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.
Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21218, USA.
Mumtaz Yaseen
MY
Balkhi
Katherine A
KA
Fitzgerald
Paula M
PM
Pitha
D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D054875:Ubiquitination
C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D048029:TNF Receptor-Associated Factor 6; D051550:I-kappa B Kinase