Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling

Nat Immunol. 2006 Feb;7(2):139-47. doi: 10.1038/ni1294. Epub 2005 Dec 25.

Abstract

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is critical for mediating Toll-like receptor (TLR)-interleukin 1 receptor (IL-1R) signaling and subsequent activation of NF-kappaB and AP-1, transcriptional activators of innate immunity. Here we show that beta-arrestins, a family of multifunctional proteins, directly interacted with TRAF6 after TLR-IL-1R activation. Formation of the beta-arrestin-TRAF6 complex prevented autoubiquitination of TRAF6 and activation of NF-kappaB and AP-1. Endotoxin-treated beta-arrestin 2-deficient mice had higher expression of proinflammatory cytokines and were more susceptible to endotoxic shock. Thus, beta-arrestins are essential negative regulators of innate immune activation via TLR-IL-1R signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrestins / deficiency
  • Arrestins / genetics
  • Arrestins / metabolism*
  • Binding Sites
  • Cell Line
  • Cytokines / biosynthesis
  • Female
  • HeLa Cells
  • Humans
  • Immunity, Innate
  • Interleukin-1 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Toll-Like Receptor 1 / metabolism*
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Transcription Factor AP-1 / metabolism
  • Ubiquitin / metabolism
  • beta-Arrestin 2
  • beta-Arrestins

Substances

  • ARRB2 protein, human
  • Arrb2 protein, mouse
  • Arrestins
  • Cytokines
  • Interleukin-1
  • Lipopolysaccharides
  • NF-kappa B
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 1
  • Transcription Factor AP-1
  • Ubiquitin
  • beta-Arrestin 2
  • beta-Arrestins