State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China; and Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China; and Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
J Immunol. 2021 Jul 1;207(1):189-199. doi: 10.4049/jimmunol.2001030. Epub 2021 Jun 28.
Seneca Valley virus (SVV), a newly emerging virus belonging to the family, has caused vesicular disease in the swine industry. However, the molecular mechanism of viral pathogenesis remains poorly understood. This study revealed that SVV infection could induce pyroptosis in SK6 cells in a caspase-dependent and -independent manner. SVV may inhibit caspase-1 activation at late infection because of 3C cleavage of NLRP3, which counteracted pyroptosis activation. Further study showed that 3C targeted porcine gasdermin D (pGSDMD) for cleavage through its protease activity. 3C cleaved porcine GSDMD (pGSDMD) at two sites, glutamine 193 (Q193) and glutamine 277 (Q277), and Q277 was close to the caspase-1-induced pGSDMD cleavage site. pGSDMD triggered cell death, which was similar to N-terminal fragment produced by caspase-1 cleavage of pGSDMD, and other fragments exhibited no significant inhibitory effects on cellular activity. Ectopic expression of pGSDMD converted 3C-induced apoptosis to pyroptosis in 293T cells. Interestingly, 3C did not cleave mouse GSDMD or human GSDMD. And, both pGSDMD and pGSDMD exhibited bactericidal activities in vivo. Nevertheless, pGSDMD cannot kill bacteria in vitro. Taken together, our results reveal a novel pyroptosis activation manner produced by viral protease cleavage of pGSDMD, which may provide an important insight into the pathogenesis of SVV and cancer therapy.
辛诺柏病毒（SVV）是一种新兴的病毒，属于 科，已在养猪业中引起疱疹疾病。然而，病毒发病机制的分子机制仍知之甚少。本研究表明，SVV 感染可通过半胱天冬酶依赖性和非依赖性方式诱导 SK6 细胞发生细胞焦亡。SVV 可能在晚期感染时通过 3C 对 NLRP3 的切割抑制半胱天冬酶-1 的激活，从而抵消细胞焦亡的激活。进一步的研究表明，3C 通过其蛋白酶活性靶向猪 Gasdermin D（pGSDMD）进行切割。3C 在两个位点切割 pGSDMD，即谷氨酰胺 193（Q193）和谷氨酰胺 277（Q277），且 Q277 接近半胱天冬酶-1 诱导的 pGSDMD 切割位点。pGSDMD 引发的细胞死亡类似于半胱天冬酶-1 切割 pGSDMD 产生的 N 端片段，其他片段对细胞活性没有明显的抑制作用。293T 细胞中 pGSDMD 的异位表达将 3C 诱导的细胞凋亡转化为细胞焦亡。有趣的是，3C 不能切割小鼠 GSDMD 或人 GSDMD。并且，pGSDMD 和 pGSDMD 均在体内具有杀菌活性。然而，pGSDMD 不能在体外杀死细菌。总之，我们的结果揭示了病毒蛋白酶切割 pGSDMD 产生的新型细胞焦亡激活方式，这可能为 SVV 和癌症治疗的发病机制提供重要的见解。
