The Ubiquitin-Proteasome System Facilitates Membrane Fusion and Uncoating during Coronavirus Entry

by Selleckchem | Dec 19 2023

Although the involvement of the ubiquitin-proteasome system (UPS) in several coronavirus-productive infections has been reported, whether the UPS is required for infectious bronchitis virus (IBV) and porcine epidemic diarrhea virus (PEDV) infections is unclear. In this study, the role of UPS in the IBV and PEDV life cycles was investigated. When the UPS was suppressed by pharmacological inhibition at the early infection stage, IBV and PEDV infectivity were severely impaired. Further study showed that inhibition of UPS did not change the internalization of virus particles; however, by using R18 and DiOC-labeled virus particles, we found that inhibition of UPS prevented the IBV and PEDV membrane fusion with late endosomes or lysosomes. In addition, proteasome inhibitors blocked the degradation of the incoming viral protein N, suggesting the uncoating process and genomic RNA release were suppressed. Subsequently, the initial translation of genomic RNA was blocked. Thus, UPS may target the virus-cellular membrane fusion to facilitate the release of incoming viruses from late endosomes or lysosomes, subsequently blocking the following virus uncoating, initial translation, and replication events. Similar to the observation of proteasome inhibitors, ubiquitin-activating enzyme E1 inhibitor PYR-41 also impaired the entry of IBV, enhanced the accumulation of ubiquitinated proteins, and depleted mono-ubiquitin. In all, this study reveals an important role of UPS in coronavirus entry by preventing membrane fusion and identifies UPS as a potential target for developing antiviral therapies for coronavirus.

Comments:

The passage you provided describes a study investigating the role of the ubiquitin-proteasome system (UPS) in the life cycles of two coronaviruses, Infectious Bronchitis Virus (IBV) and Porcine Epidemic Diarrhea Virus (PEDV). The study found that when the UPS was pharmacologically inhibited at the early infection stage, the infectivity of both IBV and PEDV was severely impaired.

The researchers observed that inhibition of the UPS did not affect the internalization of virus particles but prevented the fusion of IBV and PEDV with late endosomes or lysosomes. This inhibition of membrane fusion led to the blockage of the uncoating process and genomic RNA release. Additionally, the initial translation of genomic RNA was hindered, suggesting a multi-step impact of UPS inhibition on the viral life cycle.

The study also found that proteasome inhibitors blocked the degradation of the incoming viral protein N, indicating a role of UPS in the uncoating process. Furthermore, the ubiquitin-activating enzyme E1 inhibitor PYR-41 impaired IBV entry, increased the accumulation of ubiquitinated proteins, and depleted mono-ubiquitin.

In summary, the findings suggest that the UPS plays a crucial role in coronavirus entry by preventing membrane fusion. The study identifies the UPS as a potential target for developing antiviral therapies for coronaviruses. This information could be valuable for future research and drug development efforts aimed at combating coronavirus infections.