Elucidating the role of dynein-cargo adaptor proteins in Human papillomavirus infection

阐明动力蛋白-货物衔接蛋白在人乳头瘤病毒感染中的作用

• 批准号: 10908071
• 负责人: Kaitlyn Noel Speckhart
• 金额: $ 0.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10908071
• 关键词: Adaptor Signaling Protein; Anogenital cancer; Antiviral Agents; Binding; Biochemical; Cancer Etiology; Capsid Proteins; Cell Nucleus; Cell membrane; Cells; Complex; Cytosol; DNA Viruses; Data; Disease; Dynein ATPase; Encapsulated; Endocytosis; Endosomes; Etiology; Event; Exposure to; Genome; Goals; Golgi Apparatus; Human Papillomavirus; Human papilloma virus infection; Image; Infection; Integration Host Factors; Intracellular Transport; Malignant neoplasm of cervix uteri; Mediating; Membrane; Minor; Mitosis; Modeling; Molecular; Motor; Nuclear Envelope; Pathway interactions; Peptide Hydrolases; Preventive vaccine; Public Health; Role; Route; Screening Result; Sexually Transmitted Diseases; Small Interfering RNA; Sorting; Testing; Transport Process; Vesicle; Viral; Virus; combat; ds-DNA; endosome membrane; genetic approach; imaging approach; loss of function; malignant oropharynx neoplasm; new therapeutic target; novel; novel strategies; particle; prevent; receptor; receptor mediated endocytosis; recruit; secretase; therapeutic development; trafficking

Abstract Human papillomavirus (HPV) is the etiologic agent of cervical cancer, as well as anogenital and oropharyngeal cancers. It is also the most common sexually transmitted infection. Despite the availability of prophylactic vaccines, there are no effective antivirals against active HPV infection. Illuminating the cellular basis of HPV infection is therefore crucial to therapeutic development. Upon receptor-mediated endocytosis, HPV is trafficked to the endosome, the Golgi, and then the nucleus to cause infection. How HPV navigates through this endomembranous network of the host cell remains mysterious. Although recent studies have suggested a role of the host motor dynein in HPV entry, the molecular mechanism by which dynein promotes HPV infection remains unclear. Our preliminary data identified two dynein “cargo adaptors” – the endosome-localized FIP3 and the Golgi-localized BICD2 - as critical host factors during HPV infection. These results suggest that HPV hijacks distinct dynein-cargo adaptor complexes at different entry steps to successfully reach the nucleus. Based on these findings, we hypothesize that the dynein-FIP3 adaptor complex is exploited to transport HPV from the endosome to the Golgi (Aim 1), while the dynein-BICD2 adaptor complex traffics the virus from the Golgi to the nucleus (Aim 2). We will use biochemical, cell-based, and genetic approaches, under loss-of- function conditions, to elucidate the mechanism by which the dynein-adaptor complex drives viral transport. We anticipate that clarifying the role of host components in HPV entry will provide novel strategies to combat HPV-induced diseases.

摘要 人乳头瘤病毒(HPV)是宫颈癌的病原体，也是肛门和口咽癌的病原体。 癌症。它也是最常见的性传播感染。尽管有可用的避孕药 在疫苗方面，目前还没有有效的抗病毒药物来对抗活动性HPV感染。阐明人乳头瘤病毒的细胞学基础 因此，感染对治疗的发展至关重要。在受体介导的内吞作用中，HPV是 贩运到内体，高尔基体，然后是细胞核，引起感染。HPV如何渡过难关 宿主细胞的这种膜内网络仍然是个谜。尽管最近的研究表明， 宿主动力蛋白在HPV进入中的作用，动力蛋白促进HPV感染的分子机制 目前仍不清楚。我们的初步数据确定了两个动力蛋白“货物适配器”--内小体定位的FIP3 高尔基体定位的BICD2-是HPV感染过程中的关键宿主因子。这些结果表明，人乳头瘤病毒 在不同的进入步骤劫持不同的动力蛋白-货物适配器复合体，成功地到达细胞核。 基于这些发现，我们假设dynein-fip3接头复合体被用来运输HPV。 从内体到高尔基体(目标1)，而动力蛋白-BICD2适配器复合体将病毒从 高尔基体到细胞核(目标2)。我们将使用生化、基于细胞和遗传的方法，在- 功能条件，以阐明动力蛋白-接头复合体驱动病毒运输的机制。 我们预计，澄清宿主成分在HPV进入中的作用将提供新的战略来对抗 人乳头瘤病毒引起的疾病。