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: 10461590
• 负责人: Kaitlyn Noel Speckhart
• 金额: $ 3.94万
• 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/10461590
• 关键词: Adaptor Signaling Protein; Anogenital cancer; Antiviral Agents; Binding; Biochemical; Cancer Etiology; Capsid; Capsid Proteins; Cell Nucleus; Cell membrane; Cells; Complex; Cytosol; DNA Viruses; Data; Disease; Dynein ATPase; Encapsulated; Endocytosis; Endosomes; Etiology; 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; Mind; Minor; Mitosis; Modeling; Molecular; Motor; Nuclear Envelope; Pathway interactions; Peptide Hydrolases; Preventive vaccine; Public Health; Role; Route; Screening Result; Sexual Transmission; Sexually Transmitted Diseases; Small Interfering RNA; Testing; Vesicle; Viral; Virus; base; combat; ds-DNA; gamma secretase; genetic approach; imaging approach; loss of function; malignant oropharynx neoplasm; new therapeutic target; novel; novel strategies; particle; prevent; receptor; receptor mediated endocytosis; recruit; 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，也是肛门生殖器癌和口咽癌的病原体。 癌的它也是最常见的性传播感染。尽管有预防性药物 目前还没有针对活动性HPV感染的有效抗病毒药物。阐明HPV的细胞基础 因此，感染对于治疗发展至关重要。在受体介导的内吞作用后，HPV被 运输到内体、高尔基体，然后是细胞核以引起感染。HPV如何通过导航 这种宿主细胞的内膜网络仍然是个谜。尽管最近的研究表明， 宿主运动动力蛋白在HPV进入中的作用，动力蛋白促进HPV感染的分子机制 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”-内体定位的FIP 3 和高尔基体定位的BICD 2-作为HPV感染过程中的关键宿主因子。这些结果表明，HPV 在不同的进入步骤劫持不同的动力蛋白-货物适配器复合物以成功到达细胞核。 基于这些发现，我们假设动力蛋白-FIP 3接头复合物被利用来转运HPV 从核内体到高尔基体（Aim 1），而动力蛋白-BICD 2适配器复合物则将病毒从核内体运输到高尔基体（Aim 1）。 高尔基体到细胞核（目的2）。我们将使用生物化学，细胞为基础的，和遗传的方法，根据损失- 功能条件下，阐明动力蛋白接头复合物驱动病毒运输的机制。 我们预计，阐明宿主成分在HPV进入中的作用将提供新的策略来对抗HPV感染。 HPV引起的疾病