IκB kinase α phosphorylation of TRAF4 downregulates innate immune signaling.

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.
Mesh Terms:
Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Cell Line, Crohn Disease, DNA Primers, Down-Regulation, HCT116 Cells, HEK293 Cells, Humans, I-kappa B Kinase, Immunity, Innate, Mice, Models, Molecular, Molecular Sequence Data, NF-kappa B, Nod2 Signaling Adaptor Protein, Peptide Library, Phosphorylation, Protein Stability, Protein Structure, Tertiary, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Serine, Signal Transduction, Substrate Specificity, TNF Receptor-Associated Factor 4
Mol. Cell. Biol.
Date: Jul. 01, 2012
Download Curated Data For This Publication
151998
Switch View:
  • Interactions 6
  • PTM Genes 1