A novel motif in the Crohn's disease susceptibility protein, NOD2, allows TRAF4 to down-regulate innate immune responses

J Biol Chem. 2011 Jan 21;286(3):1938-50. doi: 10.1074/jbc.M110.189308. Epub 2010 Nov 19.

Abstract

The Crohn's disease and early onset sarcoidosis susceptibility protein, NOD2, coordinates innate immune signaling pathways. Because dysregulation of this coordination can lead to inflammatory disease, maintaining appropriate activation of the NOD2 signaling pathway is paramount in immunologic homeostasis. In this work, we identify the atypical tumor necrosis factor-associated factor (TRAF) family member, TRAF4, as a key negative regulator of NOD2 signaling. TRAF4 inhibits NOD2-induced NF-κB activation and directly binds to NOD2 to inhibit NOD2-induced bacterial killing. We find that two consecutive glutamate residues in NOD2 are required for interaction with TRAF4 and inhibition of NOD2 signaling because mutation of these residues abrogated both TRAF4 binding and inhibition of NOD2. This work identifies a novel negative regulator of NOD2 signaling. Additionally, it defines a TRAF4 binding motif within NOD2 involved in termination of innate immune signaling responses.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Crohn Disease / genetics
  • Crohn Disease / immunology
  • Crohn Disease / metabolism*
  • Down-Regulation*
  • Genetic Predisposition to Disease / genetics
  • HEK293 Cells
  • Humans
  • Immunity, Innate
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / immunology
  • Nod2 Signaling Adaptor Protein / metabolism*
  • Protein Binding
  • Salmonella Infections / immunology
  • Salmonella Infections / metabolism
  • Salmonella typhimurium / immunology
  • Salmonella typhimurium / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • TNF Receptor-Associated Factor 4 / genetics
  • TNF Receptor-Associated Factor 4 / immunology
  • TNF Receptor-Associated Factor 4 / metabolism*

Substances

  • NF-kappa B
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse
  • TNF Receptor-Associated Factor 4
  • TRAF4 protein, human
  • Traf4 protein, mouse