Casein Kinase 1gamma1 Inhibits the RIG-I/TLR Signaling Pathway through Phosphorylating p65 and Promoting Its Degradation----中国科学院微生物研究所

科研成果

论文题目:	Casein Kinase 1gamma1 Inhibits the RIG-I/TLR Signaling Pathway through Phosphorylating p65 and Promoting Its Degradation
作者:	Wang Yetao, Hu Lei, Tong Xiaomei, Ye Xin*
联系作者:	Ye Xin*
刊物名称:	J Immunol
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卷:
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年份:	2014
影响因子:	5.673
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摘要:	The casein kinase 1 (CK1) plays an important role in various biological processes by phosphorylating its target proteins. In this study, we demonstrate that CK1gamma1 inhibits RNA virus-mediated activation of retinoic acid-inducible gene I (RIG-I) signaling by affecting the stability of NF-kappaB subunit p65. First, we found that ectopic expression of CK1gamma1 inhibits RIG-I pathway-mediated activation of IFN-beta, whereas knockdown of CK1gamma1 potentiates the activation of IFN-beta and NF-kappaB induced by Sendai virus (SeV). We then revealed that CK1gamma1 interacts with p65 and specifically enhances its phosphorylation at Ser536 induced by SeV. By using an in vitro kinase assay, we confirmed that CK1gamma1 can phosphorylate p65 at Ser536. We also showed that the kinase dead mutants CK1gamma1K73A and CK1gamma1N169A did not inhibit SeV-induced activation of IFN-beta and NF-kappaB, suggesting that the kinase activity of CK1gamma1 is critical for its inhibitory effect on RIG-I signaling. Additionally, we found that CK1gamma1 also has the similar effect on TLR signaling. Further analysis indicated that CK1gamma1 phosphorylates p65 and consequently promotes its degradation by ubiquitin E3 ligases CUL2 and COMMD1. These results revealed a novel negative regulatory manner of CK1gamma1 on innate immune signaling.