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Papillomavirus E6 cellular targets

乳头瘤病毒 E6 细胞靶标

基本信息

批准号：
10686180
负责人：
Scott Brian Vande Pol
金额：
$ 51.79万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686180
关键词：
Adaptor Signaling Protein Adrenergic Agents Animals Benign Binding Biological Assay Biology Cell Proliferation Cells Cervical Complex Cutaneous Data Disease Dissection Distant Epithelial Cells Epithelioma Eye G-Protein-Coupled Receptors Genetic Genital Genitalia Goals Human Papillomavirus Life Life Cycle Stages Location Low risk HPV Malignant - descriptor Malignant Neoplasms Measures Medical Modality Mutate Normal Cell Nose Oncogenic Oncoproteins PDZ protein Papilloma Papillomavirus Pathway interactions Peptides Pharyngeal structure Process Production Proteins Recurrent respiratory papillomatosis Risk Role Signal Pathway Signal Transduction Site Squamous Cell Papillomas Structure Surface TP53 gene Testing Time Tissues UBE3A gene Viral Virus WNT Signaling Pathway cellular targeting comparative derepression high risk insight keratinocyte knock-down medical complication model organism mutant novel penis foreskin protein expression recruit sodium-hydrogen exchanger regulatory factor trait transcription factor tumor tumorigenesis ubiquitin ligase

项目摘要

Alpha genus human papillomaviruses (HPV’s) cause benign squamous papillomas in which the virus persists and replicates. “Low risk” HPV types cause papillomas that while persisting, very rarely progress to malignancy, but can cause serious, even life-threatening medical complications due to the size and location of the papilloma. In both high-risk and low-risk HPV types, papilloma formation is driven by the expression of viral oncoproteins termed E6 and E7. Both high risk and low risk HPV E6 proteins associate with a cellular ubiquitin ligase termed E6AP. When high-risk E6 binds E6AP, E6 then recruits the cellular tumor suppressor p53 which is then ubiquitinated and degraded. Low-risk E6 proteins, while also binding E6AP, do not interact with p53, and the cellular targets it binds and degrades have until recently remained undescribed. Since low- risk and high-risk HPV both co-evolved on the same host, it is reasonable to speculate that there might be common cellular targets for both high and low risk E6 oncoproteins. Identifying cellular proteins that are broadly E6-targeted is a long-sought goal of the viral oncogenesis field. This application describes the first cellular target of the E6 + E6AP complex that is targeted for degradation by both high risk and low risk E6 proteins, NHERF1. Importantly, E6 proteins from cutaneous HPV’s as well as evolutionarily distant animal papillomaviruses also target the degradation of NHERF1. The broad tissue-type and broad species targeting of NHERF1 by their cognate E6 proteins argues for its importance in the papillomavirus life-cycle. We will present data showing how the targeting of NHERF1 by both high and low risk E6 augments cellular WNT signaling, and augments cell-cell competition in cells that express E6. We propose additional studies on both the mechanism of E6 interaction with NHERF1 and the consequences of NHERF1 degradation by E6.

α属人乳头瘤病毒（HPV）引起良性鳞状乳头瘤，病毒持续存在并复制。“低风险”型HPV引起的乳头状瘤虽然持续存在，但很少进展为恶性肿瘤，但由于乳头状瘤的大小和位置，可能导致严重的，甚至危及生命的医学并发症。在高风险和低风险HPV类型中，乳头状瘤的形成是由称为E6和E7的病毒癌蛋白的表达驱动的。高风险和低风险的HPV E6蛋白都与称为E6AP的细胞泛素连接酶相关。当高风险的E6结合E6AP时，E6招募细胞肿瘤抑制因子p53，然后泛素化和降解。低风险的E6蛋白，虽然也结合E6AP，但不与p53相互作用，并且它结合和降解的细胞靶标直到最近仍未被描述。由于低风险和高风险的HPV都在同一宿主上共同进化，我们有理由推测高风险和低风险的E6癌蛋白可能有共同的细胞靶点。识别广泛靶向e6的细胞蛋白是病毒肿瘤发生领域长期寻求的目标。该应用程序描述了E6 + E6AP复合物的第一个细胞靶标，该靶标可被高风险和低风险E6蛋白NHERF1降解。重要的是，来自皮肤HPV以及进化上遥远的动物乳头瘤病毒的E6蛋白也靶向NHERF1的降解。NHERF1的同源E6蛋白具有广泛的组织类型和广泛的物种靶向性，这证明了它在乳头瘤病毒生命周期中的重要性。我们将提供数据，显示高风险和低风险E6如何靶向NHERF1增强细胞WNT信号，并增强表达E6的细胞中的细胞间竞争。我们建议进一步研究E6与NHERF1相互作用的机制以及E6降解NHERF1的后果。