Persistent activation of NF-kappaB by the tax transforming protein of HTLV-1: hijacking cellular IkappaB kinases

Oncogene. 1999 Nov 22;18(49):6948-58. doi: 10.1038/sj.onc.1203220.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Cysteine Endopeptidases / physiology
  • Gene Products, tax / physiology*
  • Human T-lymphotropic virus 1 / physiology*
  • Humans
  • I-kappa B Kinase
  • Multienzyme Complexes / physiology
  • NF-kappa B / physiology*
  • Proteasome Endopeptidase Complex
  • Protein-Serine-Threonine Kinases / physiology*
  • Signal Transduction

Substances

  • Gene Products, tax
  • Multienzyme Complexes
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex