Interferon-inducible phospholipids govern IFITM3-dependent endosomal antiviral immunity

Area of Science:

• Virology
• Cell Biology
• Immunology

Background:

• Interferon-induced transmembrane proteins (IFITM) play a role in antiviral defense, but their precise mechanisms are not fully understood.
• IFITM proteins are known to restrict viral entry, but their function differs depending on their cellular location.

Purpose of the Study:

• To investigate the host co-factors involved in endosomal antiviral restriction mediated by IFITM proteins.
• To elucidate the specific molecular mechanisms by which IFITM proteins inhibit viral entry into endosomes.

Main Methods:

• Utilized pseudotyped viral entry assays and replicating viruses in cellular models.
• Employed high-throughput proteomics and lipidomics to identify interacting host factors.
• Investigated the role of specific IFITM residues and phospholipids in antiviral activity.

Main Results:

• Endosomal IFITM restriction requires lysines in the conserved intracellular loop, which recruit Phosphatidylinositol 3,4,5-trisphosphate (PIP3).
• PIP3 is identified as an interferon-inducible phospholipid essential for endosomal IFITM antiviral activity.
• Exogenous PIP3 enhanced the inhibition of endocytic viruses, including SARS-CoV2 Omicron variant.

Conclusions:

• PIP3 is a critical regulator of endosomal IFITM restriction, linking it to the Pi3K/Akt/mTORC pathway.
• Identified cell-compartment-specific antiviral mechanisms involving IFITM proteins and PIP3.
• Findings offer potential relevance for developing broadly acting antiviral strategies.