Mechanisms of Virus Entry into Cells and Antiviral Barriers Limiting Entry

病毒进入细胞的机制和限制进入的抗病毒屏障

• 批准号: 10702668
• 负责人: Alex Compton
• 金额: $ 67.15万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702668
• 关键词: Address; Affect; Amino Acids; Amphipathic Alpha Helix; Antiviral Therapy; Binding; Categories; Cell fusion; Cell membrane; Cell-Matrix Junction; Cells; Cellular Membrane; Cholesterol; Development; Evolution; Exhibits; Glean; Glycoproteins; Goals; HIV-1; Human; IFITM1 gene; Infection; Influenza A virus; Integral Membrane Protein; Interferons; Journals; Measures; Mediating; Membrane; Membrane Fusion; Molecular Biology; Murine leukemia virus; Mutation; Oncogenic; Pathogenicity; Physiological; Play; Process; Protein Family; Proteins; Publishing; RNA Viruses; Reporting; Retroviridae; Role; Route; Signal Transduction; System; Therapeutic Intervention; Viral Proteins; Virion; Virus; Work; Zika Virus; base; biophysical properties; cell type; experimental study; gene therapy; insight; mutant; novel; preservation; scaffold; therapeutic target; transmission process; tumorigenic

We published two articles pertaining to this project in 2020 (Ahi et al., mBio, 2020; Rahman et al., eLife 2020) and one article in 2022 (Rahman et al., Journal of Molecular Biology, 2022). Our work provides extensive insight into the function of IFITM proteins as well as the extended CD225 protein family to which they belong and will provide leverage for the development of new antiviral therapies. Notably, we identified an amphipathic alpha helix that is required for the antiviral activity of IFITM3 against multiple viruses, including HIV-1, Zika virus, and Influenza A virus (Chesarino, Compton et al. EMBO Reports, 2017). Subsequently, we showed that the amphipathic helix is required for the ability of IFITM3 to alter the biophysical properties of cellular membranes (membrane rigidity and curvature) (Rahman et al., eLife, 2020). Most recently, we demonstrated that the amphipathic helix exhibits direct cholesterol binding activity, providing a possible explanation for its impacts on membranes and a plausible mechanism for how IFITM3 restricts membrane fusion pore formation (Rahman et al., Journal of Molecular Biology, 2022). We now plan to directly measure cholesterol binding by IFITM3 contributes to its effect on membrane rigidity, a feature that is functionally tied to its capacity to inhibit virus entry. Furthermore, we plan to assess the functional role played by the amphipathic helix in the oncogenic functions of IFITM3, including its ability to act as a scaffold for PI3K signaling at the plasma membrane. Our findings will provide insight into the poorly characterized tumorigenic roles played by this family of proteins and provide therapeutic targets for inactivation.

我们于 2020 年发表了两篇与该项目相关的文章（Ahi 等人，mBio，2020；Rahman 等人，eLife 2020），并于 2022 年发表了一篇文章（Rahman 等人，Journal of Molecular Biology，2022）。我们的工作对 IFITM 蛋白及其所属的扩展 CD225 蛋白家族的功能提供了广泛的了解，并将为新的抗病毒疗法的开发提供杠杆作用。值得注意的是，我们发现了 IFITM3 针对多种病毒（包括 HIV-1、寨卡病毒和甲型流感病毒）的抗病毒活性所需的两亲性 α 螺旋（Chesarino、Compton 等人 EMBO 报告，2017）。 随后，我们证明了 IFITM3 改变细胞膜生物物理特性（膜刚性和曲率）的能力需要两亲螺旋（Rahman 等人，eLife，2020）。最近，我们证明两亲性螺旋表现出直接的胆固醇结合活性，为其对膜的影响提供了可能的解释，并为 IFITM3 如何限制膜融合孔形成提供了合理的机制（Rahman 等人，分子生物学杂志，2022）。我们现在计划直接测量 IFITM3 与胆固醇的结合有助于其对膜刚性的影响，这一特征在功能上与其抑制病毒进入的能力有关。此外，我们计划评估两亲性螺旋在 IFITM3 致癌功能中所发挥的功能作用，包括其作为质膜 PI3K 信号传导支架的能力。我们的研究结果将深入了解该蛋白质家族所发挥的尚未明确的致瘤作用，并提供失活的治疗靶点。