S-Palmitoylation and Sterol Interactions Mediate Antiviral Specificity of IFITMs

Tandrila Das, Xinglin Yang, Hwayoung Lee, Emma H. Garst, Estefania Valencia, Kartik Chandran, Wonpil Im, Howard C. Hang

Research output: Contribution to journalArticlepeer-review

Abstract

Interferon-induced transmembrane proteins (IFITM1, 2, and 3) are important antiviral proteins that are active against many viruses, including influenza A virus (IAV), dengue virus (DENV), Ebola virus (EBOV), Zika virus (ZIKV), and severe acute respiratory syndrome coronavirus (SARS-CoV). IFITM proteins exhibit specificity in activity, but their distinct mechanisms of action and regulation are unclear. Since S-palmitoylation and cholesterol homeostasis are crucial for viral infections, we investigated IFITM interactions with cholesterol by photoaffinity cross-linking in mammalian cells along with molecular dynamic simulations and nuclear magnetic resonance analysis in vitro. These studies suggest that cholesterol can directly interact with S-palmitoylated IFITMs in cells and alter the conformation of IFITMs in membrane bilayers. Notably, we discovered that the S-palmitoylation levels regulate differential IFITM protein interactions with cholesterol in mammalian cells and specificity of antiviral activity toward IAV, SARS-CoV-2, and EBOV. Our studies suggest that modulation of IFITM S-palmitoylation levels and cholesterol interaction influence host susceptibility to different viruses.

Original languageEnglish (US)
Pages (from-to)2109-2120
Number of pages12
JournalACS Chemical Biology
Volume17
Issue number8
DOIs
StatePublished - Aug 19 2022

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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