PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination.

Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is a key mediator in TNF signaling. Previous studies suggested that TRAF2 functions as an adaptor in the NF-kappaB and AP-1 pathways. However, the precise molecular mechanisms by which TRAF2 relays signals are unknown. We previously reported that TRAF2 is phosphorylated following TNF stimulation and now identify the PKC kinases responsible for phosphorylation. Phosphorylated TRAF2 facilitates recruitment of IKKalpha and IKKbeta to the TNF receptor. Phosphorylation also determines K63-linked polyubiquitination of TRAF2 at lysine 31. TRAF2 K63-linked ubiquitination contributes to associations with TAB2/3 and activation of the downstream IKK and JNK kinases. The combined data reveal that phosphorylation of TRAF2 plays a critical role in TNF signaling by directing the IKK complex to the membrane, promoting TRAF2 K63-linked ubiquitination, and positioning the IKKalpha and IKKbeta chains with the TAK1/TAB kinase.