paris, Hôpital Saint-Louis
Olivier Schwartz: Institut Pasteur, Virus and Immunity Unit, CNRS-UMR3569
Baek Kim: Emory School of Medicine
Florence Margottin-Goguet: Université de Paris, Institut Cochin, INSERM, CNRS
Ali Saïb: INSERM U944, CNRS UMR 7212, Genomes & Cell Biology of Disease Unit, Institut de Recherche Saint-Louis, Université de Paris, Hôpital Saint-Louis
Alessia Zamborlini: INSERM U944, CNRS UMR 7212, Genomes & Cell Biology of Disease Unit, Institut de Recherche Saint-Louis, Université de Paris, Hôpital Saint-Louis

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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 T592E 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.

Date: 2021
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DOI: 10.1038/s41467-021-24802-5

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