State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, China.
Department of preventive veterinary medicine, College of Life Science & Technology, Southwest Minzu University, Chengdu, Sichuan, China.
Autophagy. 2022 Apr;18(4):816-828. doi: 10.1080/15548627.2021.1959086. Epub 2021 Aug 2.
While the functions of STING1 (stimulator of interferon response cGAMP interactor 1) during DNA virus infection had been well documented, the roles STING1 plays during RNA viruses infection is obscure. Infection with foot-and-mouth disease virus (FMDV), a well-known picornavirus, induces endoplasmic reticulum (ER) stress response and autophagy. Here, we found that the FMDV-induced integrated stress response originates from the cellular pattern recognition receptor DDX58/RIG-I (DExD/H-box helicase 58). DDX58 transmits signals to the ER-anchored adaptor protein STING1, which specifically activates the EIF2AK3/PERK (eukaryotic translation initiation factor 2A)-dependent integrated stress response and finally leads to reticulophagy and degradation of STING1 itself. Knockdown/knockout of STING1 or EIF2AK3 suppresses FMDV genome replication and viral protein expression. Reticulophagy induction by STING1 does not require its translocation to the Golgi or IFN response activation. However, STING1 polymerization is necessary for the FMDV-induced integrated stress response and reticulophagy. Our work illustrated the signaling cascades that mediate the cellular stress response to FMDV infection and indicated that induction of autophagy in response to both DNA and RNA virus infection may be an evolutionarily conserved function of STING1. ATF6: activating transcription factor 6; CGAS: cyclic GMP-AMP synthase; DDX58/RIG-I: DExD/H-box helicase 58; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 2; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; FMD: foot-and-mouth disease; FMDV: foot-and-mouth disease virus; IFIH1/MDA5: interferon induced with helicase C domain 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; RETREG1/FAM134B: reticulophagy regulator 1; STING1: stimulator of interferon response cGAMP interactor 1; TCID50: 50% tissue culture infectious dose; XBP1: X-box binding protein 1.
虽然 STING1（干扰素反应 cGAMP 相互作用因子 1 的刺激物）在 DNA 病毒感染期间的功能已经得到很好的证明，但 STING1 在 RNA 病毒感染期间的作用尚不清楚。口蹄疫病毒（FMDV）感染，一种已知的小核糖核酸病毒，诱导内质网（ER）应激反应和自噬。在这里，我们发现 FMDV 诱导的整合应激反应源自细胞模式识别受体 DDX58/RIG-I（DExD/H 盒解旋酶 58）。DDX58 将信号传递到 ER 锚定衔接蛋白 STING1，后者特异性激活 EIF2AK3/PERK（真核翻译起始因子 2A）依赖性整合应激反应，最终导致网织红细胞自噬和 STING1 自身降解。STING1 或 EIF2AK3 的敲低/敲除抑制 FMDV 基因组复制和病毒蛋白表达。STING1 诱导的网织红细胞自噬不需要其易位到高尔基体或 IFN 反应激活。然而，STING1 聚合对于 FMDV 诱导的整合应激反应和网织红细胞自噬是必需的。我们的工作说明了介导细胞对 FMDV 感染应激反应的信号级联，表明对 DNA 和 RNA 病毒感染的自噬诱导可能是 STING1 的一种进化保守功能。ATF6：激活转录因子 6；CGAS：环 GMP-AMP 合酶；DDX58/RIG-I：DExD/H 盒解旋酶 58；EIF2A/eIF2α：真核翻译起始因子 2A；EIF2AK3/PERK：真核翻译起始因子 2α激酶 2；ER：内质网；ERN1/IRE1：内质网向核信号 1；FMD：口蹄疫；FMDV：口蹄疫病毒；IFIH1/MDA5：干扰素诱导的具有螺旋酶 C 结构域 1；MAP1LC3B/LC3B：微管相关蛋白 1 轻链 3β；MAVS：线粒体抗病毒信号蛋白；MOI：感染复数；RETREG1/FAM134B：网织红细胞自噬调节因子 1；STING1：干扰素反应 cGAMP 相互作用因子 1 的刺激物；TCID50：50%组织培养感染剂量；XBP1：X 盒结合蛋白 1。
