Mouse SAMHD1 Has Antiretroviral Activity and Suppresses a Spontaneous Cell-Intrinsic Antiviral Response

Cell Rep. 2013 Aug 29;4(4):689-96. doi: 10.1016/j.celrep.2013.07.037. Epub 2013 Aug 22.

Abstract

Aicardi-Goutières syndrome (AGS), a hereditary autoimmune disease, clinically and biochemically overlaps with systemic lupus erythematosus (SLE) and, like SLE, is characterized by spontaneous type I interferon (IFN) production. The finding that defects of intracellular nucleases cause AGS led to the concept that intracellular accumulation of nucleic acids triggers inappropriate production of type I IFN and autoimmunity. AGS can also be caused by defects of SAMHD1, a 3' exonuclease and deoxynucleotide (dNTP) triphosphohydrolase. Human SAMHD1 is an HIV-1 restriction factor that hydrolyzes dNTPs and decreases their concentration below the levels required for retroviral reverse transcription. We show in gene-targeted mice that also mouse SAMHD1 reduces cellular dNTP concentrations and restricts retroviral replication in lymphocytes, macrophages, and dendritic cells. Importantly, the absence of SAMHD1 triggered IFN-β-dependent transcriptional upregulation of type I IFN-inducible genes in various cell types indicative of spontaneous IFN production. SAMHD1-deficient mice may be instrumental for elucidating the mechanisms that trigger pathogenic type I IFN responses in AGS and SLE.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dendritic Cells / metabolism
  • Dendritic Cells / virology
  • Deoxyribonucleotides / metabolism
  • Friend murine leukemia virus / metabolism
  • Friend murine leukemia virus / physiology
  • HIV-1 / metabolism
  • HIV-1 / physiology
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Lymphocytes / metabolism
  • Lymphocytes / virology
  • Macrophages / metabolism
  • Macrophages / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism
  • Reverse Transcription
  • SAM Domain and HD Domain-Containing Protein 1
  • Transcription, Genetic
  • Up-Regulation
  • Virus Replication*

Substances

  • Deoxyribonucleotides
  • Ifnar1 protein, mouse
  • Receptor, Interferon alpha-beta
  • Interferon-beta
  • SAM Domain and HD Domain-Containing Protein 1
  • Samhd1 protein, mouse
  • Monomeric GTP-Binding Proteins

Associated data

  • GEO/GSE37236
  • GEO/GSE41879
  • GEO/GSE45358