IKKalpha negatively regulates IRF-5 function in a MyD88-TRAF6 pathway
Name:
Publisher version
View Source
Access full-text PDFOpen Access
View Source
Check access options
Check access options
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2010-01-30Keywords
HumansI-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
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
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.Source
Cell Signal. 2010 Jan;22(1):117-27. Epub 2009 Sep 25. Link to article on publisher's siteDOI
10.1016/j.cellsig.2009.09.021Permanent Link to this Item
http://hdl.handle.net/20.500.14038/35221PubMed ID
19786094Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.cellsig.2009.09.021