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

乳头瘤病毒感染鳞状上皮组织，其复制生命周期与被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，这些细胞分布在上皮的底层。在那里，人乳头瘤病毒建立了持续感染，病毒基因组与宿主细胞DNA同步复制。然而，感染性病毒子代的产生仅限于终末分化的上皮细胞。这些细胞生长受阻，因此，它们不再产生支持HPV基因组合成所必需的因子。人乳头瘤病毒编码多达三种辅助蛋白，E5、E6和E7，它们对终末分化的上皮细胞进行重编程，以支持大规模的病毒基因组合成。E5， E6和E7蛋白的机制贡献已经被广泛研究，仅针对一种特定的HPV， HPV16， α属的成员。考虑到所有hpv都必须在最终分化的、生长受阻的细胞中建立一个复制能力强的环境来产生病毒后代，我们可以合理地假设，从HPV16研究中获得的见解将适用于440多种系统发育不同的hpv。然而，最近对β属人乳头瘤病毒的研究表明，这是一个错误的假设。人乳头瘤病毒只编码两个辅助蛋白，E6和E7。它们缺乏e5， E6和E7蛋白的分子靶点和生物活性完全不同。与hpv16e6结合并靶向p53降解不同，β HPV E6蛋白分别通过结合MAML和SMAD蛋白抑制NOTCH和tgf - β信号传导。伽玛人乳头瘤病毒属包括300多个成员，与β人乳头瘤病毒相似，它们不编码E5蛋白。伽玛型人乳头瘤病毒几乎完全没有被研究过，因为大多数感染与临床相关的病变没有联系。然而，与大多数感染皮肤上皮的γ hpv不同，γ 6种的成员之所以突出，是因为它们都是从肛门生殖道粘膜上皮中分离出来的。与HPV16类似，它们很可能是性传播的，并与医学上相关的宫颈病变有关。此外，γ - 6 hpv因其独特的基因组组织而脱颖而出。与所有其他hpv不同，γ - 6 hpv没有E6蛋白，而是编码独特的，微小的疏水跨膜蛋白，称为E10。我们将确定γ 6 HPV101 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，将是完全新颖的HPV领域。这些研究将揭示HPV101 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。

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.