The tax oncoprotein of human T-cell leukemia virus type 1 associates with and persistently activates IκB kinases containing IKKα and IKKβ

Abstract

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 KKα and IKKβ, which mediate phosphorylation of IκBα at Set-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.