The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation

The death domain kinase RIP and the TNF receptor-associated factor 2 (TRAF2 ) are essential effecters in TNF signaling. To understand the mechanism by which RIP and TRAF2 regulate TNF-induced activation of the transcription fa ctor NF-KB, we investigated their respective roles in TNF-R1-mediated IKK a ctivation using both RIP-/- and TRAF2(-/-) fibroblasts. We found that TNF-R 1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TR AF2 or RIP can be independently recruited to the TNF-R1 complex, neither on e of them alone is capable of transducing the TNF signal that leads to IKK activation. Moreover, we demonstrated that IKK is recruited to the TNF-R1 c omplex through TRAF2 upon TNF treatment and that IKK activation requires th e presence of RIP in the same complex.