Human T-cell Lymphotropic Virus Type 1 Tax Induction of Biologically Active NF-κB Requires IκB Kinase-1-mediated Phosphorylation of RelA/p65

Alison M. O'Mahony, Mauricio Montano, Katrien Van Beneden, Lin Feng Chen, Warner C. Greene

Research output: Contribution to journalArticle

Abstract

Activation of the NF-κB/Rel family of transcription factors proceeds through a catalytic complex containing IκB kinase (IKK)-1 and IKK2. Targeted disruption of each of the IKK genes suggests that these two kinases may mediate distinct functions in the activation pathway. In our studies of the human T-cell lymphotropic virus type 1 (HTLV-1) Tax oncoprotein, we have uncovered a new function of IKK1 required for complete activation of the NF-κB transcriptional program. In IKK1-/- murine embryonic fibroblasts (MEFs), Tax normally induced early NF-κB activation events. However, NF-κB induced by Tax in these IKK1-/- cells was functionally impaired. In IKK1-/- (but not wild-type) MEFs, Tax failed to activate several different κB reporter constructs or to induce the endogenous IκBα gene. In contrast, Tax normally activated the cAMP-responsive element-binding protein/activating transcription factor pathway, leading to full stimulation of an HTLV-1 long terminal repeat reporter construct in IKK1-/- cells. Furthermore, reconstitution of IKK1 -/- cells with kinase-proficient (but not kinase-deficient) forms of IKK1 restored the Tax induction of full NF-κB transactivation. We further found that the defect in NF-κB action in IKK1-/- cells correlated with a failure of Tax to induce phosphorylation of the RelA/p65 subunit of NF-κB at Ser529 and Ser536. Such phosphorylation of RelA/p65 was readily detected in wild-type MEFs. Phosphorylation of Ser536 was required for a complete response to Tax expression, whereas phosphorylation of Ser529 appeared to be less critical. Together, these findings highlight distinct roles for the IKK1 and IKK2 kinases in the activation of NF-κB in response to HTLV-1 Tax. IKK2 plays a dominant role in signaling for IκBα degradation, whereas IKK1 appears to play an important role in enhancing the transcriptional activity of NF-κB by promoting RelA/p65 phosphorylation.

Original languageEnglish (US)
Pages (from-to)18137-18145
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number18
DOIs
StatePublished - Apr 30 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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