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Papillomavirus E6 cellular targets

乳头瘤病毒 E6 细胞靶点

基本信息

批准号：
10364877
负责人：
Scott Brian Vande Pol
金额：
$ 56.8万
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/10364877
关键词：
Adaptor Signaling Protein Adrenergic Agents Animal Model 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 high risk insight keratinocyte knock-down medical complication mutant novel penis foreskin protein expression recruit 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.

甲型人乳头瘤病毒(HPV)引起良性鳞状乳头状瘤，病毒在其中持续和复制。“低风险”的HPV型会导致乳头状瘤，虽然这种情况持续存在，但很少会进展为恶性肿瘤，但由于乳头状瘤的大小和位置，可能会导致严重的、甚至危及生命的医疗并发症。在高危和低危HPV类型中，乳头状瘤的形成都是由称为E6和E7的病毒癌蛋白的表达驱动的。高危和低危HPVE6蛋白都与一种称为E6AP的细胞泛素连接酶有关。当高风险的E6与E6AP结合时，E6会招募细胞肿瘤抑制因子P53，然后P53被泛素化和降解。低风险的E6蛋白虽然也与E6AP结合，但不与P53相互作用，它结合和降解的细胞靶点直到最近才被描述。由于低风险和高风险HPV都是在同一宿主上共同进化的，因此可以合理地推测，高风险和低风险E6癌蛋白可能有共同的细胞靶点。识别广泛以E6为靶点的细胞蛋白是病毒致癌领域长期寻求的目标。本申请描述了E6+E6AP复合体的第一个细胞靶点，其目标是高风险和低风险E6蛋白NHERF1的降解。重要的是，来自皮肤HPV的E6蛋白以及进化上遥远的动物乳头瘤病毒也针对NHERF1的降解。NHERF1通过其同源E6蛋白广泛的组织类型和广泛的物种靶向证明了其在乳头瘤病毒生命周期中的重要性。我们将展示高风险和低风险E6靶向NHERF1如何增强细胞WNT信号，并增强表达E6的细胞之间的竞争。我们建议对E6与NHERF1相互作用的机制以及E6降解NHERF1的后果进行进一步的研究。