Palmitoylome profiling reveals S-palmitoylation-dependent antiviral activity of IFITM3.
Identification of immune effectors and the post-translational modifications that control their activity is essential for dissecting mechanisms of immunity. Here we demonstrate that the antiviral activity of interferon-induced transmembrane protein 3 (IFITM3) is post-translationally regulated by S-palmitoylation. Large-scale profiling of palmitoylated proteins in a dendritic cell line using a chemical reporter strategy revealed over 150 lipid-modified proteins with diverse cellular functions, including innate immunity. We discovered that S-palmitoylation of IFITM3 on membrane-proximal cysteines controls its clustering in membrane compartments and its antiviral activity against influenza virus. The sites of S-palmitoylation are highly conserved among the IFITM family of proteins in vertebrates, which suggests that S-palmitoylation of these immune effectors may be an ancient post-translational modification that is crucial for host resistance to viral infections. The S-palmitoylation and clustering of IFITM3 will be important for elucidating its mechanism of action and for the design of antiviral therapeutics.
Yount
Jacob S
JS
The Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, New York, USA.
Moltedo
Bruno
B
Yang
Yu-Ying
YY
Charron
Guillaume
G
Moran
Thomas M
TM
López
Carolina B
CB
Hang
Howard C
HC
D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D055432:Metabolomics; D010169:Palmitic Acids / Q000378:metabolism*; D046188:Protein Modification, Translational; D040901:Proteomics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D000998:Antiviral Agents; C080082:IFITM3 protein, human; D008565:Membrane Proteins; D010169:Palmitic Acids; D016601:RNA-Binding Proteins; D003545:Cysteine