期刊
CELLULAR SIGNALLING
卷 26, 期 12, 页码 2930-2939出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2014.09.007
关键词
PP1; IRF3; IFN-beta; TLR; RLR
类别
资金
- National Basic Research Program of China (973) [2014CB542101]
- National Natural Science Foundation of China [81230041, 31200652]
- Natural Science Foundation of Zhejiang Province [R13C080001, LY12H10006]
The production of type I interferon must be tightly regulated, and the aberrant production of this protein is harmful or even fatal to the host. The transcription factor IRF3 phosphorylation is a central regulator of type I interferon meditated antiviral response. Protein phosphatase-1 (PP1) has been reported to be important in many cell functions, including development, differentiation, and tumorigenesis. However, the roles of PP1 in Toll-like receptor (TLR)- or retinoic acid-inducible gene I like receptor (RLR)-triggered IRF-3 activation remain unclear. Here, we show that the activity of PP1 is downregulated in macrophages upon stimulation with TLR or RLR ligands, including lipopolysaccharide, and poly(I:C), or vesicular stomatitis virus (VSV), respectively. The overexpression of PP1 selectively inhibits TLR- and VSV-induced interferon regulatory factor 3 (IRF3) activation but has no substantial effect on TANK-binding kinase 1 (TBK1),KB kinase epsilon (IKK epsilon) activation. Conversely, RNA interference of PP1 significantly promotes IRF3 activation. Consistently, The overexpression of PP1 inhibits TLR- and VSV-triggered IFN-beta production while PP1 knockdown significantly increases the production of IFN-beta in macrophages. We further demonstrate that PP1 directly interacts with IRF3 and dephosphorylates IRF3 at Ser385 and Ser396, resulting in the suppression of TLR- and RLR-triggered IFN-beta production. Thus, PP1 functions as a negative feedback regulator of TLR- and RLR-triggered antiviral immune responses by acting as an IRF3 phosphatase. (C) 2014 Elsevier Inc. All rights reserved.
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