Human cytomegalovirus IE1 protein disrupts interleukin-6 signaling by sequestering STAT3 in the nucleus

Justin M Reitsma, Hiromi Sato, Michael Nevels, Scott S Terhune, Christina Paulus

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

Abstract

In the canonical STAT3 signaling pathway, binding of agonist to receptors activates Janus kinases that phosphorylate cytoplasmic STAT3 at tyrosine 705 (Y705). Phosphorylated STAT3 dimers accumulate in the nucleus and drive the expression of genes involved in inflammation, angiogenesis, invasion, and proliferation. Here, we demonstrate that human cytomegalovirus (HCMV) infection rapidly promotes nuclear localization of STAT3 in the absence of robust phosphorylation at Y705. Furthermore, infection disrupts interleukin-6 (IL-6)-induced phosphorylation of STAT3 and expression of a subset of IL-6-induced STAT3-regulated genes, including SOCS3. We show that the HCMV 72-kDa immediate-early 1 (IE1) protein associates with STAT3 and is necessary to localize STAT3 to the nucleus during infection. Furthermore, expression of IE1 is sufficient to disrupt IL-6-induced phosphorylation of STAT3, binding of STAT3 to the SOCS3 promoter, and SOCS3 gene expression. Finally, inhibition of STAT3 nuclear localization or STAT3 expression during infection is linked to diminished HCMV genome replication. Viral gene expression is also disrupted, with the greatest impact seen following viral DNA synthesis. Our study identifies IE1 as a new regulator of STAT3 intracellular localization and IL-6 signaling and points to an unanticipated role of STAT3 in HCMV infection.
Original languageEnglish
Pages (from-to)10763-10776
Number of pages14
JournalJournal of Virology
Volume87
Issue number19
Early online date31 Jul 2013
DOIs
Publication statusPublished - Oct 2013

Keywords

  • Animals
  • Astrocytoma
  • Blotting, Western
  • Cell Nucleus
  • Cells, Cultured
  • Cytomegalovirus
  • Cytomegalovirus Infections
  • Fibroblasts
  • Fluorescent Antibody Technique
  • Humans
  • Immediate-Early Proteins
  • Interleukin-6
  • Mice
  • Phosphorylation
  • RNA, Messenger
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor
  • Signal Transduction
  • Trans-Activators
  • Virus Replication

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