Viruses elicit cell and organismic stress, and offset homeostasis. They trigger intrinsic, innate and adaptive immune responses, which limit infection. Viruses restore homeostasis by harnessing evolutionary conserved stress responses, such as the endoplasmic reticulum (ER) unfolded protein response (UPR^ER). The canonical UPR^ER restores homeostasis based on a cell-autonomous signalling network modulating transcriptional and translational output. The UPR^ER remedies cell damage, but upon severe and chronic stress leads to cell death. Signals from the UPR^ER flow along three branches with distinct stress sensors, the inositol requiring enzyme (Ire) 1, protein kinase R (PKR)-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). This review shows how both enveloped and non-enveloped viruses use the UPR^ER to control cell stress and metabolic pathways, and thereby enhance infection and progeny formation, or undergo cell death. We highlight how the Ire1 axis bypasses apoptosis, boosts viral transcription and maintains dormant viral genomes during latency and persistence periods concurrent with long term survival of infected cells. These considerations open new options for oncolytic virus therapies against cancer cells where the UPR^ER is frequently upregulated. We conclude with a discussion of the evolutionary impact that viruses, in particular retroviruses, and anti-viral defense has on the UPR^ER.

中文翻译：

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内质网未折叠蛋白反应——病毒感染中的稳态、细胞死亡和进化


病毒引起细胞和有机体应激，并抵消体内平衡。它们触发内在的、先天的和适应性的免疫反应，从而限制感染。病毒通过利用进化保守的应激反应来恢复体内平衡，例如内质网（ER）未折叠蛋白反应（UPR ^ER ）。典型的 UPR ^ER基于调节转录和翻译输出的细胞自主信号网络恢复体内平衡。 UPR ^ER可以修复细胞损伤，但严重和慢性压力会导致细胞死亡。来自 UPR ^ER的信号沿着具有不同应激传感器的三个分支流动，即肌醇需要酶 (Ire) 1、蛋白激酶 R (PKR) 样 ER 激酶 (PERK) 和激活转录因子 6 (ATF6)。这篇综述展示了包膜病毒和非包膜病毒如何利用 UPR ^ER来控制细胞应激和代谢途径，从而增强感染和后代形成，或经历细胞死亡。我们重点介绍了 Ire1 轴如何绕过细胞凋亡、增强病毒转录并在受感染细胞长期存活的潜伏期和持续期内维持休眠病毒基因组。这些考虑为针对 UPR ^ER经常上调的癌细胞的溶瘤病毒疗法开辟了新的选择。我们最后讨论了病毒（特别是逆转录病毒）和抗病毒防御对 UPR ^{ER 的}进化影响。