Pleiotropic roles of the ubiquitin-proteasome system during viral propagation

Abstract

Protein ubiquitination is a highly conserved post-translational modification affecting various biological processes including viral propagation. Ubiquitination has multiple effects on viral propagation, including viral genome uncoating, viral replication, and immune evasion. Ubiquitination of viral proteins is triggered by the ubiquitin-proteasome system (UPS). This involves the covalent attachment of the highly conserved 76 amino acid residue ubiquitin protein to target proteins by the consecutive actions of E1, E2 and E3 enzymes, and the 26S proteasome that together form a multiprotein complex that degrades target proteins. The UPS is the primary cytosolic proteolytic machinery for the selective degradation of various forms of proteins including viral proteins, thereby limiting viral growth in host cells. To combat this host anti-viral machinery, viruses have evolved the ability to employ or subvert the UPS to inactivate or degrade cellular proteins to favour viral propagation. This review highlights our current knowledge on the different roles of the UPS during viral propagation.

Integrative Network Biology Framework Elucidates Molecular Mechanisms of SARS-CoV-2 Pathogenesis

“…The ubiquitin proteasome system (UPS) constitutes the major protein degradation system of eukaryotic cells that participate in a wide range of cellular processes, and another critical target of diverse viruses 41 . UPS plays an indispensable role in finetuning the regulation of inflammatory responses.…”

“…For instance, proteasome-mediated activation of NF-κB regulates the expression of proinflammatory cytokines including TNF-α, IL-1β, IL-8. Similarly, UPS is indispensable in the regulation of leukocyte proliferation 41 . The UPS is generally considered a double-edged sword in viral pathogenesis.…”

“…The UPS is generally considered a double-edged sword in viral pathogenesis. For example, UPS is a powerhouse that eliminates viral proteins to control viral infection, but at the same time viruses hijack UPS machinery for their propagation 41 . In case of herpes simplex virus type 1, Varicella-zoster virus and Simian varicella virus, induction of NF-κB – mediated host innate immunity is suppressed by the manipulation of UPS components 42 .…”

Human cytomegalovirus protein pUL36: A dual cell death pathway inhibitor

“…Hijacking of the ubiquitin-proteasome system (UPS) to degrade host proteins is ubiquitous across many viral families (12). The proteins degraded by viruses are typically detrimental to viral replication, and can include antiviral restriction factors or components of viral sensing pathways, activating immune cell ligands, and elements of cell death pathways (13,14). We have shown previously that >900 host proteins are down-regulated more than threefold over the course of HCMV infection, with 133 proteins degraded during the early phase, of which 89% are targeted to the proteasome.…”

Human cytomegalovirus protein pUL36: a dual cell death pathway inhibitor

“…Hijacking of the ubiquitin-proteasome system (UPS) to degrade host proteins is ubiquitous across many viral families (12). The proteins degraded by viruses are typically detrimental to viral replication, and can include antiviral restriction factors or components of viral sensing pathways, activating immune cell ligands, and elements of cell death pathways (13,14). We have shown previously that >900 host proteins are downregulated >3-fold over the course of HCMV infection, with 133 proteins degraded during the early phase, of which 89% are targeted to the proteasome.…”