Metabolite-Sensing G Protein Coupled Receptor TGR5 Protects Host From Viral Infection Through Amplifying Type I Interferon Responses.
Metabolite-Sensing G Protein Coupled Receptor TGR5 Protects Host From Viral Infection Through Amplifying Type I Interferon Responses.
复制标题
代谢物感应 G 蛋白偶联受体 TGR5 通过放大 I 型干扰素反应来保护宿主免受病毒感染。
DOI：
10.3389/fimmu.2018.02289
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发表时间：
2018
影响因子：
7.3
通讯作者：
Du B
中科院分区：
文献类型：
--
作者：
Xiong Q;Huang H;Wang N;Chen R;Chen N;Han H;Wang Q;Siwko S;Liu M;Qian M;Du B
代谢物敏感G蛋白偶联受体（GPCR）与各种代谢物结合，并传递对适当的免疫和代谢功能至关重要的信号。然而，代谢物敏感GPCR在病毒感染中的作用还没有得到很好的表征。在这里，我们将代谢物敏感GPCR TGR 5鉴定为干扰素（IFN）刺激的基因（ISG），其在病毒感染或IFN-β刺激后以STAT 1依赖性方式表达增加。最重要的是，TGR 5过表达或经修饰的胆汁酸INT-777处理可广泛保护宿主细胞免受水泡性口炎病毒（VSV）、纽卡斯尔疫病毒（NDV）和1型单纯疱疹病毒（HSV-1）感染。此外，VSV和HSV-1的复制显着增加在Tgr 5缺陷的巨噬细胞和VSV分布在肝，脾和肺在Tgr 5缺陷的小鼠在VSV感染增加。因此，Tgr 5缺陷型小鼠比野生型小鼠更容易受到VSV感染。从机制上讲，TGR 5通过AKT/IRF 3信号通路促进I型干扰素（IFN-I）的产生，这在促进抗病毒先天免疫中至关重要。综上所述，我们的数据揭示了调节IRF 3信号传导的正反馈环，并表明代谢物敏感GPCR在控制病毒性疾病中的潜在治疗作用。
The metabolite-sensing G protein–coupled receptors (GPCRs) bind to various metabolites and transmit signals that are important for proper immune and metabolic functions. However, the roles of metabolite-sensing GPCRs in viral infection are not well characterized. Here, we identified metabolite-sensing GPCR TGR5 as an interferon (IFN)-stimulated gene (ISG) which had increased expression following viral infection or IFN-β stimulation in a STAT1-dependent manner. Most importantly, overexpression of TGR5 or treatment with the modified bile acid INT-777 broadly protected host cells from vesicular stomatitis virus (VSV), newcastle disease virus (NDV) and herpes simplex virus type 1 (HSV-1) infection. Furthermore, VSV and HSV-1 replication was increased significantly in Tgr5-deficient macrophages and the VSV distribution in liver, spleen and lungs was increased in Tgr5-deficient mice during VSV infection. Accordingly, Tgr5-deficient mice were much more susceptible to VSV infection than wild-type mice. Mechanistically, TGR5 facilitates type I interferon (IFN-I) production through the AKT/IRF3-signaling pathway, which is crucial in promoting antiviral innate immunity. Taken together, our data reveal a positive feedback loop regulating IRF3 signaling and suggest a potential therapeutic role for metabolite-sensing GPCRs in controlling viral diseases.
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影响因子：
7
作者：
Sun, Hui;Zhang, Aihua;Wang, Xijun
通讯作者：
Wang, Xijun
影响因子：
4.4
作者：
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Sanders CR
影响因子：
4.8
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通讯作者：
Fujino, M
影响因子：
15.9
作者：
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通讯作者：
Schoonjans, Kristina