1. Phosphorylation of SAMHD1 by Cyclin A2/CDK1 Regulates Its Restriction Activity toward HIV-1
- Author
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Alexandra Cribier, Benjamin Descours, Nadine Laguette, Monsef Benkirane, Ana Luiza Chaves Valadão, Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
CD4-Positive T-Lymphocytes ,inorganic chemicals ,Cyclin D ,Molecular Sequence Data ,Cyclin A ,macromolecular substances ,Virus Replication ,Antiviral Agents ,environment and public health ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,SAM Domain and HD Domain-Containing Protein 1 ,03 medical and health sciences ,0302 clinical medicine ,CDC2 Protein Kinase ,Animals ,Humans ,Phosphorylation ,Threonine ,lcsh:QH301-705.5 ,Monomeric GTP-Binding Proteins ,030304 developmental biology ,0303 health sciences ,Cyclin-dependent kinase 1 ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Base Sequence ,biology ,Chemistry ,Molecular biology ,3. Good health ,enzymes and coenzymes (carbohydrates) ,lcsh:Biology (General) ,Cell culture ,030220 oncology & carcinogenesis ,Interferon Type I ,HIV-1 ,Leukocytes, Mononuclear ,biology.protein ,bacteria ,Cyclin A2 ,Sequence Alignment ,SAMHD1 - Abstract
International audience; SAMHD1 restricts HIV-1 replication in myeloid andquiescent CD4+T cells. Here, we show that SAMHD1restriction activity is regulated by phosphorylation.SAMHD1 interacts with cyclin A2/cdk1 only in cyclingcells. Cyclin A2/CDK1 phosphorylates SAMHD1 atthe Threonine 592 residue both in vitro and in vivo.Phosphorylation of SAMHD1 Thr592 correlates withloss of its ability to restrict HIV-1. Indeed, whilePMA treatment of proliferating THP1 cells results inreduced Thr592 phosphorylation, activation ofresting peripheral blood mononuclear cells (PBMCs)and purified quiescent CD4+T cells results inincreased phosphorylation of SAMHD1 Thr592. Inter-estingly, we found that treatment of cells by type 1interferon reduced Thr592 phosphorylation, reinforc-ing the link between the phosphorylation of SAMHD1and its antiviral activity. Unlike wild-type SAMHD1,a phosphorylation-defective mutant was able torestrict HIV-1 replication in both PMA-treatedand untreated cells. Our results uncover the phos-phorylation of SAMHD1 at Thr592 by cyclin A2/CDK1 as a key regulatory mechanism of its antiviralactivity.
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