title: Phosphorylation of SAMHD1 by cyclin A2/CDK1 regulates its restriction activity toward HIV-1.
abstract: SAMHD1 restricts HIV-1 replication in myeloid and quiescent CD4(+) T cells. Here, we show that SAMHD1 restriction activity is regulated by phosphorylation. SAMHD1 interacts with cyclin A2/cdk1 only in cycling cells. Cyclin A2/CDK1 phosphorylates SAMHD1 at the Threonine 592 residue both in vitro and in vivo. Phosphorylation of SAMHD1 Thr592 correlates with loss of its ability to restrict HIV-1. Indeed, while PMA treatment of proliferating THP1 cells results in reduced Thr592 phosphorylation, activation of resting peripheral blood mononuclear cells (PBMCs) and purified quiescent CD4(+) T cells results in increased phosphorylation of SAMHD1 Thr592. Interestingly, we found that treatment of cells by type 1 interferon reduced Thr592 phosphorylation, reinforcing the link between the phosphorylation of SAMHD1 and its antiviral activity. Unlike wild-type SAMHD1, a phosphorylation-defective mutant was able to restrict HIV-1 replication in both PMA-treated and untreated cells. Our results uncover the phosphorylation of SAMHD1 at Thr592 by cyclin A2/CDK1 as a key regulatory mechanism of its antiviral activity.
authors.affiliation: Institut de Génétique Humaine, CNRS UPR1142, Laboratoires de Virologie Moléculaire, Montpellier 34000, France. alexandra.cribier@igh.cnrs.fr
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cribier
authors.forename: Benjamin
authors.initials: B
authors.lastname: Descours
authors.forename: Ana Luiza Chaves
authors.initials: AL
authors.lastname: Valadão
authors.forename: Nadine
authors.initials: N
authors.lastname: Laguette
authors.forename: Monsef
authors.initials: M
authors.lastname: Benkirane
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002460:Cell Line; D056751:Cyclin A2 / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000076106:SAM Domain and HD Domain-Containing Protein 1; D016415:Sequence Alignment; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D056751:Cyclin A2; D007370:Interferon Type I; D016203:CDC2 Protein Kinase; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins