Human T-lymphotropic virus type I Tax activates I-κB kinase by inhibiting I-κB kinase-associated serine/threonine protein phosphatase 2A

I-kappaB kinase (IKK) is a serine/threonine kinase that phosphorylates I-kappaBalpha and I-kappaBbeta and targets them for polyubiquitination and proteasome-mediated degradation. IKK consists of two highly related catalytic subunits, alpha and beta, and a regulatory gamma subunit, which becomes activated after serine phosphorylation of the activation loops of the catalytic domains. The human T-lymphotropic retrovirus type-I trans-activator, Tax, has been shown to interact directly with IKKgamma and activates IKK via a mechanism not fully understood. Here we demonstrate that IKK binds serine/threonine protein phosphatase 2A (PP2A), and via a tripartite protein-protein interaction, Tax, IKKgamma, and PP2A form a stable ternary complex. In vitro, PP2A down-regulates active IKK prepared from Tax-producing MT4 cells. In the presence of Tax, however, the ability of PP2A to inactivate IKK is diminished. Despite their interaction with IKKgamma, PP2A-interaction-defective Tax mutants failed to activate NF-kappaB. Our data support the notion that IKKgamma-associated PP2A is responsible for the rapid deactivation of IKK, and inhibition of PP2A by Tax in the context of IKK.PP2A.Tax ternary complex leads to constitutive IKK and NF-kappaB activation.