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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：
10349083
负责人：
Karl Munger
金额：
$ 24.36万
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/10349083
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密切相关。HPV最初感染分裂的基底上皮细胞，其占据上皮的底层。在那里，HPV建立持续感染，并且病毒基因组与宿主细胞DNA一起复制。然而，感染性病毒后代的产生仅限于终末分化的上皮细胞。这些细胞是生长停滞的，因此它们不再产生支持HPV基因组合成所必需的因子。HPV编码多达三种辅助蛋白E5、E6和E7，其重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蛋白的机制贡献仅针对一种特定的HPV（HPV 16，α属的成员）进行了广泛研究。考虑到所有HPV都必须在终末分化的生长停滞细胞中建立一个有复制能力的环境以产生病毒后代，因此可以合理地假设，从HPV 16的研究中获得的见解将适用于440多种不同遗传学的HPV中的大多数（如果不是全部的话）。然而，最近对β属HPV的研究表明，这是一个错误的假设。β HPV仅编码两种辅助蛋白，E6和E7。它们缺乏E5，并且E6和E7蛋白的分子靶点和生物活性非常不同。与结合并靶向p53进行降解的HPV 16 E6不同，β HPV E6蛋白通过分别结合MAML和SMAD蛋白来抑制NOTCH和TGF-β信号传导。γ属HPV包括超过300个成员，并且与β HPV类似，它们不编码E5蛋白。γ HPV几乎完全未被研究，因为大多数感染与临床相关病变无关。然而，γ 6种的成员很突出，因为与大多数感染皮肤上皮的γ HPV不同，它们都是从肛门生殖道粘膜上皮中分离出来的。与HPV 16类似，它们可能通过性传播，并与医学相关的宫颈病变有关。此外，γ 6 HPV因其独特的基因组结构而脱颖而出。与所有其他HPV不同，γ 6 HPV没有E6蛋白，而是编码独特的微小疏水跨膜蛋白，称为E10。我们将确定γ 6 HPV 101 E10和E7蛋白的生化靶点和生物活性。拟议的工作将提供迷人的见解，这将是HPV领域的全新之处。这些研究将揭示HPV 101 E7和E10蛋白如何合作，以允许病毒在分化的上皮细胞中的生命周期，以及这如何导致宫颈病变。