Persistent activation of NF-kappa B by the Tax transforming protein of HTLV-1: hijacking cellular I kappa B kinases

Biochemical coupling of transcription factor NF-kappa B to antigen and co-s timulatory receptors is required for the temporal control of T-cell prolife ration. In contrast to its transitory activation during normal growth-signa l transduction, NF-kappa B is Constitutively deployed in T-cells transforme d by the type 1 human T-cell leukemia virus (HTLV-1). This viral/host inter action is mediated by the HTLV-1-encoded Tax protein, which has potent onco genic 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, Ta x associates stably with a cytokine-inducible I kappa B kinase (IKK), which contains both catalytic (IKK alpha and IKK beta) and noncatalytic (IKK gam ma) subunits. Unlike their transiently induced counterparts in cytokine-tre ated cells, Tax-associated forms of IKK alpha and IKK beta are persistently activated in HTLV-1-infected T cells. Acquisition of the deregulated IKK p henotype is contingent on the presence of IKK gamma, which functions as a m olecular adaptor in the assembly of pathologic Tax/I kappa B kinase complex es. These findings highlight a key mechanistic role for Wt in the Tax/NF-ka ppa B signaling axis and define new intracellular targets for the therapeut ic control HTLV-1-associated disease.