Mechanism of Brd4-mediated papillomavirus host interactions

描述（由申请人提供）：高危人乳头瘤病毒（HPV）感染是宫颈癌的主要风险因素，宫颈癌是全球女性第二大流行癌症，占女性癌症死亡率的15%。乳头瘤病毒通过将其基因组维持为感染细胞中的附加体来建立持续感染。在与宿主上皮分化程序紧密相关的HPV生命周期中，E2确保病毒基因组在早期感染的基底上皮细胞中建立、复制和维持。在上皮细胞分化过程中，E2还有助于严格调节病毒癌基因转录，为成功完成病毒生命周期创造有利环境。E2表达的缺失导致病毒癌基因表达失调，并与HPV阳性病变的恶性进展有机械联系。我们以前的工作确定了细胞蛋白Brd 4（含溴结构域蛋白4）作为一种新的E2受体。Brd 4-E2相互作用在病毒附加体维持、病毒转录激活和病毒癌基因抑制中起作用。我们的研究表明，Brd 4在基底上皮层中高度表达，支持其在病毒生命周期早期E2功能中的作用。然而，人们对Brd 4如何调节E2的多种功能知之甚少，也不清楚这种病毒与宿主的相互作用如何有助于分化依赖性HPV生命周期。该资助申请旨在鉴定和表征调节E2-Brd 4功能的其他细胞组分，以确定Brd 4如何有助于E2转录调节，并研究上皮分化期间HPV生命周期中E2-Brd 4相互作用的功能影响。HPV感染是最常见的性传播媒介，影响50-80%的人口。这项研究将提供更好的了解调节HPV生命周期和恶性进展的分子机制。本研究中确定的新机制将为开发新化合物以消除病毒-宿主相互作用和治愈HPV持续感染提供出发点。对E2-Brd 4相互作用如何抑制病毒致癌基因的机制的深入了解将为新的治疗策略提供有希望的线索，这些病毒致癌基因是HPV相关疾病的致瘤性的原因。这项研究将为其他附加型DNA肿瘤病毒提供范例，包括卡波西肉瘤相关疱疹病毒和EB病毒，这两种病毒也靶向Brd 4。 公共卫生相关性：高危人乳头瘤病毒（HPV）与宫颈癌密切相关，宫颈癌是全球女性第二大常见癌症，占女性癌症死亡率的15%。该提案将调查在HPV生命周期和恶性进展过程中调节乳头瘤病毒和宿主相互作用的分子机制。我们的研究将确定开发治疗方法的新靶点，以治愈HPV持续感染和相关的人类癌症。

DESCRIPTION (provided by applicant): High-risk human papillomavirus (HPV) infection is the primary risk factor for cervical cancer, which is the second most prevalent cancer in women worldwide causing 15% of female cancer mortality. Papillomaviruses establish persistent infection by maintaining their genomes as episomes in infected cells. In the HPV life cycle that is tightly linked to the differentiation program of host epithelium, E2 ensures that the viral genome is established, replicated and maintained in the early-infected basal epithelial cells. During epithelium differentiation, E2 also contributes to the tight regulation of the viral oncogene transcription to create a conducive environment for successful completion of the viral life cycle. Loss of E2 expression leads to dysregulated viral oncogene expression and has been mechanistically linked to malignant progression of HPV positive lesions. Our previous work identified the cellular protein Brd4 (bromodomain-containing protein 4) as a novel receptor for E2. Brd4-E2 interaction functions in viral episome maintenance, viral transcriptional activation and repression of the viral oncogenes. Our studies established that Brd4 is highly expressed in the basal epithelial layer, supporting its role in E2 functions during the early phase of the viral life cycle. However, little is known about how Brd4 regulates the multiple functions of E2, nor is it clear how this virus-host interaction contributes to the differentiation- dependent HPV life cycle. This grant application aims to identify and characterize additional cellular components that regulate the E2-Brd4 functions, to determine how Brd4 contributes to E2 transcriptional regulation, and to investigate the functional impact of E2-Brd4 interactions in the HPV life cycle during epithelium differentiation. Infection by the HPV is the most common sexually transmitted agent, afflicting 50-80% of the population. This research will provide greater understanding of the molecular mechanisms that regulate the HPV life cycle and malignant progression. The new mechanisms identified in this study will provide a point of departure for developing new compounds to abrogate the virus-host interaction and cure HPV persistent infections. Mechanistic insights into how E2-Brd4 interactions repress the viral oncogenes that account for the tumorigenic nature of HPV-associated diseases will offer promising leads for novel therapeutic strategies. This study will provide a paradigm for other episomal DNA tumor viruses, including Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, both of which also target Brd4. PUBLIC HEALTH RELEVANCE: High-risk human papillomaviruses (HPVs) are strongly associated with cervical cancer, which is the second most common cancer in women worldwide causing 15% of female cancer mortality. This proposal will investigate the molecular mechanisms that regulate the papillomavirus and host interactions during the HPV life cycle and malignant progression. Our study will identify novel targets for developing therapeutic approaches to cure HPV persistent infection and associated human cancers.