Foot-and-Mouth Disease Virus Induces Porcine Gasdermin E-Mediated Pyroptosis through the Protease Activity of 3C(pro)

文献类型： 外文期刊

第一作者： Ren, Xujiao

作者： Ren, Xujiao;Yin, Mengge;Zhao, Qiongqiong;Zheng, Zixuan;Wang, Haoyuan;Li, Xiangmin;Qian, Ping;Ren, Xujiao;Yin, Mengge;Zhao, Qiongqiong;Zheng, Zixuan;Wang, Haoyuan;Li, Xiangmin;Qian, Ping;Li, Xiangmin;Qian, Ping;Lu, Zengjun

作者机构：

关键词： foot-and-mouth disease virus; pyroptosis; porcine gasdermin E; 3C(pro); protease activity; cleavage

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：5.4； 五年影响因子：4.9 ）

ISSN： 0022-538X

年卷期： 2023 年

页码：

收录情况： SCI

摘要： Although FMDV is an important virulent infectious disease virus, few reports have addressed its relationship with pyroptosis or pyroptosis factors, and most studies focus on the immune escape mechanism of FMDV. GSDME (DFNA5) was initially identified as being associated with deafness disorders. Foot-and-mouth disease (FMD) is an acute, highly contagious disease of cloven-hoofed animals caused by FMD virus (FMDV). Currently, the molecular pathogenesis of FMDV infection remains poorly understood. Here, we demonstrated that FMDV infection induced gasdermin E (GSDME)-mediated pyroptosis independent of caspase-3 activity. Further studies showed that FMDV 3C(pro) cleaved porcine GSDME (pGSDME) at the Q271-G272 junction adjacent to the cleavage site (D268-A269) of porcine caspase-3 (pCASP3). The inhibition of enzyme activity of 3C(pro) failed to cleave pGSDME and induce pyroptosis. Furthermore, overexpression of pCASP3 or 3C(pro)-mediated cleavage fragment pGSDME-NT was sufficient to induce pyroptosis. Moreover, the knockdown of GSDME attenuated the pyroptosis caused by FMDV infection. Our study reveals a novel mechanism of pyroptosis induced by FMDV infection and might provide new insights into the pathogenesis of FMDV and the design of antiviral drugs.IMPORTANCE Although FMDV is an important virulent infectious disease virus, few reports have addressed its relationship with pyroptosis or pyroptosis factors, and most studies focus on the immune escape mechanism of FMDV. GSDME (DFNA5) was initially identified as being associated with deafness disorders. Accumulating evidence indicates that GSDME is a key executioner for pyroptosis. Here, we first demonstrate that pGSDME is a novel cleavage substrate of FMDV 3C(pro) and can induce pyroptosis. Thus, this study reveals a previously unrecognized novel mechanism of pyroptosis induced by FMDV infection and might provide new insights into the design of anti-FMDV therapies and the mechanisms of pyroptosis induced by other picornavirus infections.

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