title: Activation of NF-kappa B/Rel by Tax involves degradation of I kappa B alpha and is blocked by a proteasome inhibitor.
abstract: The tax gene product of the human T-cell leukemia virus type I (HTLV-I) induces the nuclear expression and biological function of the NF-kappa B/Rel family of host transcription factors although the underlying mechanism remains unclear. In the present study, we demonstrate that Tax-mediated activation of NF-kappa B/Rel can be inhibited by a proteasome inhibitor, suggesting the involvement of proteolytic reactions in this Tax-specific activation pathway. Transient transfection and reporter gene assays have revealed that Tax overrides the inhibitory function of I kappa B alpha in both F9 embryonal cells and Jurkat T cells. Moreover, Tax-mediated inactivation of I kappa B alpha requires a 16 amino acid sequence element located at the N-terminal region (amino acid 21-36) of I kappa B alpha, which is also required for tumor necrosis factor alpha-induced degradation of this inhibitory protein. We further demonstrate that the proteasome inhibitor also blocks the degradation of I kappa B alpha observed in HTLV-I-infected T cells. Interestingly, inhibition of I kappa B alpha degradation in these cells led to the accumulation of a phosphorylated form of I kappa B alpha. Together, these studies suggest that Tax activation of NF-kappa B/Rel may involve induction of phosphorylation and subsequent proteasome-mediated degradation of the inhibitor I kappa B alpha.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey Medical Center, Hershey 17033, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Maggirwar
authors.forename: E
authors.initials: E
authors.lastname: Harhaj
authors.forename: S C
authors.initials: SC
authors.lastname: Sun
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016356:Gene Products, tax / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D051996:Transcription Factor RelA
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex