PPM1B negatively regulates antiviral response via dephosphorylating TBK1

Cell Signal. 2012 Nov;24(11):2197-204. doi: 10.1016/j.cellsig.2012.06.017. Epub 2012 Jun 30.

Abstract

The production of type I interferon must be tightly regulated and aberrant production of type I interferon is harmful or even fatal to the host. TBK1 phosphorylation at Ser172 plays an essential role in TBK1-mediated antiviral response. However, how TBK1 activity is negatively regulated remains poorly understood. Using a functional genomics approach, we have identified PPM1B as a TBK1 phosphatase. PPM1B dephosphorylates TBK1 in vivo and in vitro. PPM1B wild-type but not its phosphatase-deficient R179G mutant inhibits TBK1-mediated antiviral response and facilitates VSV replication in the cells. Viral infection induces association of PPM1B with TBK1 in a transient fashion in the cells. Conversely, suppression of PPM1B expression enhances virus-induced IRF3 phosphorylation and IFNβ production. Our study identifies a previously unrecognized role for PPM1B in the negative regulation of antiviral response by acting as a TBK1 phosphatase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Replication
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Phosphatase 2C
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Vesiculovirus / genetics
  • Vesiculovirus / metabolism

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • RNA, Small Interfering
  • Interferon-beta
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • PPM1B protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C