Mechanistic studies on the unique set of accessory proteins encoded by the gamma 6 human papillomaviruses

γ 6 人乳头瘤病毒编码的一组独特辅助蛋白的机制研究

基本信息

批准号：
10495249
负责人：
Karl Munger
金额：
$ 20.24万
依托单位：
TUFTS UNIVERSITY BOSTON
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：
2021-09-24 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10495249
关键词：
Applications Grants Binding Biochemical Biological Cells Cervical Clinical Cutaneous Cytostatics DNA Data Differentiation and Growth Epithelial Epithelial Cells Equilibrium Foundations Future Genetic Transcription Genome Growth HPV E7 Human Human Papillomavirus Human papillomavirus 16 Human papillomavirus 6 Hydrophobicity Immunocompetent Individual Infection Infectious Skin Diseases Integral Membrane Protein Investigation Learning Lesion Life Cycle Stages Link Longevity Medical Minority Molecular Molecular Target Mucous Membrane Papillomavirus Pathway interactions Phylogenetic Analysis Production Proliferating Property Proteins PubMed Publications Sexual Transmission Signal Transduction Smad Proteins Squamous Epithelium TP53 gene Testing Time Perception Tissues Transforming Growth Factor beta Undifferentiated Viral Viral Genome Viral Pathogenesis Viral Proteins Virus Work base cell growth cell motility cellular targeting chronic infection clinically relevant cytotoxic experimental study falls fascinate genetic makeup high risk insight intraepithelial keratinocyte member novel penis programs response

项目摘要

Papillomaviruses infect squamous epithelial tissues, and their replicative life cycle is tightly linked to the differentiation status of the infected epithelial tissues. HPVs initially infect dividing basal epithelial cells, which populate the bottom layer of the epithelium. There, HPVs establish a persistent infection, and the viral genome replicates in concert with the host cell DNA. Production of infectious viral progeny, however, is restricted to terminally differentiated epithelial cells. These cells are growth-arrested and, hence, they no longer produce the factors that are necessary to support HPV genome synthesis. HPVs encode up to three accessory proteins, E5, E6, and E7, that reprogram terminally differentiated epithelial cells to support large scale viral genome synthesis. The mechanistic contributions of the E5, E6, and E7 proteins have been extensively studied only for one specific HPV, HPV16, a member of the alpha genus. Given that all HPVs have to establish a replication-competent milieu in terminally differentiated, growth-arrested cells to produce viral progeny, it has been reasonably assumed that the insights gained from studies with HPV16 would apply to most if not all of the more than 440 phylogenetically different HPVs. More recent studies with beta genus HPVs, however, have revealed that this was an erroneous assumption. The beta HPVs only encode two accessory proteins, E6 and E7. They lack E5s and the molecular targets and biological activities of the E6 and E7 proteins are quite distinct. Unlike HPV16 E6, which binds and targets p53 for degradation, the beta HPV E6 proteins inhibit NOTCH and TGF-beta signaling by binding to MAML and SMAD proteins, respectively. The gamma genus HPVs include over 300 members, and similar to the beta HPVs, they do not encode E5 proteins. Gamma HPVs are almost entirely unstudied because most infections have not been linked to clinically relevant lesions. The members of the gamma 6 species, however, stand out because, unlike most gamma HPVs that infect cutaneous epithelia, they have all been isolated from anogenital tract mucosal epithelia. Similar to HPV16, they are likely sexually transmitted and have been linked to medically relevant cervical lesions. Moreover, the gamma 6 HPVs stand out by their unique genome organization. Unlike all other HPVs, the gamma 6 HPVs have no E6 proteins but instead encode unique, tiny hydrophobic transmembrane proteins, designated E10. We will determine the biochemical targets and biological activities of the gamma 6 HPV101 E10 and E7 proteins. The proposed work will provide fascinating insights that will be entirely novel to the HPV field. The studies will reveal how the HPV101 E7 and E10 proteins cooperate to permit the viral lifecycle in differentiated epithelial cells and how this may result in cervical lesions.

乳头瘤病毒感染了鳞状上皮组织，其复制生命周期与感染上皮组织的分化状态紧密相关。 HPV最初感染了分裂的基础上皮细胞，该细胞填充了上皮的底层。在那里，HPV建立了持续的感染，病毒基因组与宿主细胞DNA一起复制。然而，传染病后代的产生仅限于终末分化的上皮细胞。这些细胞是生长序列的，因此，它们不再产生支持HPV基因组合成所必需的因素。 HPV最多编码三种辅助蛋白E5，E6和E7，这些蛋白会重新编程终末分化的上皮细胞，以支持大规模病毒基因组合成。 E5，E6和E7蛋白的机械贡献仅针对一个特定的HPV，HPV16（Alpha Genus的成员）进行了广泛的研究。鉴于所有HPV必须在终止分化的，生长降落的细胞中建立一个复制能力的环境来产生病毒后代，因此，合理地假设，使用HPV16的研究获得的见解将适用于大多数（如果不是全部）超过440个系统上不同的HPV。然而，对β属HPV的最新研究表明，这是一个错误的假设。 Beta HPV仅编码两个附件蛋白E6和E7。它们缺乏E5S，E6和E7蛋白的分子靶标和生物学活性非常不同。与HPV16 E6（结合p53降解并靶向）不同，βHPVE6蛋白分别通过与MAML和SMAD蛋白结合来抑制Notch和TGF-β信号传导。伽马属HPV包括300多个成员，类似于Beta HPV，它们不编码E5蛋白。 Gamma HPV几乎完全未被研究，因为大多数感染与临床相关病变没有关系。但是，伽马6种的成员脱颖而出，因为与大多数感染皮肤上皮的伽马HPV不同，它们都从肛门生殖道粘膜上皮中分离出来。与HPV16相似，它们可能是性传播的，并且与医学相关的宫颈病变有关。此外，伽玛6 HPV在其独特的基因组组织中脱颖而出。与所有其他HPV不同，伽马6 HPV没有E6蛋白，但指定为E10的独特，微小的疏水跨膜蛋白。我们将确定γ6HPV101 E10和E7蛋白的生化靶标和生物学活性。拟议的工作将提供令人着迷的见解，这些见解将完全新颖。这些研究将揭示HPV101 E7和E10蛋白如何配合以允许分化上皮细胞中的病毒生命周期以及这可能导致宫颈病变。