NFκB Signaling Is Induced by the Oncoprotein Tio through Direct Interaction with TRAF6

The transcription factor NFkappaB is a major regulator of genes involved in inflammation and oncogenesis. NFkappaB is induced upon stimulation of cellular receptors coupled to different intracellular signaling molecules. Further downstream, TRAF6 links at least two receptor pathways to take control of IkappaB, the administrator of NFkappaB activity. Here we report on a strong NFkappaB activation by Tio, a unique herpesviral oncoprotein promoting transformation of human T cells in a Src-kinase-dependent manner. NFkappaB induction by Tio is independent of Src-kinase interaction and tyrosine phosphorylation of Tio. Mutation of a glutamic acid-rich motif at the N terminus of Tio, corresponding to a TRAF6 consensus binding motif, completely abrogated NFkappaB activation. Cotransfection of a dominant negative TRAF6 construct led to a decrease in NFkappaB activation. Furthermore, we provide evidence that TRAF6 directly binds to the Tio oncoprotein. Identification of TRAF6 as the direct target of Tio describes a novel mechanism for the constitutive activation of NFkappaB through an oncoprotein.