Interferon-Induced Transmembrane Proteins: Membrane Gatekeepers of Fusion and Infection

Abstract

Interferon-induced transmembrane proteins (IFITMs) are small, non-enzymatic factors that reshape host cell membranes to block pathogen entry. In this review, we bring together what is known about their genetics and evolution, how their structure relates to function, and how they are regulated after translation. A central theme is how the amphipathic helix organizes lipids and bends membranes to stop fusion pores from forming. We connect well-studied antiviral cases, influenza A, HIV-1, flaviviruses, and the context-dependent effects seen with coronaviruses, to newer cell-biology insights, including cooperation with ZMPSTE24 and dependence on phosphoinositides. Beyond viruses, IFITMs appear to control how extracellular vesicles deliver cargo, acting as broader "membrane gatekeepers" of cell-to-cell communication. Placing IFITMs in the host– pathogen arms race, we outline how viruses evade IFITM activity or dampen its induction, while helminth and protozoan parasites rewire interferon pathways more broadly; their secreted miRNAs and proteases commonly suppress NF-κB and may intersect with IFITM-regulated uptake. Finally, we survey noncanonical roles in development, immunity, and cancer, and highlight open questions about topology, lipid dynamics, and targeting specificity. Together, these threads present IFITMs as adaptable effectors linking innate immunity, membrane biophysics, and disease, with clear implications for antivirals, immuno-oncology, and vesicle-based therapies.