NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4

Nat Immunol. 2012 Mar 4;13(4):387-95. doi: 10.1038/ni.2239.

Abstract

Stringent control of the type I interferon signaling pathway is important for maintaining host immune responses and homeostasis, yet the molecular mechanisms responsible for its tight regulation are still poorly understood. Here we report that the pattern-recognition receptor NLRP4 regulated the activation of type I interferon mediated by double-stranded RNA or DNA by targeting the kinase TBK1 for degradation. NLRP4 recruited the E3 ubiquitin ligase DTX4 to TBK1 for Lys48 (K48)-linked polyubiquitination at Lys670, which led to degradation of TBK1. Knockdown of either DTX4 or NLRP4 abrogated K48-linked ubiquitination and degradation of TBK1 and enhanced the phosphorylation of TBK1 and the transcription factor IRF3. Our results identify a previously unrecognized role for NLRP4 in the regulation of type I interferon signaling and provide molecular insight into the mechanisms by which NLRP4-DTX4 targets TBK1 for degradation.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Cell Line
  • Fluorescent Antibody Technique
  • Gene Knockdown Techniques
  • Humans
  • Immunity, Innate / immunology
  • Immunoblotting
  • Immunoprecipitation
  • Interferon Type I / immunology
  • Interferon Type I / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / immunology
  • Protein-Serine-Threonine Kinases / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Repressor Proteins / immunology
  • Repressor Proteins / metabolism*
  • Signal Transduction / immunology*
  • Transfection
  • Ubiquitin-Protein Ligases / immunology
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Interferon Type I
  • NLRP4 protein, human
  • Repressor Proteins
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human