title: Protein phosphatase PP1 negatively regulates the Toll-like receptor- and RIG-I-like receptor-triggered production of type I interferon by inhibiting IRF3 phosphorylation at serines 396 and 385 in macrophage.
abstract: 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),ΚB kinase ε (IKKε) activation. Conversely, RNA interference of PP1 significantly promotes IRF3 activation. Consistently, The overexpression of PP1 inhibits TLR- and VSV-triggered IFN-β production while PP1 knockdown significantly increases the production of IFN-β 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-β production. Thus, PP1 functions as a negative feedback regulator of TLR- and RLR-triggered antiviral immune responses by acting as an IRF3 phosphatase.
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Meidi
authors.initials: M
authors.lastname: Gu
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: lin
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Lai
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Dajing
authors.initials: D
authors.lastname: Xia
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China. Electronic address: wangxiaojian@cad.zju.edu.cn.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D015536:Down-Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008024:Ligands; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D010768:Phosphoserine; D012694:Serine; D016899:Interferon-beta; D054645:Protein Phosphatase 1
keywords: IFN-β; IRF3; PP1; RLR; TLR