Mechanisms of Virus Entry into Cells and Antiviral Barriers Limiting Entry

我们在2020年发表了两篇关于该项目的文章（Ahi et al., mBio, 2020; Rahman et al., eLife 2020），在2022年发表了一篇文章（Rahman et al., Journal of Molecular Biology, 2022）。我们的工作为IFITM蛋白及其所属的扩展CD225蛋白家族的功能提供了广泛的见解，并将为开发新的抗病毒疗法提供杠杆作用。值得注意的是，我们发现了IFITM3对多种病毒（包括HIV-1、寨卡病毒和甲型流感病毒）的抗病毒活性所必需的两型α螺旋（Chesarino， Compton等）。EMBO报告，2017)。随后，我们证明了IFITM3改变细胞膜生物物理特性（膜刚度和曲率）的能力需要两亲螺旋（Rahman等，eLife, 2020）。最近，我们证明了两亲螺旋具有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如何限制膜融合孔的形成提供了可能的机制（Rahman等人，Journal of Molecular Biology, 2022）。我们现在计划直接测量IFITM3对胆固醇结合的影响，这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，我们计划评估两亲螺旋在IFITM3的致癌功能中所起的功能作用，包括其作为质膜PI3K信号传导支架的能力。我们的发现将为这一蛋白家族所扮演的不为人知的致瘤作用提供见解，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) 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.