Evidence in support of a role for human T-cell leukemia virus type I Tax in activating NF-κB via stimulation of signaling pathways

Abstract

The human T-cell leukemia virus type I Tax protein activates NF-κB transcription factors from preformed cytoplasmic pools, including those pools that are retained by the IκB-α inhibitory protein. Degradation of IκB-α is enhanced by Tax, resulting in the liberation of some NF-κB, which then translocates into the nucleus. Here we have investigated the mechanism by which Tax causes degradation of IκB-α. Two IκB-α mutants defective in extracellular signal-induced degradation of IκB-α also blocked Tax-mediated κB-dependent transactivation when cotransfected into Jurkat T cells. Cotransfected wild-type IκB-α or an irrelevant mutant did not significantly effect transactivation induced by Tax. The signal-defective IκB-α proteins are mutated at either of two closely spaced serines in the N terminus of the protein (Ser32 and Ser36). In wild-type IκB-α, one or both of these serines are inducibly phosphorylated with extracellular stimuli, and such phosphorylation appears necessary for subsequent degradation and thus activation of NF-κB. These results suggest that Tax triggers IκB-α degradation and thus NF-κB activation by a mechanism that converges with that induced by extracellular stimulation such as phorbol 12-myristate 13- acetate/ionomycin or tumor necrosis factor α. A role for Tax in activating signal transduction pathways upstream of IκB-α is implied.