Domain-specific interaction with the I kappa B kinase (IKK) regulatory subunit IKK gamma is an essential step in tax-mediated activation of IKK

The human T-cell leukemia virus type 1 Tax oncoprotein deregulates the NF-k appaB signaling pathway by persistently stimulating a key signal transducer , the I kappaB kinase (IKK). Tax physically associates with the IKK regulat ory subunit, IKK gamma, although the underlying biochemical mechanism and f unctional significance remain unclear. We show that the Tax-IKK gamma inter action requires two homologous leucine zipper domains located within IKK ga mma. These leucine zipper domains are unique for the presence of a conserve d upstream region that is essential for Tax binding. Site-directed mutagene sis analysis revealed that a leucine-repeat region of Tax is important for IKK gamma binding. Interestingly, all the Tax mutants defective in IKK gamm a binding failed to engage the IKK complex or stimulate IKK activity, and t hese functional defects can be rescued by fusing the Tax mutants to IKK gam ma These results provide mechanistic insights into how Tax specifically tar gets and functionally activates the cellular kinase IKK.