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IKKalpha negatively regulates IRF-5 function in a MyD88-TRAF6 pathway.

Transcription factors of IRF family, IRF-3, IRF-5 and IRF-7 play a critical role in the innate antiviral response. In infected cells, IRF-3 and IRF-7 are activated by TBK-1 and IKK epsilon mediated phosphorylation, while the kinase, phosphorylating IRF-5 in the MyD88 signalling pathway has not yet been identified. We now show that IKK alpha phosphorylates IRF-5 and induces formation of IRF-5 dimers, which have been indicative of IRF-5 activation. However, IKK alpha induced IRF-5 phosphorylation exerts inhibitory effect on the transcriptional activation of type 1 interferon and promoters of the inflammatory cytokines. Addressing the molecular mechanism of IKK alpha mediated inhibition of IRF-5 activity, we show that phosphorylation of IRF-5 by IKK alpha inhibits K63 ubiquitination that is essential for IRF-5 activity. Furthermore, we have identified interaction of IRF-5 with alkaline phosphatase, which causes its de-phosphorylation. The observation that MyD88 activated IRF-5 induces expression of alkaline phosphatase suggests that IRF-5 is under autoregulating loop. Thus these completely new observations identify IKK alpha kinase and alkaline phosphatase as negative regulators of IRF-5 activity in MyD88 pathway and implicate their role in the control of the inflammatory response by attenuation of IRF-5 activity.

Pubmed ID: 19786094

Authors

  • Balkhi MY
  • Fitzgerald KA
  • Pitha PM

Journal

Cellular signalling

Publication Data

January 23, 2010

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI067497
  • Agency: NCI NIH HHS, Id: CA19737-22A1
  • Agency: NIAID NIH HHS, Id: R01 AI067632-02A1

Mesh Terms

  • Humans
  • I-kappa B Kinase
  • Inflammation
  • Interferon Regulatory Factors
  • Interferon Type I
  • Myeloid Differentiation Factor 88
  • Phosphorylation
  • Protein Binding
  • Signal Transduction
  • TNF Receptor-Associated Factor 6
  • Ubiquitination