Persistent activation of NF-kappaB by the tax transforming protein of HTLV-1: hijacking cellular IkappaB kinases.
Biochemical coupling of transcription factor NF-kappaB to antigen and co-stimulatory receptors is required for the temporal control of T-cell proliferation. In contrast to its transitory activation during normal growth-signal transduction, NF-kappaB is constitutively deployed in T-cells transformed by the type 1 human T-cell leukemia virus (HTLV-1). This viral/host interaction is mediated by the HTLV-1-encoded Tax protein, which has potent oncogenic properties. As reviewed here, Tax activates NF-kappaB primarily via a pathway leading to the chronic phosphorylation and degradation of IkappaBalpha, a cytoplasmic inhibitor of NF-kappaB. To access this pathway, Tax associates stably with a cytokine-inducible IkappaB kinase (IKK), which contains both catalytic (IKKalpha and IKKbeta) and noncatalytic (IKKgamma) subunits. Unlike their transiently induced counterparts in cytokine-treated cells, Tax-associated forms of IKKalpha and IKKbeta are persistently activated in HTLV-1-infected T cells. Acquisition of the deregulated IKK phenotype is contingent on the presence of IKKgamma, which functions as a molecular adaptor in the assembly of pathologic Tax/IkappaB kinase complexes. These findings highlight a key mechanistic role for IKK in the Tax/NF-kappaB signaling axis and define new intracellular targets for the therapeutic control of HTLV-1-associated disease.
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Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania, PA 17033, USA.
Ballard
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D000818:Animals; D003546:Cysteine Endopeptidases / Q000502:physiology; D016356:Gene Products, tax / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase; D009097:Multienzyme Complexes / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction
D016356:Gene Products, tax; D009097:Multienzyme Complexes; 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; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex