Broad antagonism of coronaviruses nsp5 to evade the host antiviral responses by cleaving POLDIP3

文献类型： 外文期刊

第一作者： Wu, Yang

作者： Wu, Yang;Li, Mingwei;Tian, Jin;Yan, Haoxin;Pan, Yudi;Shi, Hongyan;Shi, Da;Chen, Jianfei;Guo, Longjun;Feng, Li

作者机构：

期刊名称：PLOS PATHOGENS （ 影响因子：6.7； 五年影响因子：6.7 ）

ISSN： 1553-7366

年卷期： 2023 年 19 卷 10 期

页码：

收录情况： SCI

摘要： Coronaviruses (CoVs) are a family of the largest RNA viruses that typically cause respiratory, enteric, and hepatic diseases in animals and humans, imposing great threats to the public safety and animal health. Porcine deltacoronavirus (PDCoV), a newly emerging enteropathogenic coronavirus, causes severe diarrhea in suckling piglets all over the world and poses potential risks of cross-species transmission. Here, we use PDCoV as a model of CoVs to illustrate the reciprocal regulation between CoVs infection and host antiviral responses. In this study, downregulation of DNA polymerase delta interacting protein 3 (POLDIP3) was confirmed in PDCoV infected IPEC-J2 cells by isobaric tags for relative and absolute quantification (iTRAQ) and Western blotting analysis. Overexpression of POLDIP3 inhibits PDCoV infection, whereas POLDIP3 knockout (POLDIP3-/-) by CRISPR-Cas9 editing significantly promotes PDCoV infection, indicating POLDIP3 as a novel antiviral regulator against PDCoV infection. Surprisingly, an antagonistic strategy was revealed that PDCoV encoded nonstructural protein 5 (nsp5) was responsible for POLDIP3 reduction via its 3C-like protease cleavage of POLDIP3 at the glutamine acid 176 (Q176), facilitating PDCoV infection due to the loss of antiviral effects of the cleaved fragments. Consistent with the obtained data in IPEC-J2 cell model in vitro, POLDIP3 reduction by cleavage was also corroborated in PDCoV infected-SPF piglets in vivo. Collectively, we unveiled a new antagonistic strategy evolved by PDCoV to counteract antiviral innate immunity by nsp5-mediated POLDIP3 cleavage, eventually ensuring productive virus replication. Importantly, we further demonstrated that nsp5s from PEDV and TGEV harbor the conserved function to cleave porcine POLDIP3 at the Q176 to despair POLDIP3-mediated antiviral effects. In addition, nsp5 from SARS-CoV-2 also cleaves human POLDIP3. Therefore, we speculate that coronaviruses employ similar POLDIP3 cleavage mechanisms mediated by nsp5 to antagonize the host antiviral responses to sustain efficient virus infection. Coronavirus encodes the conserved 3C-like protease nsp5, which has been reported to antagonize interferon (IFN) responses by cleaving a variety of subtracts critical for interferon signaling pathways. In this study, POLDIP3 was screened with apparent downregulation post PDCoV infection and identified as a novel antiviral regulator against PDCoV infection. Notably, PDCoV employs its nsp5 to directly cleave POLDIP3 in favor of its replication. We revealed that nsp5 proteins from other coronaviruses, such as porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also had the protease activity to cleave porcine and human POLDIP3. Thus, the findings will deepen our better understanding of pathogenic mechanisms of coronavirus infections and provide nsp5 as an appealing target for the therapeutic design against coronavirus infections.

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