Activation of I-kappaB kinase by the HTLV type 1 Tax protein: mechanistic insights into the adaptor function of IKKgamma.
The Tax protein encoded by human T cell leukemia virus type 1 (HTLV-1) induces constitutive nuclear expression of the transcription factor NF-kappaB, causing aberrant expression of a large array of cellular genes. Tax activates NF-kappaB by stimulating the activity of the I-kappaB kinase (IKK), which in turn leads to phosphorylation and degradation of the NF-kappaB inhibitor I-kappaBalpha. 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-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 mutant Jurkat T cell lines. One of the mutant cell lines was shown to have a defect in NF-kappaB activation by both T cell mitogens and Tax. Interestingly, this mutant cell line lacks expression of the IKK regulatory protein, IKKgamma. Expression of exogenous IKKgamma in the mutant cells restored NF-kappaB 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 IKKgamma via specific domains, including two homologous leucine zipper motifs present in IKKgamma. The Tax/IKKgamma interaction serves to recruit Tax to the IKK catalytic subunits, IKKalpha and IKKbeta, and this recruitment appears to be an essential mechanism by which Tax stimulates the activity of IKK.
Sun
S C
SC
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. sxs70@psu.edu
Harhaj
E W
EW
Xiao
G
G
Good
L
L
D000595:Amino Acid Sequence; D004789:Enzyme Activation; D016356:Gene Products, tax / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D051550:I-kappa B Kinase; D019169:Jurkat Cells; D016350:Leucine Zippers; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000821:virology
D016356:Gene Products, tax; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human