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SAMHD1's protein expression profile in humans.

Sarah Schmidt1, Kristina Schenkova1, Tarek Adam1

  • 1*Institute of Medical Virology, National Reference Center for Retroviruses, University of Frankfurt, Germany; Department of Infectious Diseases, Integrative Virology, Institute of Pathology, and Department of Otolaryngology, Head and Neck Surgery, University of Heidelberg, Germany; German Centre for Infection Research, Heidelberg, Germany; and Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.

Journal of Leukocyte Biology
|February 4, 2015
PubMed
Summary

SAMHD1 protein is expressed in most immune cells, including HIV target cells in the anogenital tract. Its phosphorylation state, not cytokine exposure, influences its HIV restriction activity in vivo.

Keywords:
HIVHSVinnate immunityrestriction factor

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Area of Science:

  • Immunology
  • Virology
  • Cell Biology

Background:

  • SAMHD1 (sterile alpha motif and HD domain containing protein 1) is a deoxynucleoside triphosphate triphosphohydrolase and 3' → 5' exonuclease that restricts HIV-1 infection in noncycling hematopoietic cells.
  • SAMHD1 mutations are linked to Aicardi-Goutières syndrome (AGS).
  • Limited information exists regarding the in vivo expression and functional regulation of SAMHD1.

Purpose of the Study:

  • To determine the in vivo expression profile of SAMHD1 protein across various human tissues and primary cell populations.
  • To investigate the impact of cellular activation status and proinflammatory cytokines on SAMHD1 expression and phosphorylation.
  • To assess SAMHD1's potential role in HIV transmission efficiency.

Main Methods:

  • Protein expression analysis of SAMHD1 using a microarray of 25 human tissues from over 210 donors.
  • Assessment of SAMHD1 expression in purified primary immune cell populations.
  • Examination of SAMHD1 phosphorylation (pSAMHD1) and expression levels following stimulation with various cytokines (IFN-α, IFN-γ, IL-4, IL-6, IL-12, IL-18, IL-27, TNF-α, IL-1β) and in different cell activation states.

Main Results:

  • SAMHD1 is expressed in most nucleated cells of hematopoietic origin, including macrophages, dendritic cells (DCs), plasmacytoid DCs (pDCs), T cells, monocytes, and NK cells, with lower levels in B cells.
  • Abundant SAMHD1 expression was observed in HIV target cells within the anogenital mucosa.
  • Activated CD4(+) T cells showed phosphorylated SAMHD1 (pSAMHD1 at T592), while resting CD4(+) T cells and macrophages expressed unphosphorylated SAMHD1, correlating with HIV-restrictive activity.
  • Proinflammatory cytokines generally did not alter SAMHD1 expression or T592 phosphorylation, except for a moderate downregulation by IL-1β in activated CD4(+) T cells.

Conclusions:

  • This study provides the first comprehensive cross-sectional protein expression profile of SAMHD1 in human tissues.
  • SAMHD1 expression is widespread in hematopoietic cells, including key HIV target cells in the anogenital tract.
  • Cell cycle-dependent phosphorylation, rather than cytokine stimulation, appears to be a key regulator of SAMHD1's HIV-restrictive activity.