Positive Role of Promyelocytic Leukemia Protein in Type I Interferon Response and Its Regulation by Human Cytomegalovirus

PLoS Pathog. 2015 Mar 26;11(3):e1004785. doi: 10.1371/journal.ppat.1004785. eCollection 2015 Mar.

Abstract

Promyelocytic leukemia protein (PML), a major component of PML nuclear bodies (also known as nuclear domain 10), is involved in diverse cellular processes such as cell proliferation, apoptosis, gene regulation, and DNA damage response. PML also acts as a restriction factor that suppresses incoming viral genomes, therefore playing an important role in intrinsic defense. Here, we show that PML positively regulates type I interferon response by promoting transcription of interferon-stimulated genes (ISGs) and that this regulation by PML is counteracted by human cytomegalovirus (HCMV) IE1 protein. Small hairpin RNA-mediated PML knockdown in human fibroblasts reduced ISG induction by treatment of interferon-β or infection with UV-inactivated HCMV. PML was required for accumulation of activated STAT1 and STAT2, interacted with them and HDAC1 and HDAC2, and was associated with ISG promoters after HCMV infection. During HCMV infection, viral IE1 protein interacted with PML, STAT1, STAT2, and HDACs. Analysis of IE1 mutant viruses revealed that, in addition to the STAT2-binding domain, the PML-binding domain of IE1 was necessary for suppression of interferon-β-mediated ISG transcription, and that IE1 inhibited ISG transcription by sequestering interferon-stimulated gene factor 3 (ISGF3) in a manner requiring its binding of PML and STAT2, but not of HDACs. In conclusion, our results demonstrate that PML participates in type I interferon-induced ISG expression by regulating ISGF3, and that this regulation by PML is counteracted by HCMV IE1, highlighting a widely shared viral strategy targeting PML to evade intrinsic and innate defense mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytomegalovirus / genetics
  • Cytomegalovirus / metabolism*
  • HEK293 Cells
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase 2 / genetics
  • Histone Deacetylase 2 / metabolism
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Interferon Type I / genetics
  • Interferon Type I / metabolism*
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Promyelocytic Leukemia Protein
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • STAT2 Transcription Factor / genetics
  • STAT2 Transcription Factor / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • IE1 protein, cytomegalovirus
  • IRF9 protein, human
  • Immediate-Early Proteins
  • Interferon Type I
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Nuclear Proteins
  • Promyelocytic Leukemia Protein
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT2 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • PML protein, human
  • HDAC1 protein, human
  • HDAC2 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylase 2

Grant support

This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIP) (2012R1A2A2A01002551). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.