Abstract
Simple SummaryEpstein–Barr virus (EBV) is the first discovered human tumor virus, which contributes to the oncogenesis of many human cancers. The ubiquitin–proteasome system is a key player during EBV-mediated oncogenesis and has been developed as a crucial therapeutic target for treatment. In this review, we briefly describe how EBV antigens can modulate the ubiquitin–proteasome system for targeted protein degradation and how they are regulated in the EBV life cycle to mediate oncogenesis. Additionally, the developed proteasome inhibitors are discussed for the treatment of EBV-associated cancers.Deregulation of the ubiquitin–proteasome system (UPS) plays a critical role in the development of numerous human cancers. Epstein–Barr virus (EBV), the first known human tumor virus, has evolved distinct molecular mechanisms to manipulate the ubiquitin–proteasome system, facilitate its successful infection, and drive opportunistic cancers. The interactions of EBV antigens with the ubiquitin–proteasome system can lead to oncogenesis through the targeting of cellular factors involved in proliferation. Recent studies highlight the central role of the ubiquitin–proteasome system in EBV infection. This review will summarize the versatile strategies in EBV-mediated oncogenesis that contribute to the development of specific therapeutic approaches to treat EBV-associated malignancies.
Highlights
Ubiquitin is a 76-amino acids polypeptide that is highly conserved in eukaryotic cells.Ubiquitination is a type of post-translational modification that targets specific proteins by covalent ligation to ubiquitin
In the process of polyubiquitination, seven lysines located in the ubiquitin polypeptide can be utilized to form polyubiquitin chains that lead to various functions
Ubiquitination can be reversed by deubiquitinating enzymes (DUBs), and it is important to note that the dysregulation of DUBs is highly linked to many human diseases [1,4]
Summary
Ubiquitin is a 76-amino acids polypeptide that is highly conserved in eukaryotic cells. Previous studies showed that EBNA3C can induce the degradation of Bcl protein through the ubiquitin–proteasome-dependent signaling pathway, further promoting cell proliferation, and the cell cycle by targeting Bcl and cyclin D1 [21]. LMP1 activates NF-κB (p65) signaling pathway by inducing TRAF6 poly-ubiquitinated modification in EBV latency, while EBV-encoded BPLF1 interacts with, and deubiquitinates TRAF6 to inhibit the previous studies showed that EBNA3C can induce the degradation of BCcHl6IP protein through the ubiquitin–proteasome-dependent signaling pathway, further TpRrAo-FD1 moting cell proliferation, and the cell cycle by targeting Bcl and cyclin D1 [21]. LMP2A activates the extracellular signal regulated kinase (ERK) signaling pathway and downregulates levels of the pro-apoptotic protein Bim via proteasomal degradation in EBV-infected cells [68] Both LMP1 and LMP2A can interact with cellular ubiquitin ligases to modulate the ubiquitin–proteasome pathway. EBV-encoded lytic protein BBRF2 interacts with its partner BSRF1 to tether EBV nucleocapsids, and mechanistically, BBRF2 stabilizes BSRF1 by inhibiting the ubiquitin–proteasome pathway, contributing to augmented EBV infectivity [84,85]
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