Mechanisms of Virus Entry into Cells and Antiviral Barriers Limiting Entry

我们在2020年发表了两篇与该项目有关的文章（Ahi et al.，mBio，2020; Rahman等人，eLife 2020），2022年的两篇文章（Rahman等人，Journal of Molecular Biology，2022; Majdoul et al.，Nature Reviews Immunology，2022），以及2023年迄今为止的一份预印本（Shi等人，bioRxiv，2023）。我们的工作为IFITM蛋白的功能以及它们所属的扩展的CD 225蛋白家族提供了广泛的见解，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，我们鉴定了IFITM 3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 Reports，2017）。随后，我们表明两亲性螺旋是IFITM 3改变细胞膜的生物物理性质（膜刚性和曲率）的能力所必需的（Rahman等人，eLife，2020年）。最近，我们证明了两亲性螺旋表现出直接的胆固醇结合活性，为它对膜的影响提供了可能的解释，并为IFITM 3如何限制膜融合孔形成提供了合理的机制（Rahman et al.，Journal of Molecular Biology，2022）。我们现在计划研究胆固醇结合IFITM 3如何直接有助于其抗病毒活性，通过使用分子动力学模拟纳入计算机分析。我们还将评估IFITM 3的脂质结合如何影响其通过细胞和蛋白质半衰期的运输。此外，我们的研究结果将使我们能够更好地了解IFITM 3和相关蛋白质所发挥的细胞作用，包括其作为质膜脂筏上受体酪氨酸受体信号传导支架的能力。我们的研究结果将提供深入了解这个蛋白质家族所发挥的不良特征的致瘤作用，并提供灭活的治疗靶点。

We published two articles pertaining to this project in 2020 (Ahi et al., mBio, 2020; Rahman et al., eLife 2020), two articles in 2022 (Rahman et al., Journal of Molecular Biology, 2022; Majdoul et al., Nature Reviews Immunology, 2022), and one preprint so far in 2023 (Shi et al., bioRxiv, 2023). 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 examine how cholesterol binding by IFITM3 directly contributes to its antiviral activities by incorporating in silico analyses using molecular dynamics simulations. We will also assess how lipid binding by IFITM3 affects its trafficking through the cell and protein half-life. In addition, our findings will allow us to better understand the cellular roles played by IFITM3 and related proteins, including its ability to act as a scaffold for receptor tyrosine receptor signaling at lipid rafts in 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.