Activation of I-κB kinase by the HTLV type 1 Tax protein: Mechanistic insights into the adaptor function of IKKγ

S. C. Sun, E. W. Harhaj, G. Xiao, L. Good

Research output: Contribution to journalArticlepeer-review

Abstract

The Tax protein encoded by human T cell leukemia virus type 1 (HTLV-1) induces constitutive nuclear expression of the transcription factor NF-κB, causing aberrant expression of a large array of cellular genes. Tax activates NF-κB by stimulating the activity of the I-κB kinase (IKK), which in turn leads to phosphorylation and degradation of the NF-κB inhibitor I-κBα. In normal T cells, IKK activation occurs transiently on cellular stimulation through the T cell receptor (TCR) and the CD28 costimulatory molecule. However, this inducible kinase is constitutively activated in Tax-expressing and HTLV-1-infected T cells, which contributes to the deregulated nuclear expression of NF-κB. 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 mutant Jurkat T cell lines. One of the mutant cell lines was shown to have a defect in NF-κB activation by both T cell mitogens and Tax. Interestingly, this mutant cell line lacks expression of the IKK regulatory protein, IKKγ. Expression of exogenous IKKγ in the mutant cells restored NF-κB activation, thus confirming the essential role of this regulatory factor in IKK activation by the cellular and viral stimuli. Mechanistic studies have shown that Tax physically interacts with IKKγ via specific domains, including two homologous leucine zipper motifs present in IKKγ. The Tax/IKKγ interaction serves to recruit Tax to the IKK catalytic subunits, IKKα and IKKβ, and this recruitment appears to be an essential mechanism by which Tax stimulates the activity of IKK.

Original languageEnglish (US)
Pages (from-to)1591-1596
Number of pages6
JournalAIDS research and human retroviruses
Volume16
Issue number16
DOIs
StatePublished - Nov 1 2000

ASJC Scopus subject areas

  • Immunology
  • Virology
  • Infectious Diseases

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