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
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
复制标题
蛋白磷酸酶 PP1 通过抑制巨噬细胞中 IRF3 丝氨酸 396 和 385 的磷酸化，负调节 Toll 样受体和 RIG-I 样受体触发的 I 型干扰素产生。
DOI：
10.1016/j.cellsig.2014.09.007
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发表时间：
2014-12-01
影响因子：
4.8
通讯作者：
Wang, Xiaojian
中科院分区：
文献类型：
--
作者：
Gu, Meidi;Zhang, Ting;Wang, Xiaojian
I型干扰素的产生必须受到严格的调控，这种蛋白质的异常产生对宿主有害甚至致命。转录因子IRF 3磷酸化是I型干扰素介导的抗病毒应答的中心调节因子。蛋白磷酸酶-1（PP 1）已被报道在许多细胞功能中起重要作用，包括发育、分化和肿瘤发生。然而，PP 1在Toll样受体（TLR）或视黄酸诱导基因I样受体（RLR）触发的IRF-3激活中的作用尚不清楚。在这里，我们表明，PP 1的活性下调巨噬细胞刺激TLR或RLR配体，包括脂多糖，聚（I：C），或水泡性口炎病毒（VSV），分别。PP 1的过表达选择性地抑制TLR和VSV诱导的干扰素调节因子3（IRF 3）活化，但对TANK结合激酶1（TBK 1）、KB激酶1（IKK）活化没有实质性影响。相反，PP 1的RNA干扰显著促进IRF 3激活。一致地，PP 1的过表达抑制TLR和VSV触发的IFN-β产生，而PP 1敲低显著增加巨噬细胞中IFN-β的产生。我们进一步证明，PP 1直接与IRF 3相互作用，并使IRF 3在Ser 385和Ser 396处去磷酸化，从而抑制TLR和TLR触发的IFN-β产生。因此，PP 1通过充当IRF 3磷酸酶而充当TLR和TLR触发的抗病毒免疫应答的负反馈调节剂。(C)2014爱思唯尔公司All rights reserved.
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.