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The Tax Oncoprotein of Human T-cell Leukemia Virus Type 1 Associates with and Persistently Activates IκB Kinases Containing IKKα and IKKβ*

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The Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV1) chronically activates transcription factor NF-κB by a mechanism involving degradation of IκBα, an NF-κB-associated cytoplasmic inhibitor. Tax-induced breakdown of IκBα requires phosphorylation of the inhibitor at Ser-32 and Ser-36, which is also a prerequisite for the transient activation of NF-κB in cytokine-treated T lymphocytes. However, it remained unclear how Tax interfaces with the cellular NF-κB/IκB signaling machinery to generate a chronic rather than a transient NF-κB response. We now demonstrate that Tax associates with cytokine-inducible IκB kinase (IKK) complexes containing catalytic subunits IKKα and IKKβ, which mediate phosphorylation of IκBα 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-κB. Together, these findings suggest that the persistent activation of NF-κB in HTLV1-infected T-cells is mediated by a direct Tax/IKK coupling mechanism.

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This work was supported by Grants RO1 AI33839 (to D. W. B.) and RO1 HL45994 (to J. H.) from the National Institutes of Health, by Training Grant T32 CA09385 (to Z.-L. C.) from the NCI, and by the Howard Hughes Medical Institute. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.