The role of HPV E1 in regulating the NRF2-KEAP1 pathway

HPV E1在调节NRF2-KEAP1通路中的作用

• 批准号: 10646778
• 负责人: Jennifer Binning
• 金额: $ 8.43万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-19 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646778
• 关键词: Affinity Chromatography; Binding; Biological Assay; Biology; Biophysics; CUL3 gene; Cell Nucleus; Cell Survival; Cells; Chronic; Complex; Cytoplasm; Data; Drug Targeting; Enzymatic Biochemistry; Failure; Genes; Genetic Transcription; Goals; HPV-negative head and neck cancer; Head and Neck Cancer; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16 E1 protein; In Vitro; Incidence; Inhibition of Apoptosis; Knowledge; Link; Literature; Low risk HPV; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Maps; Mass Spectrum Analysis; Mediating; Metabolism; Metastatic Neoplasm to Lymph Nodes; Molecular; Mutation; Mutation Analysis; NQO1 gene; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Phenocopy; Phenotype; Positioning Attribute; Prognostic Marker; Proliferating; Proteins; Regulation; Reporter; Resolution; Role; Signal Transduction; Solid Neoplasm; Structure; Structure-Activity Relationship; Testing; Therapeutic; Viral; Viral Pathogenesis; Viral Proteins; Virus; Virus Replication; Work; antagonist; biological adaptation to stress; cancer cell; design; experimental study; global health; helicase; high risk; inhibitor; insight; migration; mimetics; mutant; new therapeutic target; novel; novel therapeutics; oral HPV-positive head and neck cancers; overexpression; pathogen; patient subsets; structural biology; targeted treatment; treatment comparison; tumor; tumorigenesis; ubiquitin-protein ligase; young adult

Persistent HPV infections alone are linked to ~ 4.5% of the total cancer incidence worldwide and can cause up to six different cancers. The global incidence of HPV-positive HNSCC is currently on the rise, particularly among younger adults. Despite these tumors responding more readily to treatment compared to HPV- HNSCC, a subset of patients (~10%) will fail therapy. The global health burden of HPV+ cancers and the growing incidence of HPV-related HNSCC underscore the need to expand our knowledge of HPV biology to inform the design of targeted therapeutics. A growing body of literature highlights the function of NRF2 in HPV-associated cancers. As NRF2 is implicated in numerous cancers, including ~30% of solid tumors, and their failure to respond to therapies, this pathway provides a potential therapeutic vulnerability that could be targeted in chronic HPV infection and HPV-associated cancers. To date, we have an incomplete understanding of how NRF2 is activated in HPV-infected cells. It was recently discovered that HPV E1 directly interacts with KEAP1 and we have validated this finding. This interaction phenocopies inactivating mutations in the CUL3-KEAP1-NRF2 pathway to activate NRF2 transcriptional activity. How E1 binds to KEAP1 to activate NRF2 and the conservation of this E1 function across different HPV types is currently unknown. In this proposal, we will determine the molecular mechanism by which HPV E1 activates NRF2. We hypothesize that E1 functions as a viral NRF2 mimetic to compete for KEAP1 binding. This hypothesis will be tested through 2 specific aims. In Aim 1, we will establish the molecular determinants for E1 engagement of KEAP1 and NRF2 activation. We will also assess the ability of both high-risk and low-risk HPV types to bind KEAP1 and activate NRF2. In Aim2, we will determine the structural and biophysical basis for E1-KEAP1 interactions. The ultimate goal and the overall impact of this project are to advance our understanding of HPV regulation of NRF2 signaling by the agonistic viral protein E1. This work will in turn enable us to study the E1-KEAP1-NRF2 axis as a novel vulnerability that could be targeted in chronic HPV infection and HPV-associated cancers, which currently lack targeted therapy.

仅持续性 HPV 感染就与全球癌症总发病率的约 4.5% 有关，并可导致多达六种不同的癌症。目前，全球 HPV 阳性 HNSCC 的发病率正在上升，尤其是在年轻人中。尽管与 HPV-HNSCC 相比，这些肿瘤更容易对治疗产生反应，但仍有一部分患者 (~10%) 治疗失败。 HPV+ 癌症的全球健康负担以及 HPV 相关 HNSCC 发病率的不断上升，强调需要扩大我们对 HPV 生物学的了解，以便为靶向治疗的设计提供信息。越来越多的文献强调了 NRF2 在 HPV 相关癌症中的功能。由于 NRF2 与多种癌症（包括约 30% 的实体瘤）有关，并且它们对治疗没有反应，因此该途径提供了潜在的治疗脆弱性，可以针对慢性 HPV 感染和 HPV 相关癌症。迄今为止，我们对 NRF2 在 HPV 感染细胞中如何被激活的了解还不完全。最近发现 HPV E1 直接与 KEAP1 相互作用，我们已经验证了这一发现。这种相互作用使 CUL3-KEAP1-NRF2 通路中的突变失活，从而激活 NRF2 转录活性。目前尚不清楚 E1 如何与 KEAP1 结合以激活 NRF2，以及该 E1 功能在不同 HPV 类型中的保守性。在本提案中，我们将确定 HPV E1 激活 NRF2 的分子机制。我们假设 E1 作为病毒 NRF2 模拟物来竞争 KEAP1 结合。该假设将通过两个具体目标进行检验。在目标 1 中，我们将建立 E1 参与 KEAP1 和 NRF2 激活的分子决定因素。我们还将评估高风险和低风险 HPV 类型结合 KEAP1 和激活 NRF2 的能力。在 Aim2 中，我们将确定 E1-KEAP1 相互作用的结构和生物物理基础。该项目的最终目标和总体影响是加深我们对激动性病毒蛋白 E1 对 NRF2 信号传导的 HPV 调节的理解。这项工作反过来将使我们能够研究 E1-KEAP1-NRF2 轴作为一种新的脆弱性，可以针对目前缺乏靶向治疗的慢性 HPV 感染和 HPV 相关癌症。