PubMed:19786094 JSONTXT

{"project":"Inflammaging","denotations":[{"id":"T1","span":{"begin":0,"end":70},"obj":"Sentence"},{"id":"T2","span":{"begin":71,"end":185},"obj":"Sentence"},{"id":"T3","span":{"begin":186,"end":386},"obj":"Sentence"},{"id":"T4","span":{"begin":387,"end":521},"obj":"Sentence"},{"id":"T5","span":{"begin":522,"end":695},"obj":"Sentence"},{"id":"T6","span":{"begin":696,"end":899},"obj":"Sentence"},{"id":"T7","span":{"begin":900,"end":1016},"obj":"Sentence"},{"id":"T8","span":{"begin":1017,"end":1152},"obj":"Sentence"},{"id":"T9","span":{"begin":1153,"end":1403},"obj":"Sentence"},{"id":"T1","span":{"begin":0,"end":70},"obj":"Sentence"},{"id":"T2","span":{"begin":71,"end":185},"obj":"Sentence"},{"id":"T3","span":{"begin":186,"end":386},"obj":"Sentence"},{"id":"T4","span":{"begin":387,"end":521},"obj":"Sentence"},{"id":"T5","span":{"begin":522,"end":695},"obj":"Sentence"},{"id":"T6","span":{"begin":696,"end":899},"obj":"Sentence"},{"id":"T7","span":{"begin":900,"end":1016},"obj":"Sentence"},{"id":"T8","span":{"begin":1017,"end":1152},"obj":"Sentence"},{"id":"T9","span":{"begin":1153,"end":1403},"obj":"Sentence"}],"text":"IKKalpha negatively regulates IRF-5 function in a MyD88-TRAF6 pathway.\nTranscription 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."}

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