Activation of I-kappa B kinase by the HTLV type 1 Tax protein: Mechanisticinsights into the adaptor function of IKK gamma

The Tax protein encoded by human T cell leukemia virus type 1 (HTLV-1) indu ces constitutive nuclear expression of the transcription factor NF-kappaB, causing aberrant expression of a large array of cellular genes. Tax activat es NF-kappaB by stimulating the activity of the I-kappaB kinase (IKK), whic h in turn leads to phosphorylation and degradation of the NF-kappaB inhibit or I-kappaB alpha. In normal T cells, IKK activation occurs transiently on cellular stimulation through the T cell receptor (TCR) and the CD28 costimu latory molecule. However, this inducible kinase is constitutively activated in Tax-expressing and HTLV-1-infected T cells, which contributes to the de regulated nuclear expression of NP-kappaB. As a genetic approach to dissect the pathways mediating IKK activation by Tax and T cell activation signals , somatic cell mutagenesis was performed to isolate signaling-defective mut ant Jurkat T cell lines. One of the mutant cell lines was shown to have a d efect in NF-kappaB activation by both T cell mitogens and Tax. Interestingl y, this mutant cell line lacks expression of the IKK regulatory protein, IK K gamma. Expression of exogenous IKK gamma in the mutant cells restored NF- kappaB activation, thus confirming the essential role of this regulatory fa ctor in IKK activation by the cellular and viral stimuli. Mechanistic studi es have shown that Tax physically interacts with IKK gamma via specific dom ains, including two homologous leucine zipper motifs present in IKK gamma. The Tax/IKK gamma interaction serves to recruit Tax to the IKK catalytic su bunits, IKK alpha and IKK beta, and this recruitment appears to be an essen tial mechanism by which Tax stimulates the activity of IKK.