THE TAX ONCOPROTEIN OF HUMAN T-CELL LEUKEMIA-VIRUS TYPE-1 ASSOCIATES WITH AND PERSISTENTLY ACTIVATES I-KAPPA-B KINASES CONTAINING IKK-ALPHAAND IKK-BETA

The Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV1) chro nically activates transcription factor NF-kappa B by a mechanism invol ving degradation of I kappa B alpha, an NF-kappa B-associated cytoplas mic inhibitor. Tax-induced breakdown of I kappa B alpha requires phosp horylation of the inhibitor at Ser-32 and Ser-36, which is also a prer equisite for the transient activation of NF-kappa B in cytokine-treate d T lymphocytes. However, it remained unclear how Tax interfaces with the cellular NF-kappa B/I kappa B signaling machinery to generate a ch ronic rather than a transient NF-kappa B response. We now demonstrate that Tax associates with cytokine-inducible I kappa B kinase (IKK) com plexes containing catalytic subunits IKK alpha and IKK beta, which med iate phosphorylation of I kappa B alpha at Ser-32 and Ser-36, Unlike t heir transiently activated counterparts in cytokine-treated cells, Tax -associated forms of Wt are constitutively active in either Tax transf ectants or HTLV1-infected T lymphocytes. Moreover, point mutations in Tax that ablate its IKK-binding function also prevent Tax-mediated act ivation of IKK and NF-kappa B, Together, these findings suggest that t he persistent activation of NF-kappa B in HTLV1-infected T-cells is me diated by a direct Tax/IKK coupling mechanism.