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Activation and inhibition of the IRE1-mediated unfolded protein response by cytomegalovirus

巨细胞病毒对 IRE1 介导的未折叠蛋白反应的激活和抑制

基本信息

批准号：
327299022
负责人：
Professor Dr. Wolfram Brune
金额：
--
依托单位：
Leibniz-Institut für Virologie (LIV)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/327299022?language=en
关键词：
Activation inhibition IRE1 mediated unfolded

项目摘要

During viral infection, a massive demand for viral glycoproteins can overwhelm the capacity of the protein folding and quality control machinery, leading to an accumulation of unfolded proteins in the endoplasmic reticulum (ER). To restore ER homeostasis, cells initiate the unfolded protein response (UPR) by activating three ER-to-nucleus signaling pathways, of which the inositol-requiring enzyme 1 (IRE1)-dependent pathway is the evolutionary most conserved. To reduce ER stress, the UPR decreases protein synthesis, increases degradation of unfolded proteins, and upregulates chaperone expression to enhance protein folding. Cytomegaloviruses, as other viral pathogens, modulate the UPR to their own advantage. However, the molecular mechanisms and the viral proteins responsible for UPR modulation remain poorly defined. In previous work we demonstrated that murine and human cytomegalovirus (MCMV and HCMV) repress IRE1-mediated mRNA splicing and expression of the X-box binding protein 1s (XBP1s) at late times post infection. We identified the MCMV M50 protein as an IRE1-interacting protein that induces proteasomal degradation of IRE1. We further showed that viral infection briefly activates the IRE1-XBP1 signaling pathway. This activation appears to be important as genetic inactivation of IRE1 resulted in a massive reduction of viral replication. Surprisingly, however, XBP1 inactivation caused only a minor decrease in viral productivity. Based on our preliminary data we propose that cytomegaloviruses first activate an IRE-dependent pathway and later block IRE1 signaling by targeting it for degradation. Therefore, the aims of this project is to identify the IRE1-dependent signaling pathway required for efficient viral replication, to determine the mechanism and biological impact of viral induced IRE1 degradation, and to investigate whether the activation and inhibition of IRE1 signaling is conserved among beta- and gamma-herpesviruses. The results will provide a better understanding how viruses manipulate the UPR to their own advantage and might reveal new targets for therapeutic intervention.

在病毒感染期间，对病毒糖蛋白的大量需求可能压倒蛋白质折叠和质量控制机制的能力，导致未折叠蛋白质在内质网（ER）中积累。为了恢复ER稳态，细胞通过激活三条ER至核信号通路来启动未折叠蛋白反应（UPR），其中肌醇需要酶1（IRE 1）依赖性通路是进化上最保守的。为了减少ER应激，UPR减少蛋白质合成，增加未折叠蛋白质的降解，并上调伴侣蛋白表达以增强蛋白质折叠。巨细胞病毒，作为其他病毒病原体，调节UPR，以自己的优势。然而，分子机制和负责UPR调制的病毒蛋白仍然不清楚。在以前的工作中，我们证明了小鼠和人巨细胞病毒（MCMV和HCMV）抑制IRE 1介导的mRNA剪接和表达的X-box结合蛋白1 s（XBP 1 s）在感染后的后期。我们确定MCMV M50蛋白作为IRE 1相互作用蛋白，诱导IRE 1的蛋白酶体降解。我们进一步表明，病毒感染短暂激活IRE 1-XBP 1信号通路。这种激活似乎很重要，因为IRE 1的基因失活导致病毒复制的大量减少。然而，令人惊讶的是，XBP 1失活仅引起病毒生产率的轻微降低。基于我们的初步数据，我们提出巨细胞病毒首先激活IRE依赖性通路，然后通过靶向降解来阻断IRE 1信号传导。因此，本项目的目的是确定有效的病毒复制所需的IRE 1依赖的信号通路，以确定病毒诱导的IRE 1降解的机制和生物学影响，并研究IRE 1信号的激活和抑制是否在β-和γ-疱疹病毒中是保守的。这些结果将使我们更好地了解病毒如何操纵UPR以使其发挥自身优势，并可能揭示治疗干预的新靶点。