Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
Elife. 2020 Feb 17;9:e51804. doi: 10.7554/eLife.51804.
The unfolded protein response (UPR) is a cellular homeostatic circuit regulating protein synthesis and processing in the ER by three ER-to-nucleus signaling pathways. One pathway is triggered by the inositol-requiring enzyme 1 (IRE1), which splices the X-box binding protein 1 () mRNA, thereby enabling expression of XBP1s. Another UPR pathway activates the activating transcription factor 6 (ATF6). Here we show that murine cytomegalovirus (MCMV), a prototypic β-herpesvirus, harnesses the UPR to regulate its own life cycle. MCMV activates the IRE1-XBP1 pathway early post infection to relieve repression by XBP1u, the product of the unspliced mRNA. XBP1u inhibits viral gene expression and replication by blocking the activation of the viral major immediate-early promoter by XBP1s and ATF6. These findings reveal a redundant function of XBP1s and ATF6 as activators of the viral life cycle, and an unexpected role of XBP1u as a potent repressor of both XBP1s and ATF6-mediated activation.
未折叠蛋白反应（UPR）是一种细胞内稳态回路，通过三条 ER 到核信号通路调节 ER 中的蛋白质合成和加工。其中一条途径是由肌醇需求酶 1（IRE1）触发的，它拼接 X 盒结合蛋白 1（XBP1）mRNA，从而使 XBP1s 的表达得以激活。另一条 UPR 途径则激活激活转录因子 6（ATF6）。在这里，我们发现鼠巨细胞病毒（MCMV），一种典型的β疱疹病毒，利用 UPR 来调节自身的生命周期。MCMV 在感染后早期激活 IRE1-XBP1 途径，以解除 XBP1u 的抑制，XBP1u 是未剪接 mRNA 的产物。XBP1u 通过阻止 XBP1s 和 ATF6 激活病毒主要即刻早期启动子，从而抑制病毒基因的表达和复制。这些发现揭示了 XBP1s 和 ATF6 作为病毒生命周期激活剂的冗余功能，以及 XBP1u 作为 XBP1s 和 ATF6 介导的激活的有效抑制剂的意外作用。
