The PERK Arm of the Unfolded Protein Response Negatively Regulates Transmissible Gastroenteritis Virus Replication by Suppressing Protein Translation and Promoting Type I Interferon Production

文献类型： 外文期刊

第一作者： Xue, Mei

作者： Xue, Mei;Fu, Fang;Ma, Yanlong;Zhang, Xin;Li, Liang;Feng, Li;Liu, Pinghuang

作者机构：

关键词： endoplasmic reticulum stress; unfolded protein response; protein kinase R-like ER kinase; transmissible gastroenteritis virus; translation attenuation; interferon

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：5.103； 五年影响因子：5.078 ）

ISSN： 0022-538X

年卷期： 2018 年 92 卷 15 期

页码：

收录情况： SCI

摘要： 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 alphacoronavirus 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 (activating transcription factor 6 [ATF6], inositol-requiring enzyme 1 [IRE1], and protein kinase R-like ER kinase [PERK]), the virus-triggered UPR suppressed TGEV replication in both swine testicular (ST) and IPEC-J2 cells primarily through activation of the PERK-eukaryotic initiation factor 2 alpha (elF2 alpha) axis, as shown by functional studies with overexpression, small interfering RNA (siRNA), or specific chemical inhibitors. More-over, we demonstrated that PERK-elF2 alpha axis-mediated inhibition of TGEV replication occurs through phosphorylated elF2 alpha-induced overall attenuation of protein translation. In addition to direct inhibition of viral production, the PERK-elF2 alpha pathway activated NF-kappa B and then facilitated type I IFN production, resulting in TGEV suppression. Taken together, our results suggest that the TGEV-triggered PERK-elF2 alpha pathway negatively regulates TGEV replication and represents a vital aspect of host innate responses to invading pathogens. IMPORTANCE The induction of ER stress is a common outcome in cells infected with coronaviruses. The UPR initiated by ER stress is actively involved in viral replication and modulates the host innate responses to the invading viruses, but these underlying mechanisms remain incompletely understood. We show here that infection with the alphacoronavirus TGEV elicited ER stress in vitro and in vivo, and the UPR PERK-elF2 alpha branch was predominantly responsible for the suppression of TGEV replication by ER stress. Furthermore, the PERK-elF2 alpha axis inhibited TGEV replication through direct inhibition of viral proteins due to global translation inhibition and type I IFN induction. These findings highlight a critical role of the UPR PERK-elF2 alpha pathway in modulating host innate immunity and coronavirus replication.

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