Commandeering the controller: The ubiquitin-proteasome tug-of-war between coronavirus and host

The ubiquitin-proteasome system (UPS) plays a pivotal role in the precise regulation of innate immunity. Within the spatiotemporal framework of coronavirus (CoV) infection, the UPS emerges as a critical arena and a molecular switch, dynamically mediating the balance between host antiviral defense and viral replication alongside immune evasion. The host leverages the UPS to activate interferon (IFN) signaling pathways and to directly target viral proteins for degradation. Conversely, CoVs have developed sophisticated mechanisms to exploit this system, either by degrading antiviral proteins or by encoding viral deubiquitinases (DUBs) to counteract host ubiquitination signals. Notably, CoV proteins themselves undergo ubiquitination, which can lead to either their functional activation or proteasomal degradation, underscoring the dual-edged nature of the UPS. In this review, we initially examined the mechanisms by which the UPS regulates the IFN system. Subsequently, we highlighted the strategies employed by CoVs to inhibit the IFN system through the manipulation of the UPS. Thirdly, we synthesized findings regarding how the UPS specifically targets and degrades the principal virulence proteins of CoVs. Finally, we investigated the potential of the UPS as a therapeutic target for developing resistance against CoV infections.