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 11：e03088-19，2020; Rahman等人，eLife 9：e58537，2020）。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。该项目现在的重点是了解人类编码的其他CD 225蛋白（包括IFITM 5）的抗病毒潜力（或缺乏）。IFITM 5参与骨形成，并且不知道参与抗病毒免疫。我们发现IFITM 5不像它的免疫相关的表亲（IFITM 1，IFITM 2和IFITM 3）那样二聚化，这与影响膜流动性的能力降低有关。因此，我们提供了一个了解相关基因如何分歧后复制和如何获得抗病毒活性（或在这种情况下，失去）。由于大多数IFITM蛋白具有形成同源二聚体的能力，我们现在正在研究异源二聚体如何促进其各自的功能。我们正在使用无偏见的蛋白质组学和免疫共沉淀，以及基于FRET的显微镜来研究IFITM蛋白与其他细胞因子的相互作用，我们正在确定这些相互作用在多大程度上对其已知的抗病毒功能产生影响。这些结果也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。

We published two articles pertaining to this project in 2020 (Ahi et al., mBio 11: e03088-19, 2020; Rahman et al., eLife 9: e58537, 2020). 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. The focus of this project now is to understand the antiviral potential (or lack thereof) of other CD225 proteins encoded by humans, including IFITM5. IFITM5 is involved in bone formation and is not known to participate in antiviral immunity. We found that IFITM5 does not dimerize like its immune-related cousins (IFITM1, IFITM2, and IFITM3) and this is associated with a decreased capacity to impact membrane fluidity. Therefore, we provide an understanding of how related genes diverge following duplication and how antiviral activity is gained (or in this case, lost). Since most IFITM proteins possess the capacity to form homodimers, we are now in the process of characterizing how heterodimers contribute to their respective function. We are using unbiased proteomics and co-immunoprecipitation, and FRET-based microscopy to study the interaction of IFITM proteins with other cellular factors, and we are determining to what extent these interactions are consequential for their known antiviral functions. These results will also provide insight into the poorly characterized tumorigenic roles played by this family of proteins.