导 读
猪传染性胃肠炎病毒（Transmissible Gastroenteritis Virus，TGEV）属于α冠状病毒，是引起规模化养猪场新生仔猪腹泻性死亡的重要原因，给我国养猪业造成了严重的经济损失。近日，中国农业科学院哈尔滨兽医研究所冯力研究员团队在国际期刊Journal of Virology发表了题为The PERK Arm of the Unfolded Protein Response Negatively Regulates Transmissible Gastroenteritis Virus Replication by Suppressing Protein Translation and Promoting Type I IFN Production 的论文。研究阐明了内质网应激（ER stress）抑制TGEV复制的分子机制，为研发抗冠状病毒药物靶点和制定抗病毒新策略提供了重要理论依据。

Fig . TGEV感染通过PERK通路激活导致eIF2α磷酸化模式图

研究背景
猪传染性胃肠炎病毒（TransmissibleGastroenteritis Virus，TGEV）属于α冠状病毒，能引起猪呕吐、脱水和严重腹泻等症状，2周龄内的仔猪死亡率可达90%-100%。TGEV是引起规模化养猪场新生仔猪腹泻性死亡的重要原因，给我国养猪业造成了严重的经济损失。
内质网作为蛋白质折叠和翻译后修饰的重要场所，是病毒复制和成熟的必需细胞器。病毒感染后，细胞内合成大量的病毒蛋白，从而增加内质网的负担，进而增加了未折叠蛋白和错误折叠蛋白的堆积。病毒感染后通常会诱发内质网应激，但对于内质网应激如何调控冠状病毒的复制及其调控机制目前还不明确。

结果速览
本研究发现：
（1）TGEV感染在体内和体外均能诱导内质网应激，激活未折叠蛋白反应，进一步研究发现TGEV诱导的内质网应激负调控病毒复制（图1）。尽管TGEV感染能够不同程度的激活PERK、ATF6和IRE1三个信号通路（图2-3），利用RNA干扰和特异性抑制剂处理发现仅PERK通路发挥抑制TGEV复制的功能（图4）。
（2）分子机制研究发现，TGEV感染通过PERK通路激活导致eIF2α磷酸化，磷酸化的eIF2α通过抑制蛋白翻译抑制TGEV复制；除了对病毒复制直接的抑制作用，PERK-eIF2α通路还激活NF-κB，促进I型干扰素产生，从而抑制TGEV复制（图5）。
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Fig. 1. TGEV infection induces ER stress in ST and IPEC-J2 cells
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Fig 2. TGEV infection activates all three UPR signaling pathways in vitro.
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Fig 3. TGEV infection activates all three UPR signaling pathways in vivo.
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Fig 4. The activated PERK-eIF2 pathway of the UPR inhibits TGEV replication.
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Fig5 . Model depicting the viral suppression by PERK-eIF2α pathway 1027 activation during TGEV infection

结 语
本研究表明内质网应激的PERK-eIF2α通路在调节天然免疫和冠状病毒复制方面发挥重要作用。研究受到国家重点研发计划（2016YFD0500100和2017YFD0502200）的资助，薛美博士为本文第一作者，冯力研究员和刘平黄研究员为共同通讯作者。

ABSTRACT

Coronavirus replication is closely associated with the endoplasmic reticulum (ER), the primary cellular organelle for protein synthesis, folding, and modification. ER stress is a common consequence in coronavirus-infected cells. However, how the virus-induced ER stress influences coronavirus replication and pathogenesis remains controversial. Here, we demonstrated that infection with the alpha coronavirus transmissible gastroenteritis virus (TGEV) induced ER stress and triggered the unfolded protein response (UPR) in vitro and in vivo, and ER stress negatively regulated TGEV replication in vitro. Although TGEV infection activated all three UPR pathways (ATF6, IRE1, and PERK), the virus-triggered UPR suppressed TGEV replication in both ST and IPEC-J2 cells primarily through activation ofthe PERK-eIF2α axis, as shown by functional studies with overexpression, siRNA,or specific chemical inhibitors. Moreover, we demonstrated that PERK-eIF2αaxis-mediated inhibition of TGEV replication is through phosphorylated eIF2α-inducedoverall attenuation of protein translation. In addition to direct inhibition of viral production, the PERK-eIF2α pathway activated NF-κB and then facilitated type I IFN production, resulting in TGEV suppression. Taken together, our results suggest that the TGEV-triggered PERK-eIF2α pathway negatively regulates TGEV replication and represents a vital aspect of host innate responses to invading pathogens.

参考文献：

1. Mei Xue, Fang Fu, Yanlong Ma, XinZhang, Liang Li, Li Feng* and Pinghuang Liu*.The PERK Arm of the UnfoldedProtein Response Negatively Regulates Transmissible Gastroenteritis VirusReplication by Suppressing Protein Translation and Promoting Type I IFNProduction. Accepted manuscript posted online 16 May 2018, doi: 10.1128/JVI.00431-18

http://jvi.asm.org/content/early/2018/05/10/JVI.00431-18.abstract

2.哈兽研官网：哈兽研发现内质网应激调控冠状病毒TGEV感染的新机制。

http://www.hvri.ac.cn/html/zonghexinwen/keyanjinzhan/2018/0521/1674.html

本期编辑：Annabella