Interaction with TopBP1 Is Required for Human Papillomavirus 16 E2 Plasmid Segregation/Retention Function during Mitosis

Prabhakar, Apurva T.; James, Claire D.; Das, Diptikanta; Fontan, Christian T.; Otoa, Raymonde; Wang, Xu; Bristol, Molly L.; Morgan, Iain M.

doi:10.1128/jvi.00830-22

Cited by 15 publications

(67 citation statements)

References 56 publications

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“…We have generated N/Tert-1 cells stably expressing E2-S23A (N/Tert-1+E2-S23A) (34, 35). Figure 2A demonstrates that, when J2 cells are added to N/Tert-1+E2-S23A, the E2 protein becomes undetectable by western blotting.…”

Section: Resultsmentioning

confidence: 99%

“…Overexpression of the BRD4 carboxylterminal domain (CTD) results in E2 protein stabilization and disruption of HPV16 E2 interaction with the cullin-3 complex (54). Recently, we demonstrated E2 stabilization during mitosis (irrespective of J2 fibroblasts), and that this stabilization is required for the plasmid segregation function of E2 (34,35).…”

Section: Discussionmentioning

confidence: 99%

“…Not only does E2 regulate transcription from and replication of the viral genome, it is also required for viral genome segregation during mitosis (11). Recently we demonstrated that an interaction between E2 and the cellular protein TopBP1 is critical for the viral genome segregation function of E2 (34, 35). In this model, CK2 phosphorylation of E2 at serine 23 is required for the interaction between E2 and TopBP1.…”

Section: Discussionmentioning

confidence: 99%

“…Stably expressing HPV16 wild type E2 (E2-WT), E2-S23A (E2 with serine 23 mutated to alanine, abrogating interaction with TopBP1) and pcDNA empty vector plasmid control were generated in N/Tert-1 cells as described previously (34, 35). Stable HPV11 E2 cell lines was also generated in N/Tert-1 cells using the HPV11 E2 expression vector, which was a kind gift from Dr. Reet Kurg (58).…”

Section: Methodsmentioning

confidence: 99%

“…Several cellular factors have been implicated in mediating E2 association with mitotic chromatin to facilitate viral genome segregation, including BRD4 and ChlR1 (25–33). Recently we demonstrated that, for HPV16 E2, interaction with the cellular protein TopBP1 is required for E2 plasmid segregation function (34, 35). CK2 phosphorylation of E2 on serine 23 is required for HPV16 E2 interaction with TopBP1 (35).…”

Section: Introductionmentioning

confidence: 99%

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Human papillomavirus 16 E2 interaction with TopBP1 is required for E2 and viral genome stability during the viral life cycle

Prabhakar

James

Fontan

et al. 2023

Preprint

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CK2 phosphorylation of HPV16 E2 at serine 23 promotes interaction with TopBP1, and this interaction is important for E2 plasmid segregation function. Here we demonstrate that the E2-TopBP1 interaction is critical for E2 and viral genome stability during the viral life cycle. Introduction of the S23A mutation into the HPV16 genome results in a loss of E2 expression and viral genome integration during organotypic rafting. Co-culture of N/Tert-1+E2-S23A cells with J2 fibroblasts results in E2-S23A degradation via the proteasome, wild-type E2 is not degraded. TopBP1 siRNA treatment of N/Tert-1+E2-WT cells results in E2 degradation only in the presence of J2 cells demonstrating the critical role for TopBP1 in maintaining E2 stability. The CK2 inhibitor CX4945 promotes E2-WT degradation in the presence of fibroblasts as it disrupts E2-TopBP1 interaction. siRNA targeting SIRT1 rescues E2-S23A stability in N/Tert-1 cells treated with J2 fibroblasts, with an increased E2-S23A acetylation. The results demonstrate that the E2-TopBP1 interaction is critical during the viral life cycle as it prevents fibroblast stimulated SIRT1 mediated deacetylation of E2 that promotes protein degradation. This means that the E2-TopBP1 complex maintains E2 and viral genome stability and that disruption of this complex can promote viral genome integration. Finally, we demonstrate that HPV11 E2 also interacts with TopBP1 and that this interaction is critical for HPV11 E2 stability in the presence of J2 cells. Treatment of N/Tert-1+11E2-WT cells with CX4945 results in 11E2 degradation. Therefore, CK2 inhibition is a therapeutic strategy for alleviating HPV11 diseases, including juvenile respiratory papillomatosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human papillomavirus 16 E2 interaction with TopBP1 is required for E2 and viral genome stability during the viral life cycle

Prabhakar

James

Fontan

et al. 2023

Preprint

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Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

Ye,

Zheng,

et al. 2023

MedComm

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Human papillomavirus (HPV) is the most prevalent sexually transmitted virus globally. Persistent high‐risk HPV infection can result in cervical precancerous lesions and cervical cancer, with 70% of cervical cancer cases associated with high‐risk types HPV16 and 18. HPV infection imposes a significant financial and psychological burden. Therefore, studying methods to eradicate HPV infection and halt the progression of precancerous lesions remains crucial. This review comprehensively explores the mechanisms underlying HPV‐related cervical lesions, including the viral life cycle, immune factors, epithelial cell malignant transformation, and host and environmental contributing factors. Additionally, we provide a comprehensive overview of treatment methods for HPV‐related cervical precancerous lesions and cervical cancer. Our focus is on immunotherapy, encompassing HPV therapeutic vaccines, immune checkpoint inhibitors, and advanced adoptive T cell therapy. Furthermore, we summarize the commonly employed drugs and other nonsurgical treatments currently utilized in clinical practice for managing HPV infection and associated cervical lesions. Gene editing technology is currently undergoing clinical research and, although not yet employed officially in clinical treatment of cervical lesions, numerous preclinical studies have substantiated its efficacy. Therefore, it holds promise as a precise treatment strategy for HPV‐related cervical lesions.

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Inhibition of human cytomegalovirus entry into mucosal epithelial cells

He,

Hertel,

James

et al. 2024

Antiviral Research

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Interaction with TopBP1 Is Required for Human Papillomavirus 16 E2 Plasmid Segregation/Retention Function during Mitosis

Abstract: HPV16 causes 3% to 4% of all human cancers. It is proposed that during the viral life cycle, the viral genome is actively segregated into daughter nuclei, ensuring viral replication in the subsequent S phase.

Cited by 15 publications

References 56 publications

Human papillomavirus 16 E2 interaction with TopBP1 is required for E2 and viral genome stability during the viral life cycle

Human papillomavirus 16 E2 interaction with TopBP1 is required for E2 and viral genome stability during the viral life cycle

Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

Inhibition of human cytomegalovirus entry into mucosal epithelial cells

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