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

The transcription factor NF kappa B is a major regulator of genes involved in inflammation and oncogenesis. NF kappa B 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 I kappa B, the administrator of NF kappa B activity. Here we report on a strong NF kappa B activation by Tio, a unique herpesviral oncoprotein promoting transformation of human T cells in a Src-kinase-dependent manner. NF kappa B 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 NF kappa B activation. Cotransfection of a dominant negative TRAF6 construct led to a decrease in NF kappa B 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 NF kappa B through an oncoprotein.