The interferon-related developmental regulator 1 is used by human papillomavirus to suppress NFκB activation

Nat Commun. 2015 Mar 13;6:6537. doi: 10.1038/ncomms7537.

Abstract

High-risk human papillomaviruses (hrHPVs) infect keratinocytes and successfully evade host immunity despite the fact that keratinocytes are well equipped to respond to innate and adaptive immune signals. Using non-infected and freshly established or persistent hrHPV-infected keratinocytes we show that hrHPV impairs the acetylation of NFκB/RelA K310 in keratinocytes. As a consequence, keratinocytes display a decreased pro-inflammatory cytokine production and immune cell attraction in response to stimuli of the innate or adaptive immune pathways. HPV accomplishes this by augmenting the expression of interferon-related developmental regulator 1 (IFRD1) in an EGFR-dependent manner. Restoration of NFκB/RelA acetylation by IFRD1 shRNA, cetuximab treatment or the HDAC1/3 inhibitor entinostat increases basal and induced cytokine expression. Similar observations are made in IFRD1-overexpressing HPV-induced cancer cells. Thus, our study reveals an EGFR-IFRD1-mediated viral immune evasion mechanism, which can also be exploited by cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cells, Cultured
  • Cytokines / biosynthesis
  • ErbB Receptors / metabolism
  • Histone Deacetylases / metabolism
  • Humans
  • Immediate-Early Proteins / physiology*
  • Immune Evasion
  • Interferon-gamma / physiology
  • NF-kappa B / metabolism*
  • Papillomaviridae / physiology*
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Cytokines
  • IFRD1 protein, human
  • Immediate-Early Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • ErbB Receptors
  • Histone Deacetylases