Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China.
Cell Death Dis. 2023 Jul 4;14(7):396. doi: 10.1038/s41419-023-05923-9.
Uncontrolled viral replication and excessive inflammation are the main causes of death in the host infected with virus. Hence inhibition of intracellular viral replication and production of innate cytokines, which are the key strategies of hosts to fight virus infections, need to be finely tuned to eliminate viruses while avoid harmful inflammation. The E3 ligases in regulating virus replication and subsequent innate cytokines production remain to be fully characterized. Here we report that the deficiency of the E3 ubiquitin-protein ligase HECTD3 results in accelerated RNA virus clearance and reduced inflammatory response both in vitro and in vivo. Mechanistically, HECTD3 interacts with dsRNA-dependent protein kinase R (PKR) and mediates Lys33-linkage of PKR, which is the first non-proteolytic ubiquitin modification for PKR. This process disrupts the dimerization and phosphorylation of PKR and subsequent EIF2α activation, which results in the acceleration of virus replication, but promotes the formation of PKR-IKK complex and subsequent inflammatory response. The finding suggests HECTD3 is the potential therapeutic target for simultaneously restraining RNA virus replication and virus-induced inflammation once pharmacologically inhibited.
病毒的失控复制和过度炎症是宿主感染病毒后死亡的主要原因。因此，抑制细胞内病毒复制和先天细胞因子的产生，是宿主对抗病毒感染的关键策略，需要精细调节，以在消除病毒的同时避免有害炎症。调节病毒复制和随后的先天细胞因子产生的 E3 连接酶仍有待充分表征。在这里，我们报告 E3 泛素蛋白连接酶 HECTD3 的缺乏会导致体外和体内 RNA 病毒清除加速和炎症反应减少。在机制上，HECTD3 与双链 RNA 依赖性蛋白激酶 R（PKR）相互作用，并介导 PKR 的 Lys33 连接，这是 PKR 的第一个非蛋白水解泛素修饰。这一过程破坏了 PKR 的二聚化和磷酸化以及随后的 EIF2α 激活，导致病毒复制加速，但促进了 PKR-IKK 复合物的形成和随后的炎症反应。这一发现表明，一旦药理学抑制，HECTD3 是同时抑制 RNA 病毒复制和病毒诱导的炎症的潜在治疗靶点。
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