State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; Key Laboratory of Preventive Veterinary Medicine in Hubei Province, the Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; Key Laboratory of Preventive Veterinary Medicine in Hubei Province, the Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
Vet Microbiol. 2022 Aug;271:109494. doi: 10.1016/j.vetmic.2022.109494. Epub 2022 Jun 14.
Porcine deltacoronavirus (PDCoV) is an emerging enteropathogenic coronavirus that has the potential for cross-species infection. Many viruses have been reported to induce endoplasmic reticulum stress (ERS) and activate the unfolded protein response (UPR). To date, little is known about whether and, if so, how the UPR is activated by PDCoV infection. Here, we investigated the activation state of UPR pathways and their effects on viral replication during PDCoV infection. We found that PDCoV infection induced ERS and activated all three known UPR pathways (inositol-requiring enzyme 1 [IRE1], activating transcription factor 6 [ATF6], and PKR-like ER kinase [PERK]), as demonstrated by IRE1-mediated XBP1 mRNA cleavage and increased mRNA expression of XBP1s, ATF4, CHOP, GADD34, GRP78, and GRP94, as well as phosphorylated eIF2α expression. Through pharmacologic treatment, RNA interference, and overexpression experiments, we confirmed the negative role of the PERK-eIF2α pathway and the positive regulatory role of the ATF6 pathway, but found no obvious effect of IRE1 pathway, on PDCoV replication. Taken together, our results characterize, for the first time, the state of the ERS response during PDCoV infection and identify the PERK and ATF6 pathways as potential antiviral targets.
猪德尔塔冠状病毒（PDCoV）是一种新兴的肠致病性冠状病毒，具有跨种感染的潜力。许多病毒已被报道能诱导内质网应激（ERS）并激活未折叠蛋白反应（UPR）。迄今为止，尚不清楚 PDCoV 感染是否以及如何激活 UPR，知之甚少。在这里，我们研究了 UPR 途径的激活状态及其对 PDCoV 感染期间病毒复制的影响。我们发现 PDCoV 感染诱导 ERS 并激活所有三种已知的 UPR 途径（肌醇需求酶 1[IRE1]、激活转录因子 6[ATF6]和蛋白激酶 R 样内质网激酶[PERK]），这表现为 IRE1 介导的 XBP1 mRNA 切割和 XBP1s、ATF4、CHOP、GADD34、GRP78 和 GRP94 的 mRNA 表达增加，以及磷酸化 eIF2α 的表达增加。通过药理学处理、RNA 干扰和过表达实验，我们证实了 PERK-eIF2α 途径的负作用和 ATF6 途径的正调节作用，但发现 IRE1 途径对 PDCoV 复制没有明显影响。总之，我们的研究结果首次描述了 PDCoV 感染期间 ERS 反应的状态，并确定了 PERK 和 ATF6 途径是潜在的抗病毒靶点。
