HUMAN T-CELL LEUKEMIA-VIRUS TYPE-1 TAX INDUCTION OF NF-KAPPA-B INVOLVES ACTIVATION OF THE I-KAPPA-B KINASE-ALPHA (IKK-ALPHA) AND IKK-BETA CELLULAR KINASES

Tax corresponds to a 40-kDa transforming protein from the pathogenic r etrovirus human T-cell leukemia virus type 1 (HTLV-1) that activates n uclear expression of the NF-kappa B/Rel family of transcription factor s by an unknown mechanism. Tax expression promotes N-terminal phosphor ylation and degradation of I kappa B alpha, a principal cytoplasmic in hibitor of NF-kappa B. Our studies now demonstrate that HTLV-1 Tax act ivates the recently identified cellular kinases I kappa B kinase alpha (IKK alpha) and IKK beta, which normally phosphorylate I kappa B alph a on both of its N-terminal regulatory serines in response to tumor ne crosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) stimulation. In contrast, a mutant of Tax termed M22, which does not induce NF-kapp a B, fails to activate either IKK alpha or IKK beta. Furthermore, endo genous IKK enzymatic activity was significantly elevated in HTLV-1-inf ected and Tax-expressing T-cell lines. Transfection of kinase-deficien t mutants of IKK alpha and IKK beta into either human Jurkat T or 293 cells also inhibits NF-kappa B dependent reporter gene expression indu ced by Tax. Similarly, a kinase-deficient mutant of NIK (NF-kappa B-in ducing kinase), which represents an upstream kinase in the TNF-alpha a nd IL-1 signaling pathways leading to IKK alpha and IKK beta activatio n, blocks Tax induction of NF-kappa B. However, plasma membrane-proxim al elements in these proinflammatory cytokine pathways are apparently not involved since dominant negative mutants of the TRAF2 and TRAF6 ad aptors, which effectively block signaling through the cytoplasmic tail s of the TNF-alpha and IL-1 receptors, respectively, do not inhibit Ta x induction of NF-kappa B. Together, these studies demonstrate that HT LV-1 Tax exploits a distal part of the proinflammatory cytokine signal ing cascade leading to induction of NF-kappa B. The pathological alter ation of this cytokine pathway leading to NF-kappa B activation by Tax may play a central role in HTLV-1-mediated transformation of human T cells, clinically manifested as the adult T-cell leukemia.