Site-Specific Lipidation Enhances IFITM3 Membrane Interactions and Antiviral Activity

ACS Chem Biol. 2021 May 21;16(5):844-856. doi: 10.1021/acschembio.1c00013. Epub 2021 Apr 22.


Interferon-induced transmembrane proteins (IFITMs) are S-palmitoylated proteins in vertebrates that restrict a diverse range of viruses. S-palmitoylated IFITM3 in particular engages incoming virus particles, prevents their cytoplasmic entry, and accelerates their lysosomal clearance by host cells. However, how S-palmitoylation modulates the structure and biophysical characteristics of IFITM3 to promote its antiviral activity remains unclear. To investigate how site-specific S-palmitoylation controls IFITM3 antiviral activity, we employed computational, chemical, and biophysical approaches to demonstrate that site-specific lipidation of cysteine 72 enhances the antiviral activity of IFITM3 by modulating its conformation and interaction with lipid membranes. Collectively, our results demonstrate that site-specific S-palmitoylation of IFITM3 directly alters its biophysical properties and activity in cells to prevent virus infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology
  • Binding Sites
  • Cell Membrane / metabolism*
  • Cell Membrane / ultrastructure
  • Computational Biology
  • Drug Design
  • Humans
  • Interferons / chemistry*
  • Interferons / pharmacology
  • Lipids / chemistry*
  • Lipoylation
  • Lysosomes / metabolism
  • Membrane Proteins / metabolism*
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Conformation
  • RNA-Binding Proteins / metabolism*
  • Signal Transduction


  • Antiviral Agents
  • IFITM3 protein, human
  • Lipids
  • Membrane Proteins
  • RNA-Binding Proteins
  • Interferons