Opposing activities of IFITM proteins in SARS-CoV-2 infection

Area of Science:

• Virology
• Cell Biology
• Immunology

Background:

• Interferon-induced transmembrane proteins (IFITMs) are known to restrict viral infections.
• However, some IFITM proteins can enhance infections by specific coronaviruses via unknown mechanisms.

Purpose of the Study:

• To elucidate the mechanisms by which IFITM proteins, particularly IFITM3, modulate SARS-CoV-2 infection.
• To differentiate between restrictive and enhancing roles of IFITM3 in viral entry.

Main Methods:

• Utilized gain- and loss-of-function approaches with human and mouse IFITM1, IFITM2, and IFITM3.
• Investigated the role of IFITM3 S-palmitoylation, amphipathic helix, and endocytosis-promoting motif (YxxФ).
• Performed cell-to-cell fusion assays and analyzed the impact of TMPRSS2 overexpression.

Main Results:

• Human and mouse IFITM1, IFITM2, and IFITM3 generally restrict SARS-CoV-2 infection.
• IFITM3 restriction is independent of S-palmitoylation but requires its amphipathic helix.
• Mutations in the IFITM3 endocytosis-promoting motif convert it into an enhancer of SARS-CoV-2 infection and plasma membrane fusion.
• TMPRSS2 overexpression attenuates IFITM3 restriction and promotes enhancement by mutants.

Conclusions:

• Uncovered distinct pro- and anti-viral mechanisms of IFITM3 against SARS-CoV-2.
• IFITM3 restricts SARS-CoV-2 via endosomal pathways, dependent on its amphipathic properties.
• Mutants can enhance viral infection by promoting plasma membrane fusion, highlighting context-dependent roles.