Papillomavirus E6 cellular targets

α属人乳头瘤病毒（HPV）引起良性鳞状乳头瘤，其中病毒持续存在并复制。“低风险”HPV类型导致乳头状瘤，虽然持续存在，但很少进展为恶性肿瘤，但由于乳头状瘤的大小和位置，可能导致严重的，甚至危及生命的医疗并发症。在高风险和低风险HPV类型中，乳头状瘤的形成是由称为E6和E7的病毒癌蛋白的表达驱动的。高风险和低风险HPV E6蛋白都与称为E6 AP的细胞泛素连接酶相关。当高风险E6结合E6 AP时，E6然后招募细胞肿瘤抑制因子p53，然后泛素化和降解。低风险E6蛋白虽然也结合E6 AP，但不与p53相互作用，并且它结合和降解的细胞靶点直到最近仍然没有描述。由于低风险和高风险HPV都在同一宿主上共同进化，因此推测高风险和低风险E6癌蛋白可能存在共同的细胞靶点是合理的。鉴定广泛靶向E6的细胞蛋白是病毒肿瘤发生领域长期追求的目标。本申请描述了E6 + E6 AP复合物的第一个细胞靶点，该靶点是高风险和低风险E6蛋白NHERF 1降解的目标。重要的是，来自皮肤HPV以及进化上遥远的动物乳头瘤病毒的E6蛋白也靶向NHERF 1的降解。通过其同源E6蛋白靶向NHERF 1的广泛组织类型和广泛物种论证了其在乳头瘤病毒生命周期中的重要性。我们将提供数据，显示高风险和低风险E6如何靶向NHERF 1增强细胞WNT信号传导，并增强表达E6的细胞中的细胞-细胞竞争。我们建议对E6与NHERF 1相互作用的机制以及E6降解NHERF 1的后果进行额外的研究。

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.