The highly infectious coronavirus SARS-CoV-2 relies on the viral main protease (M^pro, also known as 3CLpro or Nsp5) to proteolytically process the polyproteins encoded by the viral genome for the release of functional units in the host cells to initiate viral replication. M^pro also interacts with host proteins of the innate immune pathways, such as IRF3 and STAT1, to suppress their activities and facilitate virus survival and proliferation. To identify the host mechanism for regulating M^pro, we screened various classes of E3 ubiquitin ligases and found that Parkin of the RING-between-RING family can induce the ubiquitination and degradation of M^pro in the cell. Furthermore, when the cells undergo mitophagy, the PINK1 kinase activates Parkin and enhances the ubiquitination of M^pro. We also found that elevated expression of Parkin in the cells significantly decreased the replication of SARS-CoV-2 virus. Interestingly, SARS-CoV-2 infection downregulates Parkin expression in the mouse lung tissues compared to healthy controls. These results suggest an antiviral role of Parkin as a ubiquitin ligase targeting M^pro and the potential for exploiting the virus–host interaction mediated by Parkin to treat SARS-CoV-2 infection.

中文翻译：

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泛素连接酶 Parkin 调节 SARS-CoV-2 主要蛋白酶的稳定性并抑制病毒复制

高度传染性的冠状病毒SARS-CoV-2依赖病毒主蛋白酶（M ^pro，也称为3CLpro或Nsp5）对病毒基因组编码的多蛋白进行蛋白水解处理，在宿主细胞中释放功能单元以启动病毒复制。M ^pro还与先天免疫途径的宿主蛋白（例如 IRF3 和 STAT1）相互作用，以抑制其活性并促进病毒存活和增殖。^{为了确定调节M pro}的宿主机制，我们筛选了各类E3泛素连接酶，发现RING- Between-RING家族的Parkin可以诱导细胞内M ^{pro的泛素化和降解。}此外，当细胞进行线粒体自噬时，PINK1 激酶会激活 Parkin 并增强 M ^pro的泛素化。我们还发现细胞中 Parkin 表达升高显着降低了 SARS-CoV-2 病毒的复制。有趣的是，与健康对照相比，SARS-CoV-2 感染下调了小鼠肺组织中 Parkin 的表达。^{这些结果表明 Parkin 作为靶向 M pro 的}泛素连接酶具有抗病毒作用，并且具有利用 Parkin 介导的病毒与宿主相互作用来治疗 SARS-CoV-2 感染的潜力。