Domain-specific interaction with the IκB kinase (IKK) regulatory subunit IKKγ is an essential step in tax-mediated activation of IKK

The human T-cell leukemia virus type 1 Tax oncoprotein deregulates the NF-κB signaling pathway by persistently stimulating a key signal transducer, the IκB kinase (IKK). Tax physically associates with the IKK regulatory subunit, IKKγ, although the underlying biochemical mechanism and functional significance remain unclear. We show that the Tax-IKKγ interaction requires two homologous leucine zipper domains located within IKKγ. These leucine zipper domains are unique for the presence of a conserved upstream region that is essential for Tax binding. Site-directed mutagenesis analysis revealed that a leucine-repeat region of Tax is important for IKKγ binding. Interestingly, all the Tax mutants defective in IKKγ binding failed to engage the IKKγ complex or stimulate IKK activity, and these functional defects can be rescued by fusing the Tax mutants to IKKγ. These results provide mechanistic insights into how Tax specifically targets and functionally activates the cellular kinase IKK.