TY - JOUR
T1 - S-Palmitoylation and Sterol Interactions Mediate Antiviral Specificity of IFITMs
AU - Das, Tandrila
AU - Yang, Xinglin
AU - Lee, Hwayoung
AU - Garst, Emma H.
AU - Valencia, Estefania
AU - Chandran, Kartik
AU - Im, Wonpil
AU - Hang, Howard C.
N1 - Funding Information:
T.D. and E.H.G., acknowledge support from Tri-Institutional Program in Chemical Biology. H.C.H., W.I., and K.C. acknowledge grant support from NIH-NIGMS R01GM087544. K.C. was also supported by NIH R01AI134824. We thank R. He for the generation of IFITM1, 2, 3 knockout mammalian cell lines. We also thank S. Bhattacharya for help with NMR data collection at New York Structural Biology Center. We also thank Z. Wu for help with polarimetry measurements at Scripps Research. We also thank M. Griffin and X. Zhao for helpful discussions.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/8/19
Y1 - 2022/8/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85136535107&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85136535107&partnerID=8YFLogxK
U2 - 10.1021/acschembio.2c00176
DO - 10.1021/acschembio.2c00176
M3 - Article
C2 - 35861660
AN - SCOPUS:85136535107
SN - 1554-8929
VL - 17
SP - 2109
EP - 2120
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 8
ER -
