The tax oncoprotein of human T-cell leukemia virus type 1 associates with and persistently activates IκB kinases containing IKKα and IKKβ

The Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV1) chronically activates transcription factor NF-kappa B by a mechanism involving degradation of I kappa B alpha, an NF-kappa B-associated cytoplasmic inhibitor. Tax-induced breakdown of I kappa B alpha requires phosphorylation of the inhibitor at Ser-32 and Ser-36, which is also a prerequisite for the transient activation of NF-kappa B in cytokine-treated T lymphocytes. However, it remained unclear how Tax interfaces with the cellular NF-kappa B/I kappa B signaling machinery to generate a chronic rather than a transient NF-kappa B response. We now demonstrate that Tax associates with cytokine-inducible I kappa B kinase (IKK) complexes containing catalytic subunits IKK alpha and IKK beta, which mediate phosphorylation of I kappa B alpha at Ser-32 and Ser-36, Unlike their transiently activated counterparts in cytokine-treated cells, Tax-associated forms of Wt are constitutively active in either Tax transfectants or HTLV1-infected T lymphocytes. Moreover, point mutations in Tax that ablate its IKK-binding function also prevent Tax-mediated activation of IKK and NF-kappa B, Together, these findings suggest that the persistent activation of NF-kappa B in HTLV1-infected T-cells is mediated by a direct Tax/IKK coupling mechanism.