SARS-CoV-2 and UPS with potentials for therapeutic interventions

• Published in: Gene 2024-06, Vol.912, p.148377-148377, Article 148377
• Main Authors: Ferdoush, Jannatul, Abdul Kadir, Rizwaan, Simay Kaplanoglu, Selin, Osborn, Morgan
• Format: Article
• Language: English
• Subjects: Nsp12; ORF3a; ORF7a; ORF8; ORF9b; PLpro; SARS-CoV-2; UPS
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2024.148377

•SARS-CoV-2 significantly impacts the UPS, a key cellular regulatory mechanism.•SARS-CoV-2 encoded proteinsinteract with host UPS, influencing immune signaling and apoptosis.•Stability of ORF3a and ORF8 may or may not be influenced by host proteasome.•Unlike previous studies, recent studies do not show ORF3a as an ion channel.•SARS-CoV-2 PLpro alters host immune responses via interfering withUPS.•Proteomic studies reveal changes in ubiquitination in SARS-CoV-2 infected cells.•Promising treatment include targeting PLpro with zinc-ejector drugs, targeting viral nsp12 via heat treatment. The Ubiquitin proteasome system (UPS), an essential eukaryotic/host/cellular post-translational modification (PTM), plays a critical role in the regulation of diverse cellular functions including regulation of protein stability, immune signaling, antiviral activity, as well as virus replication. Although UPS regulation of viral proteins may be utilized by the host as a defense mechanism to invade viruses, viruses may have adapted to take advantage of the host UPS. This system can be manipulated by viruses such as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) to stimulate various steps of the viral replication cycle and facilitate pathogenesis, thereby causing the respiratory disease COVID-19. Many SARS-CoV-2 encoded proteins including open reading frame 3a (ORF3a), ORF6, ORF7a, ORF9b, and ORF10 interact with the host's UPS machinery, influencing host immune signaling and apoptosis. Moreover, SARS-CoV-2 encoded papain-like protease (PLpro) interferes with the host UPS to facilitate viral replication and to evade the host’s immune system. These alterations in SARS-CoV-2 infected cells have been revealed by various proteomic studies, suggesting potential targets for clinical treatment. To provide insight into the underlying causes of COVID-19 and suggest possible directions for therapeutic interventions, this paper reviews the intricate relationship between SARS-CoV-2 and UPS. Promising treatment strategies are also investigated in this paper including targeting PLpro with zinc-ejector drugs, as well as targeting viral non-structural protein (nsp12) via heat treatment associated ubiquitin-mediated proteasomal degradation to reduce viral pathogenesis.