Seneca Valley Virus 3C Protease Induces Pyroptosis by Directly Cleaving Porcine Gasdermin D
Seneca Valley Virus 3C Protease Induces Pyroptosis by Directly Cleaving Porcine Gasdermin D
复制标题
塞内卡谷病毒 3C 蛋白酶通过直接裂解猪 Gasdermin D 诱导焦亡
DOI：
10.4049/jimmunol.2001030
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Ping Qian
中科院分区：
文献类型：
--
作者：
Wei Wen;Xiangmin Li;Haoyuan Wang;Qiongqiong Zhao;Mengge Yin;Wenqiang Liu;Huanchun Chen;Ping Qian
要点 SVV 3Cpro 直接裂解 pGSDMD 以诱导细胞焦亡。 SVV 3Cpro 可以裂解猪体内的 GSDMD，但不能裂解人类或小鼠体内的 GSDMD。塞内卡谷病毒（SVV）是一种属于小核糖核酸病毒科的新出现的病毒，已引起养猪业的水疱病。然而，病毒发病机制的分子机制仍知之甚少。这项研究表明，SVV 感染可以以 caspase 依赖性和非依赖性方式诱导 SK6 细胞焦亡。由于 NLRP3 的 3Cpro 裂解，SVV 可能会在感染后期抑制 caspase-1 激活，从而抵消焦亡激活。进一步研究表明，3Cpro 通过其蛋白酶活性靶向猪gasdermin D (pGSDMD) 进行切割。 3Cpro 在两个位点（谷氨酰胺 193 (Q193) 和谷氨酰胺 277 (Q277)）切割猪 GSDMD (pGSDMD)，并且 Q277 靠近 caspase-1 诱导的 pGSDMD 切割位点。 pGSDMD1-277触发细胞死亡，与caspase-1裂解pGSDMD产生的N端片段相似，其他片段对细胞活性没有明显的抑制作用。 pGSDMD 的异位表达将 3Cpro 诱导的细胞凋亡转变为 293T 细胞焦亡。有趣的是，3Cpro 不会裂解小鼠 GSDMD 或人 GSDMD。并且，pGSDMD 和 pGSDMD1-277 均表现出体内杀菌活性。然而，pGSDMD 不能在体外杀死细菌。总而言之，我们的结果揭示了病毒蛋白酶裂解 pGSDMD 产生的一种新的焦亡激活方式，这可能为 SVV 的发病机制和癌症治疗提供重要的见解。
Key Points SVV 3Cpro directly cleaves pGSDMD to induce pyroptosis. SVV 3Cpro cleaves GSDMD in pigs, but not in humans or mice. Seneca Valley virus (SVV), a newly emerging virus belonging to the Picornaviridae 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 3Cpro cleavage of NLRP3, which counteracted pyroptosis activation. Further study showed that 3Cpro targeted porcine gasdermin D (pGSDMD) for cleavage through its protease activity. 3Cpro 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. pGSDMD1–277 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 3Cpro-induced apoptosis to pyroptosis in 293T cells. Interestingly, 3Cpro did not cleave mouse GSDMD or human GSDMD. And, both pGSDMD and pGSDMD1–277 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.
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