The tax oncoprotein of human T-cell leukemia virus type 1 associates with and persistently activates IkappaB kinases containing IKKalpha and IKKbeta.
The Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV1) chronically activates transcription factor NF-kappaB by a mechanism involving degradation of IkappaBalpha, an NF-kappaB-associated cytoplasmic inhibitor. Tax-induced breakdown of IkappaBalpha requires phosphorylation of the inhibitor at Ser-32 and Ser-36, which is also a prerequisite for the transient activation of NF-kappaB in cytokine-treated T lymphocytes. However, it remained unclear how Tax interfaces with the cellular NF-kappaB/IkappaB signaling machinery to generate a chronic rather than a transient NF-kappaB response. We now demonstrate that Tax associates with cytokine-inducible IkappaB kinase (IKK) complexes containing catalytic subunits IKKalpha and IKKbeta, which mediate phosphorylation of IkappaBalpha at Ser-32 and Ser-36. Unlike their transiently activated counterparts in cytokine-treated cells, Tax-associated forms of IKK are constitutively active in either Tax transfectants or HTLV1-infected T lymphocytes. Moreover, point mutations in Tax that ablate its IKK-binding function also prevent Tax-mediated activation of IKK and NF-kappaB. Together, these findings suggest that the persistent activation of NF-kappaB in HTLV1-infected T-cells is mediated by a direct Tax/IKK coupling mechanism.
Chu
Z L
ZL
Howard Hughes Medical Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
DiDonato
J A
JA
Hawiger
J
J
Ballard
D W
DW
D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D016356:Gene Products, tax / Q000378:metabolism*; D015490:HTLV-I Infections / Q000201:enzymology*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D051550:I-kappa B Kinase; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D016356:Gene Products, tax; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human