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

Abstract

I-κB kinase (IKK) is a serine/threonine kinase that phosphorylates I-κBα and I-κBβ and targets them for polyubiquitination and proteasome-mediated degradation. IKK consists of two highly related catalytic subunits, α and β and a regulatory γ 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 IKKγ 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 proteinprotein interaction, Tax, IKKγ, 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 IKKγ, PP2A-interaction-defective Tax mutants failed to activate NF-κB. Our data support the notion that IKKγ-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-κB activation.