Interferon-induced transmembrane protein 3 (IFITM3) and its antiviral activity

TL;DR

This paper explores how IFITM3 inhibits viral fusion by stalling membrane fusion processes, emphasizing the role of its amphipathic helix and discussing factors influencing its antiviral activity.

Contribution

It provides a detailed analysis of IFITM3's mechanism in blocking viral fusion, focusing on its structure, topology, and membrane interactions, which advances understanding of its antiviral function.

Findings

IFITM3 stalls viral fusion at an intermediate membrane state.

The amphipathic helix 59V-68M is essential for antiviral activity.

Post-translational modifications and membrane composition affect IFITM3 function.

Abstract

Enveloped viral infections require fusion with cellular membranes for viral genome entry, occurring only following interaction of viral and cellular membranes allowing fusion pore formation, by which the virus accesses the cytoplasm. Here, we focus on interferon-induced transmembrane protein 3 (IFITM3) and its antiviral activity. IFITM3 is predicted to block or stall viral fusion at an intermediate state, causing viral propagation to fail. After introducing IFITM3, we describe the generalized lipid membrane fusion pathway and how it can be stalled, particularly with respect to IFITM3, and current questions regarding IFITM3's topology. Specific emphasis is placed on IFITM3's amphipathic a-helix (AAH) 59V-68M, necessary for antiviral activity. Calculations are reported of hydrophobicity and hydrophobic moment of this peptide and active site peptides from other membrane-remodeling proteins. Finally, we discuss the effects of post-translational modifications and localization, how IFITM3's AAH may block viral fusion, and possible ramifications of membrane composition.