SAMHD1 Modulates Early Steps during Human Cytomegalovirus Infection by Limiting NF-κB Activation

Eui Tae Kim, Kathryn L. Roche, Katarzyna Kulej, Lynn A. Spruce, Steven H. Seeholzer, Donald M. Coen, Felipe Diaz-Griffero, Eain A. Murphy, Matthew D. Weitzman

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Cellular SAMHD1 inhibits replication of many viruses by limiting intracellular deoxynucleoside triphosphate (dNTP) pools. We investigate the influence of SAMHD1 on human cytomegalovirus (HCMV). During HCMV infection, we observe SAMHD1 induction, accompanied by phosphorylation via viral kinase UL97. SAMHD1 depletion increases HCMV replication in permissive fibroblasts and conditionally permissive myeloid cells. We show this is due to enhanced gene expression from the major immediate-early (MIE) promoter and is independent of dNTP levels. SAMHD1 suppresses innate immune responses by inhibiting nuclear factor κB (NF-κB) activation. We show that SAMHD1 regulates the HCMV MIE promoter through NF-κB activation. Chromatin immunoprecipitation reveals increased RELA and RNA polymerase II on the HCMV MIE promoter in the absence of SAMHD1. Our studies reveal a mechanism of HCMV virus restriction by SAMHD1 and show how SAMHD1 deficiency activates an innate immune pathway that paradoxically results in increased viral replication through transcriptional activation of the HCMV MIE gene promoter. SAMHD1 has been identified as a cellular antiviral restriction factor. Kim et al. report that HCMV is restricted by SAMHD1 through inhibition of viral gene expression. They show that depletion of SAMHD1 increases activation of the NF-κB immune pathway, which paradoxically increases gene expression from the immediate-early viral promoter.

Original languageEnglish (US)
Pages (from-to)434-448.e6
JournalCell Reports
Volume28
Issue number2
DOIs
StatePublished - Jul 9 2019

Keywords

  • HCMV
  • NF-κB
  • SAMHD1
  • human cytomegalovirus
  • virus restriction

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kim, E. T., Roche, K. L., Kulej, K., Spruce, L. A., Seeholzer, S. H., Coen, D. M., Diaz-Griffero, F., Murphy, E. A., & Weitzman, M. D. (2019). SAMHD1 Modulates Early Steps during Human Cytomegalovirus Infection by Limiting NF-κB Activation. Cell Reports, 28(2), 434-448.e6. https://doi.org/10.1016/j.celrep.2019.06.027