The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated production of type I interferon

Nat Immunol. 2009 Jul;10(7):744-52. doi: 10.1038/ni.1742. Epub 2009 May 31.

Abstract

E3 ubiquitin ligases are important in both innate and adaptive immunity. Here we report that Nrdp1, an E3 ubiquitin ligase, inhibited the production of proinflammatory cytokines but increased interferon-beta production in Toll-like receptor-triggered macrophages by suppressing adaptor MyD88-dependent activation of transcription factors NF-kappaB and AP-1 while promoting activation of the kinase TBK1 and transcription factor IRF3. Nrdp1 directly bound and polyubiquitinated MyD88 and TBK1, which led to degradation of MyD88 and activation of TBK1. Knockdown of Nrdp1 inhibited the degradation of MyD88 and the activation of TBK1 and IRF3. Nrdp1-transgenic mice showed resistance to lipopolysaccharide-induced endotoxin shock and to infection with vesicular stomatitis virus. Our data suggest that Nrdp1 functions as both an adaptor protein and an E3 unbiquitin ligase to regulate TLR responses in different ways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cells, Cultured
  • Female
  • Host-Pathogen Interactions
  • Humans
  • Immunoblotting
  • Interferon Type I / metabolism*
  • Lipopolysaccharides / toxicity
  • Macrophages / cytology
  • Macrophages / metabolism
  • Macrophages / virology
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / virology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Differentiation Factor 88 / metabolism
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rhabdoviridae Infections / metabolism
  • Rhabdoviridae Infections / virology
  • Sepsis / chemically induced
  • Sepsis / metabolism
  • Toll-Like Receptors / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Vesiculovirus / physiology

Substances

  • Carrier Proteins
  • Interferon Type I
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Toll-Like Receptors
  • Rnf41 protein, mouse
  • Ubiquitin-Protein Ligases
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases