Retroviral oncoprotein Tax deregulates NF-kappaB by activating Tak1 and mediating the physical association of Tak1-IKK.

The Tax oncoprotein of human T-cell leukaemia virus type I (HTLV-I) persistently activates nuclear factor-kappaB (NF-kappaB), which is required for HTLV-I-mediated T-cell transformation. Tax activates NF-kappaB by stimulating the activity of IkappaB kinase (IKK), but the underlying mechanism remains elusive. Here, we show that Tax functions as an intracellular stimulator of an IKK-activating kinase, Tak1 (TGF-beta-activating kinase 1). In addition, Tax physically interacts with Tak1 and mediates the recruitment of IKK to Tak1. In HTLV-I-infected T cells, Tak1 is constitutively activated and complexed with both Tax and IKK. We provide genetic evidence that Tak1 is essential for Tax-induced IKK activation. Furthermore, unlike cellular stimuli, the Tax-specific NF-kappaB signalling does not require the ubiquitin-binding function of IKKgamma. These findings show a pathological mechanism of IKK activation by Tax and provide an example for how IKK is persistently activated in cancer cells.