The E3 ligase RNF5 restricts SARS-CoV-2 replication by targeting its envelope protein for degradation.
Zhaolong LiPengfei HaoZhilei ZhaoWenying GaoChen HuanLetian LiXiang ChenHong WangNingyi JinZhao-Qing LuoChang LiWenyan ZhangPublished in: Signal transduction and targeted therapy (2023)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- coronavirus disease
- dna damage response
- global health
- public health
- protein protein
- amino acid
- small molecule
- ejection fraction
- randomized controlled trial
- escherichia coli
- newly diagnosed
- immune response
- drug induced
- dna damage
- drug delivery
- dna repair
- high glucose
- patient reported outcomes