I?B Kinase ? Phosphorylation of TRAF4 Downregulates Innate Immune Signaling

Despite their homology, I Kappa B kinase alpha (IKK alpha ) and IKK beta have divergent roles in NF- Kappa B signaling. IKK beta strongly activates NF- Kappa B while IKK alpha can downregulate NF- Kappa B 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 IKK alpha . Like IKK alpha , TRAF4 is atypical within its family because it is the only TRAF family member to negatively regulate innate immune signaling. IKK alpha '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 beta -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.