GNAQ Negatively Regulates Antiviral Innate Immune Responses in a Calcineurin-Dependent Manner
GNAQ Negatively Regulates Antiviral Innate Immune Responses in a Calcineurin-Dependent Manner
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GNAQ 以钙调神经磷酸酶依赖性方式负调节抗病毒先天免疫反应
DOI：
10.4049/jimmunol.1900427
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Du Bing
中科院分区：
文献类型：
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作者：
Wang Ning;Huang Hongjun;Xiong Qingqing;Chen Naiyang;Xi Nanxi;Wu Peilun;Liu Mingyao;Qian Min;Wang Qin;Du Bing
病毒感染使GNAQ表达下调。GNAQ缺乏增加宿主体内和体外的抗病毒免疫。GNAQ以钙调磷酸酶依赖的方式负向调节IFN-I的产生。虽然鸟嘌呤核苷酸结合蛋白（G蛋白）偶联受体（gpcr）是最大的细胞膜受体家族，可将数千种细胞外信号转导到细胞质中，但只有4种G蛋白α亚基（Gαs、Gαi/o、Gαq/11和Gα12/13）偶联调节cAMP或磷脂酰肌醇信号。越来越多的证据表明，病毒倾向于劫持gpcr并利用其激活的细胞内信号通路。因此，了解G蛋白信号的作用将进一步揭示病毒利用的GPCR信号通路。在这项研究中，我们证明了GNAQ （Gq α亚基）的表达在病毒感染期间下调，并且小干扰rna介导的GNAQ敲低保护宿主细胞免受水疱性口炎病毒（VSV）和HSV 1型感染。同时，gnaq缺陷巨噬细胞中VSV和HSV 1型复制明显减少。因此，gnaq缺陷小鼠在VSV感染期间VSV在肝脏、脾脏和肺部的分布减少，gnaq缺陷小鼠对VSV感染的抵抗力远高于野生型小鼠。从机制上讲，GNAQ通过典型的PLC-β/Ca2+/CALNA信号通路限制I型IFN的产生，该信号通路已被证明可以使病毒激活的TANK-binding kinase 1 （TBK1）去磷酸化。因此，我们的数据表明GNAQ以钙调磷酸酶依赖的方式负调控抗病毒先天免疫反应。这些发现还提供了对经典GPCR信号通路与抗病毒先天免疫应答的功能和串扰的见解，并提示GNAQ在控制病毒性疾病中的潜在治疗作用。
Key Points Viral infection downregulates GNAQ expression. GNAQ deficiency increases host antiviral immunity both in vitro and in vivo. GNAQ negatively regulates IFN-I production in a calcineurin-dependent manner. Although guanine nucleotide-binding protein (G protein)–coupled receptors (GPCRs) constitute the largest cell surface membrane receptor family and transduce thousands of extracellular signals into the cytoplasm, only four kinds of G protein α subunits (Gαs, Gαi/o, Gαq/11, and Gα12/13) are coupled to regulate cAMP or phosphatidylinositol signals. Growing evidence suggests that viruses tend to hijack GPCRs and harness their activated intracellular signaling pathways. Thus, understanding the roles of G protein signaling will further uncover the GPCR signaling pathways that are exploited by viruses. In this study, we demonstrate that the expression of GNAQ (Gq α subunit) was downregulated during viral infection and that small interfering RNA–mediated GNAQ knockdown protected host cells from both vesicular stomatitis virus (VSV) and HSV type 1 infection. Meanwhile, VSV and HSV type 1 replication was reduced significantly in Gnaq-deficient macrophages. Accordingly, the VSV distribution in the liver, spleen, and lung was reduced in Gnaq-deficient mice during VSV infection, and Gnaq-deficient mice were much more resistant to VSV infection than wild-type mice. Mechanistically, GNAQ limits type I IFN production through the canonical PLC-β/Ca2+/CALNA signaling pathway, which has been demonstrated to dephosphorylate virus-activated TANK-binding kinase 1 (TBK1). Thus, our data demonstrate that GNAQ negatively regulates the antiviral innate immune responses in a calcineurin-dependent manner. These findings also provide insights into the function and cross-talk of the classic GPCR signaling pathway with antiviral innate immune responses and suggest a potential therapeutic role for GNAQ in controlling viral diseases.