Persistent activation of NF-κB by the Tax transforming protein of HTLV-1:: hijacking cellular IκB kinases

Biochemical coupling of transcription factor NF-kappa B to antigen and co-stimulatory receptors is required for the temporal control of T-cell proliferation. In contrast to its transitory activation during normal growth-signal transduction, NF-kappa B is Constitutively deployed in T-cells transformed by the type 1 human T-cell leukemia virus (HTLV-1). This viral/host interaction is mediated by the HTLV-1-encoded Tax protein, which has potent oncogenic properties. As reviewed here, Tax activates NF-kappa B primarily via a pathway leading to the chronic phosphorylation and degradation of I kappa B alpha, a cytoplasmic inhibitor of NF-kappa B. To access this pathway, Tax associates stably with a cytokine-inducible I kappa B kinase (IKK), which contains both catalytic (IKK alpha and IKK beta) and noncatalytic (IKK gamma) subunits. Unlike their transiently induced counterparts in cytokine-treated cells, Tax-associated forms of IKK alpha and IKK beta are persistently activated in HTLV-1-infected T cells. Acquisition of the deregulated IKK phenotype is contingent on the presence of IKK gamma, which functions as a molecular adaptor in the assembly of pathologic Tax/I kappa B kinase complexes. These findings highlight a key mechanistic role for Wt in the Tax/NF-kappa B signaling axis and define new intracellular targets for the therapeutic control HTLV-1-associated disease.