Mechanisms of Virus Entry into Cells and Antiviral Barriers Limiting Entry

Division Of Basic Sciences - Nci

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Abstract

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.