Departement of Infectious Diseases, Infectious Diseases and Pathogen Biology Center, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University, Changchun, China.
Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130000, Jilin, China.
Signal Transduct Target Ther. 2023 Feb 3;8(1):53. doi: 10.1038/s41392-023-01335-5.
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a severe global health crisis; its structural protein envelope (E) is critical for viral entry, budding, production, and induction of pathology which makes it a potential target for therapeutics against COVID-19. Here, we find that the E3 ligase RNF5 interacts with and catalyzes ubiquitination of E on the 63rd lysine, leading to its degradation by the ubiquitin-proteasome system (UPS). Importantly, RNF5-induced degradation of E inhibits SARS-CoV-2 replication and the RNF5 pharmacological activator Analog-1 alleviates disease development in a mouse infection model. We also found that RNF5 is distinctively expressed in different age groups and in patients displaying different disease severity, which may be exploited as a prognostic marker for COVID-19. Furthermore, RNF5 recognized the E protein from various SARS-CoV-2 strains and SARS-CoV, suggesting that targeting RNF5 is a broad-spectrum antiviral strategy. Our findings provide novel insights into the role of UPS in antagonizing SARS-CoV-2 replication, which opens new avenues for therapeutic intervention to combat the COVID-19 pandemic.
新型冠状病毒病 2019（COVID-19）大流行是由严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起的，它造成了严重的全球卫生危机；其结构蛋白包膜（E）对于病毒进入、出芽、产生和诱导病理学至关重要，这使其成为治疗 COVID-19 的潜在靶点。在这里，我们发现 E3 连接酶 RNF5 与 E 相互作用，并催化 E 在第 63 位赖氨酸上的泛素化，导致其被泛素-蛋白酶体系统（UPS）降解。重要的是，RNF5 诱导的 E 降解抑制了 SARS-CoV-2 的复制，并且 RNF5 药理学激活剂 Analog-1 缓解了小鼠感染模型中的疾病发展。我们还发现 RNF5 在不同年龄组和不同疾病严重程度的患者中表现出明显的表达，这可能被用作 COVID-19 的预后标志物。此外，RNF5 识别来自各种 SARS-CoV-2 株和 SARS-CoV 的 E 蛋白，表明靶向 RNF5 是一种广谱抗病毒策略。我们的研究结果提供了 UPS 在拮抗 SARS-CoV-2 复制中的作用的新见解，为治疗干预以对抗 COVID-19 大流行开辟了新途径。
