IκB Kinase α Phosphorylation of TRAF4 Downregulates Innate: Immune Signaling Academic Article uri icon


MeSH Major

  • I-kappa B Kinase
  • Immunity, Innate
  • TNF Receptor-Associated Factor 4


  • Despite their homology, IκB kinase α (IKKα) and IKKβ have divergent roles in NF-κB signaling. IKKβ strongly activates NF-κB while IKKα can downregulate NF-κB under certain circumstances. Given this, identifying independent substrates for these kinases could help delineate their divergent roles. Peptide substrate array technology followed by bioinformatic screening identified TRAF4 as a substrate for IKKα. Like IKKα, TRAF4 is atypical within its family because it is the only TRAF family member to negatively regulate innate immune signaling. IKKα's phosphorylation of serine-426 on TRAF4 was required for this negative regulation. Binding to the Crohn's disease susceptibility protein, NOD2, is required for TRAF4 phosphorylation and subsequent inhibition of NOD2 signaling. Structurally, serine-426 resides within an exaggerated β-bulge in TRAF4 that is not present in the other TRAF proteins, and phosphorylation of this site provides a structural basis for the atypical function of TRAF4 and its atypical role in NOD2 signaling.

publication date

  • July 2012



  • Academic Article



  • eng

PubMed Central ID

  • PMC3434482

Digital Object Identifier (DOI)

  • 10.1128/MCB.00106-12

PubMed ID

  • 22547678

Additional Document Info

start page

  • 2479

end page

  • 89


  • 32


  • 13