Viral-Mediated Tethering to SEL1L Facilitates Endoplasmic Reticulum-Associated Degradation of IRE1
Viral-Mediated Tethering to SEL1L Facilitates Endoplasmic Reticulum-Associated Degradation of IRE1
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DOI：
10.1128/jvi.01990-20
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发表时间：
2021-04-01
影响因子：
5.4
通讯作者：
Brune, Wolfram
中科院分区：
文献类型：
--
作者：
Hinte, Florian;Mueller, Jendrik;Brune, Wolfram
未折叠蛋白反应（UPR）和内质网（ER）相关降解（ERAD）是分泌途径中蛋白质质量控制系统的两个重要组成部分。当未折叠的蛋白质在ER中积累时，UPR传感器如肌醇需要酶1（IRE 1）诱导ERAD基因的表达，从而增加从ER到细胞质溶胶的蛋白质输出和随后的蛋白酶体降解。相反，IRE 1本身是ERAD底物，表明UPR和ERAD相互调节。病毒是细胞内的寄生虫，它们利用宿主细胞为自己谋利。巨细胞病毒选择性地调节UPR以利用对病毒复制的有益作用并抑制对病毒复制的有害作用。我们以前已经表明，鼠和人巨细胞病毒表达同源蛋白（M50和UL 50，分别），抑制UPR在感染后的后期时间诱导IRE 1降解。然而，降解机制仍不确定。在这里，我们表明，巨细胞病毒M50蛋白介导的IRE 1降解的蛋白酶体。M50依赖性IRE 1降解可通过药理学抑制p97/VCP（含缬沙汀蛋白）或通过基因消融SEL 1 L（两者均为ERAD机制的组成部分）来阻断。SEL 1 L作为E3泛素连接酶HRD 1的辅因子，而p97/VCP负责将泛素化蛋白从ER提取到胞质溶胶。我们进一步表明，M50通过结合IRE 1和SEL 1 L促进IRE 1-SEL 1 L相互作用。这些结果表明，病毒M50蛋白通过将IRE 1与SEL 1 L连接而抑制UPR，从而促进其被ERAD机制降解。重要信息病毒感染宿主细胞并迫使它们产生病毒后代。这可以对宿主细胞施加压力并激活反调节机制。内质网（ER）中的蛋白质过载导致ER应激并触发未折叠的蛋白质反应，这反过来上调蛋白质折叠并增加ER中蛋白质的降解。先前的工作表明，巨细胞病毒通过降解传感器分子IRE 1来干扰未折叠的蛋白质反应。在这里，我们展示了巨细胞病毒M50蛋白如何利用ER相关的降解机制来处理IRE 1。IRE 1的降解抑制了未折叠的蛋白质反应，并有助于病毒增加其自身蛋白质的合成和病毒后代的产生。
The unfolded protein response (UPR) and endoplasmic reticulum (ER)associated degradation (ERAD) are two essential components of the quality control system for proteins in the secretory pathway. When unfolded proteins accumulate in the ER, UPR sensors such as inositol-requiring enzyme 1 (IRE1) induce the expression of ERAD genes, thereby increasing protein export from the ER to the cytosol and subsequent degradation by the proteasome. Conversely, IRE1 itself is an ERAD substrate, indicating that the UPR and ERAD regulate each other. Viruses are intracellular parasites that exploit the host cell for their own benefit. Cytomegaloviruses selectively modulate the UPR to take advantage of beneficial and inhibit detrimental effects on viral replication. We have previously shown that murine and human cytomegaloviruses express homologous proteins (M50 and UL50, respectively) that dampen the UPR at late times postinfection by inducing IRE1 degradation. However, the degradation mechanism has remained uncertain. Here, we show that the cytomegalovirus M50 protein mediates IRE1 degradation by the proteasome. M50-dependent IRE1 degradation can be blocked by pharmacological inhibition of p97/VCP (valosin-containing protein) or by genetic ablation of SEL1L, both of which are components of the ERAD machinery. SEL1L acts as a cofactor of the E3 ubiquitin ligase HRD1, while p97/VCP is responsible for the extraction of ubiquitylated proteins from the ER to the cytosol. We further show that M50 facilitates the IRE1-SEL1L interaction by binding to both IRE1 and SEL1L. These results indicate that the viral M50 protein dampens the UPR by tethering IRE1 to SEL1L, thereby promoting its degradation by the ERAD machinery.IMPORTANCE Viruses infect cells of their host and force them to produce virus progeny. This can impose stress on the host cell and activate counterregulatory mechanisms. Protein overload in the endoplasmic reticulum (ER) leads to ER stress and triggers the unfolded protein response, which in turn upregulates protein folding and increases the degradation of proteins in the ER. Previous work has shown that cytomegaloviruses interfere with the unfolded protein response by degrading the sensor molecule IRE1. Here, we demonstrate how the cytomegalovirus M50 protein exploits the ER-associated degradation machinery to dispose of IRE1. The degradation of IRE1 curbs the unfolded protein response and helps the virus to increase the synthesis of its own proteins and the production of virus progeny.