Recruitment of phosphatase PP2A by RACK1 adaptor protein deactivates transcription factor IRF3 and limits type I interferon signaling

Immunity. 2014 Apr 17;40(4):515-29. doi: 10.1016/j.immuni.2014.01.015. Epub 2014 Apr 10.

Abstract

The transcription factor IRF3 is a central regulator of type I interferon (IFN) signaling. The mechanisms underlying deactivation of IRF3 are poorly understood although many studies suggest that IRF3 activity is terminated through degradation after viral infection. Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. After challenge with LPS, poly(I:C), or low-titer SeV, activated IRF3 was dephosphorylated and returned to resting state without being degraded, although high-titer SeV infection triggered the degradation of IRF3. Furthermore, PP2A-deficient macrophages showed enhanced type I IFN signaling upon LPS, poly(I:C), and SeV challenge and protected mice from lethal vesicular stomatitis virus infection. Therefore, dephosphorylation of IRF3 is a deactivation mechanism that contributes to termination of IRF3-type I IFN signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • HeLa Cells
  • Humans
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon Type I / metabolism*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Neuropeptides / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • Receptors for Activated C Kinase
  • Sendai virus / immunology
  • Signal Transduction
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / metabolism*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • Transgenes / genetics
  • Vesicular Stomatitis / immunology
  • Vesicular stomatitis Indiana virus / immunology

Substances

  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • RACK1 protein, mouse
  • Receptors for Activated C Kinase
  • Robo3 protein, mouse
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Protein Phosphatase 2