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.

仅持续的HPV感染与全球癌症总发病率的约4.5％有关，最多可能引起六种不同的癌症。 HPV阳性HNSCC的全球发病率目前正在上升，尤其是在年轻人中。尽管与HPV-HNSCC相比，这些肿瘤对治疗的反应更容易，但一部分患者（约10％）将失败治疗。 HPV+癌症的全球健康负担以及与HPV相关的HNSCC的发生率不断增长，强调了扩大我们对HPV生物学知识的需求，以告知目标治疗剂的设计。越来越多的文献强调了NRF2在与HPV相关的癌症中的功能。由于NRF2与许多癌症有关，包括约30％的实体瘤，并且对疗法没有反应，因此该途径提供了潜在的治疗脆弱性，可以针对慢性HPV感染和与HPV相关的癌症。迄今为止，我们对HPV感染的细胞中NRF2的激活方式有不完整的了解。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。这种相互作用的表现使CUL3-KEAP1-NRF2途径中的突变失活以激活NRF2转录活性。当前未知E1如何与KEAP1结合以激活NRF2和在不同HPV类型上的E1函数的保护。在此提案中，我们将确定HPV E1激活NRF2的分子机制。我们假设E1充当病毒NRF2模拟物以竞争KEAP1结合。该假设将通过2个特定目的进行检验。在AIM 1中，我们将建立用于KEAP1和NRF2激活E1参与的分子决定因素。我们还将评估高风险和低风险HPV类型结合KEAP1并激活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整体影响是促进我们对激动病毒蛋白E1对NRF2信号的HPV调节的理解。这项工作反过来将使我们能够研究E1-KEAP1-NRF2轴作为一种新型脆弱性，该脆弱性可能针对慢性HPV感染和与HPV相关的癌症，目前缺乏针对性的治疗。