Dataset Information

E2 ubiquitin-conjugating enzyme UBE2L6 promotes Senecavirus A proliferation by stabilizing the viral RNA polymerase.

ABSTRACT: Senecavirus A (SVA), discovered in 2002, is an emerging pathogen of swine that has since been reported in numerous pork producing countries. To date, the mechanism of SVA replication remains poorly understood. In this study, utilizing iTRAQ analysis we found that UBE2L6, an E2 ubiquitin-conjugating enzyme, is up-regulated in SVA-infected BHK-21 cells, and that its overexpression promotes SVA replication. We determined that UBE2L6 interacts with, and ubiquitinates the RNA-dependent RNA polymerase of SVA, (the 3D protein) and this ubiquitination serves to inhibit the degradation of 3D. UBE2L6-mediated ubiquitination of 3D requires a cystine at residue 86 in UBE2L6, and lysines at residues 169 and 321 in 3D. Virus with mutations in 3D (rK169R and rK321R) exhibited significantly decreased replication compared to wild type SVA and the repaired viruses, rK169R(R) and rK321R(R). These data indicate that UBE2L6, the enzyme, targets the 3D polymerase, the substrate, during SVA infection to facilitate replication.

SUBMITTER: Li L

PROVIDER: S-EPMC7588118 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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E2 ubiquitin-conjugating enzyme UBE2L6 promotes Senecavirus A proliferation by stabilizing the viral RNA polymerase.

Li Liang L Bai Juan J Fan Hui H Yan Junfang J Li Shihai S Jiang Ping P

PLoS pathogens 20201026 10

Senecavirus A (SVA), discovered in 2002, is an emerging pathogen of swine that has since been reported in numerous pork producing countries. To date, the mechanism of SVA replication remains poorly understood. In this study, utilizing iTRAQ analysis we found that UBE2L6, an E2 ubiquitin-conjugating enzyme, is up-regulated in SVA-infected BHK-21 cells, and that its overexpression promotes SVA replication. We determined that UBE2L6 interacts with, and ubiquitinates the RNA-dependent RNA polymerase ...[more]

PMID: 33104725

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Project description:The Androgen Receptor (AR) is a pivotal protein in human physiology, exerting significant influence on both male and female physiology (PMID: 18434134, 25905231). Functioning as a nuclear transcription factor, AR binds to testosterone, translocates to the nucleus, and subsequently regulates the expression of numerous genes, impacting vital cellular processes such as cell proliferation, differentiation, and apoptosis (PMID: 4810760, 25237629). The prominent role of AR in human physiology is particularly notable in the context of prostate cancer initiation, where aberrant AR signaling has been identified as a key driver in tumorigenesis (PMID: 4810760, 27057074, 37429011). However, despite the considerable success of the current anti-androgen therapeutic approach, it faces the formidable challenge of drug resistance, significantly limiting the clinical outcome for patients and necessitating the urgent development of new therapeutic approaches to overcome resistance (PMID: 26563462, 24881730, 31363002, 35582713). Notably, one key feature of antiandrogen resistance is the sustained or enhanced AR signaling observed in many resistant tumors (PMID: 26563462, 34449248, 23580326), although the underlying molecular mechanisms remain largely unclear. Protein degradation, with ubiquitination at its core, plays a critical role in cell functionality, ensuring the elimination of redundant and harmful proteins (PMID: 16738015, 33634825). This intricate process involves the attachment of small proteins called ubiquitin to target proteins, marking them for degradation. Dysregulation of ubiquitination can lead to the accumulation of oncogenic proteins, contributing to tumorigenesis and therapy resistance in various cancers (PMID: 32296023, 33004065). The degradation of proteins is a complex process that involves the coordination of E1, E2 and E3 enzymes, with E3 enzymes binding to the target protein (PMID: 21111229, 20930542). Logically, research has focused on finding E3s targeting AR for degradation but has overlooked the role that E2s play in the ubiquitination process. In recent years, E2s have been shown to dictate the how and where ubiquitin gets attached in the target protein, dictating the fate of the protein (PMID: 27002219, 19851334). Therefore, finding the E2 involved in the degradation of AR can prove to be essential. In this study, we conducted an in vivo library screening approach and identified UBE2J1 as the bona fide E2 ubiquitin conjugating enzyme for AR ubiquitination. Our results demonstrated that the frequent loss of UBE2J1 in prostate cancer leads to dysregulated and impaired AR ubiquitination and degradation. Consequently, this promotes the accumulation of AR proteins and confers resistance to antiandrogen treatment in UBE2J1-deficient prostate cancer cells. To address this, we developed an innovative ubiquitination-based AR degrader that effectively restores AR ubiquitination, thereby resensitizing prostate cancer cells to antiandrogen therapy. These findings not only unveil the pivotal role of UBE2J1 as the crucial E2 ubiquitin conjugating enzyme for AR degradation but also shed light on a novel mechanism through which advanced prostate cancer cells upregulate AR protein levels, thereby acquiring resistance to existing antiandrogen therapy. These novel insights hold the potential to inform the development of more effective therapeutic strategies against advanced prostate cancers.

Dataset Information

E2 ubiquitin-conjugating enzyme UBE2L6 promotes Senecavirus A proliferation by stabilizing the viral RNA polymerase.

Publications

E2 ubiquitin-conjugating enzyme UBE2L6 promotes Senecavirus A proliferation by stabilizing the viral RNA polymerase.

Similar Datasets

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