Phosphorylation of SAMHD1 by cyclin A2/CDK1 regulates its restriction activity toward HIV-1

Cell Rep. 2013 Apr 25;3(4):1036-43. doi: 10.1016/j.celrep.2013.03.017. Epub 2013 Apr 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Base Sequence
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CDC2 Protein Kinase / metabolism*
  • Cell Line
  • Cyclin A2 / metabolism*
  • HIV-1 / metabolism*
  • Humans
  • Interferon Type I / pharmacology
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Phosphorylation
  • SAM Domain and HD Domain-Containing Protein 1
  • Sequence Alignment
  • Virus Replication / drug effects


  • Antiviral Agents
  • Cyclin A2
  • Interferon Type I
  • CDC2 Protein Kinase
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Monomeric GTP-Binding Proteins