Balkhi Mumtaz Yaseen, Fitzgerald Katherine A, Pitha Paula M
Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21218, USA.
Cell Signal. 2010 Jan;22(1):117-27. doi: 10.1016/j.cellsig.2009.09.021. Epub 2009 Sep 25.
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.
IRF家族的转录因子IRF-3、IRF-5和IRF-7在先天性抗病毒反应中起关键作用。在受感染的细胞中，IRF-3和IRF-7通过TBK-1和IKKε介导的磷酸化被激活，而在MyD88信号通路中使IRF-5磷酸化的激酶尚未被鉴定出来。我们现在表明，IKKα使IRF-5磷酸化并诱导IRF-5二聚体的形成，这表明IRF-5被激活。然而，IKKα诱导的IRF-5磷酸化对1型干扰素和炎性细胞因子启动子的转录激活具有抑制作用。为了探讨IKKα介导的对IRF-5活性抑制的分子机制，我们发现IKKα对IRF-5的磷酸化抑制了对IRF-5活性至关重要的K63泛素化。此外，我们鉴定出IRF-5与碱性磷酸酶的相互作用，这导致其去磷酸化。MyD88激活的IRF-5诱导碱性磷酸酶表达这一观察结果表明IRF-5处于自身调节回路中。因此，这些全新的观察结果确定IKKα激酶和碱性磷酸酶是MyD88途径中IRF-5活性的负调节因子，并暗示它们通过减弱IRF-5活性在炎症反应控制中的作用。
