Innate sensing of picornavirus infection involves cGAS-STING-mediated antiviral responses triggered by mitochondrial DNA release.
Innate sensing of picornavirus infection involves cGAS-STING-mediated antiviral responses triggered by mitochondrial DNA release.
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小核糖核酸病毒感染的先天感知涉及由线粒体 DNA 释放触发的 cGAS-STING 介导的抗病毒反应。
DOI：
10.1371/journal.ppat.1011132
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发表时间：
2023-02
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
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作者：
环GMP-AMP合酶（cGAS）在对DNA和RNA病毒感染的先天免疫应答中起关键作用。在这里，我们发现肠道病毒71（EV-A71），塞尼卡谷病毒（SVV），口蹄疫病毒（FMDV）感染引发线粒体损伤和线粒体DNA（mtDNA）释放在体外和体内。这些反应是由小核糖核酸病毒2B蛋白介导的，该蛋白在病毒复制期间诱导mtDNA释放。SVV感染引起线粒体通透性转换孔（mPTP）开放，并导致电压依赖性阴离子通道1（VDAC 1）和BCL 2拮抗剂/杀伤剂1（巴克）以及巴克/BCL 2相关的X（Bax）依赖性mtDNA渗漏入胞浆; EV-A71和FMDV感染引起mPTP开放，并导致VDAC 1依赖性mtDNA释放。释放的mtDNA与cGAS结合并激活cGAS介导的抗病毒免疫应答。cGAS对于通过调节IFN-β产生来抑制EV-A71、SVV和FMDV复制是必需的。cGAS缺乏导致EV-A71或FMDV感染小鼠的死亡率较高。此外，我们发现SVV 2C蛋白通过自噬途径负责降低cGAS表达。2C中的第9位和第153位氨基酸位点对于诱导cGAS降解是关键的。此外，我们还表明EV-A71，CA 16和EMCV 2C通过与STING相互作用拮抗干扰素基因（STING）途径的cGAS刺激因子，高度保守的氨基酸Y155和S156对于这种抑制作用至关重要。总之，这些数据揭示了小核糖核酸病毒阻断cGAS-STING信号通路介导的抗病毒作用的新机制，这将为开发针对小核糖核酸病毒的抗病毒策略提供见解。众所周知，小核糖核酸病毒通过调节视黄酸诱导基因I（RIG-I）样受体（RLR）途径来抑制宿主先天性免疫应答。然而，小核糖核酸病毒感染对细胞溶质DNA传感器的影响仍然未知。在这里，我们发现小核糖核酸病毒感染引起线粒体功能障碍，触发线粒体DNA释放通过线粒体通透性转换孔（mPTP）。释放的线粒体DNA随后激活干扰素基因的环GMP-AMP腺苷酸酶刺激因子（cGAS-STING）介导的信号转导，促进I型干扰素表达。此外，我们确定了小核糖核酸病毒2C蛋白拮抗cGAS-STING信号通路激活的新拮抗机制，并确定了2C蛋白中的新拮抗位点。我们得出结论，cGAS-STING信号通路对于抑制小核糖核酸病毒感染至关重要，小核糖核酸病毒2C蛋白通过多种策略阻断其激活以促进病毒复制。我们的研究首次确定了cGAS-STING信号通路在小核糖核酸病毒感染中的抗病毒作用，并描述了小核糖核酸病毒介导的对DNA触发的先天免疫信号传导的抑制作用。
Cyclic GMP-AMP synthase (cGAS) plays a key role in the innate immune responses to both DNA and RNA virus infection. Here, we found that enterovirus 71 (EV-A71), Seneca Valley virus (SVV), and foot-and-mouth disease virus (FMDV) infection triggered mitochondria damage and mitochondrial DNA (mtDNA) release in vitro and vivo. These responses were mediated by picornavirus 2B proteins which induced mtDNA release during viral replication. SVV infection caused the opening of mitochondrial permeability transition pore (mPTP) and led to voltage-dependent anion channel 1 (VDAC1)- and BCL2 antagonist/killer 1 (Bak) and Bak/BCL2-associated X (Bax)-dependent mtDNA leakage into the cytoplasm, while EV-A71 and FMDV infection induced mPTP opening and resulted in VDAC1-dependent mtDNA release. The released mtDNA bound to cGAS and activated cGAS-mediated antiviral immune response. cGAS was essential for inhibiting EV-A71, SVV, and FMDV replication by regulation of IFN-β production. cGAS deficiency contributed to higher mortality of EV-A71- or FMDV-infected mice. In addition, we found that SVV 2C protein was responsible for decreasing cGAS expression through the autophagy pathway. The 9th and 153rd amino acid sites in 2C were critical for induction of cGAS degradation. Furthermore, we also show that EV-A71, CA16, and EMCV 2C antagonize the cGAS-stimulator of interferon genes (STING) pathway through interaction with STING, and highly conserved amino acids Y155 and S156 were critical for this inhibitory effect. In conclusion, these data reveal novel mechanisms of picornaviruses to block the antiviral effect mediated by the cGAS-STING signaling pathway, which will provide insights for developing antiviral strategies against picornaviruses. It is widely known that picornaviruses inhibit host innate immune responses by regulating retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) pathways. However, the impact of picornavirus infection on cytosolic DNA sensors remains unknown. Here, we found that picornavirus infection causes mitochondrial dysfunction that triggers mitochondrial DNA release via mitochondrial permeability transition pore (mPTP). The released mitochondrial DNA subsequently activates cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)-mediated signaling transduction, contributing to type I interferon expression. In addition, we identified novel antagonistic mechanisms by which picornavirus 2C proteins antagonize cGAS-STING signaling pathway activation and determined new antagonistic sites in 2C proteins. We conclude that the cGAS-STING signaling pathway is critical for suppressing picornavirus infections, and picornaviral 2C proteins block its activation through multiple strategies to favor virus replication. For the first time, our study determines the antiviral role of cGAS-STING signaling pathway in picornavirus infection and describes a picornavirus-mediated inhibitory effect on DNA-triggered innate immune signaling.
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影响因子：
3.8
作者：
Chen H;Humes ST;Rose M;Robinson SE;Loeb JC;Sabaraya IV;Smith LC;Saleh NB;Castleman WL;Lednicky JA;Sabo-Attwood T
通讯作者：
Sabo-Attwood T
影响因子：
64.8
作者：
Domizio JD;Gulen MF;Saidoune F;Thacker VV;Yatim A;Sharma K;Nass T;Guenova E;Schaller M;Conrad C;Goepfert C;de Leval L;Garnier CV;Berezowska S;Dubois A;Gilliet M;Ablasser A
通讯作者：
Ablasser A
影响因子：
4
作者：
He, Fei;Wu, Qianfu;Cheng, Jing
通讯作者：
Cheng, Jing
DOI：
10.1007/s00018-021-04001-7
发表时间：
2021-12
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Cai C;Tang YD;Xu G;Zheng C
通讯作者：
Zheng C
影响因子：
64.8
作者：
通讯作者：
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