EPSTEIN-BARR-VIRUS-TRANSFORMING PROTEIN LATENT INFECTION MEMBRANE-PROTEIN-1 ACTIVATES TRANSCRIPTION FACTOR NF-KAPPA-B THROUGH A PATHWAY THAT INCLUDES THE NF-KAPPA-B-INDUCING KINASE AND THE I-KAPPA-B KINASES IKK-ALPHA AND IKK-BETA

The Epstein-Barr virus oncoprotein latent infection membrane protein 1 (LMP1) is a constitutively aggregated pseudo-tumor necrosis factor re ceptor (TNFR) that activates transcription factor NF-kappa B through t wo sites in its C-terminal cytoplasmic domain. One site is similar to activated TNFRII in associating,vith TNFR-associated factors TRAF1 and TRAF2, and the second site is similar to TNFRI in associating with th e TNFRI death domain interacting protein TRADD. TNFRI has been recentl y shown to activate NF-kappa B through association with TRADD, RIP, an d TRAF2; activation of the NF-kappa B-inducing kinase (NIK); activatio n of the I kappa B alpha kinases (IKK alpha and IKK beta); and phospho rylation of I kappa B alpha. I kappa B alpha phosphorylation on Ser-32 and Ser-36 is followed by its degradation and NF-kappa B activation. In this report, we show that NF-kappa B activation by LMP1 or by each of its effector sites is mediated by a pathway that includes NIK IKK a lpha, and IKK beta. Dominant negative mutants of NIK, IKK alpha, or IK K beta substantially inhibited NF-kappa B activation by LMP1 or by eac h of its effector sites.