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Palmitoylome profiling reveals S-palmitoylation–dependent antiviral activity of IFITM3

Nature Chemical Biology volume 6, pages 610–614 (2010)Cite this article

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Abstract

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.

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Figure 1: Visualization and identification of palmitoylated proteins in DC2.4 cells.
Figure 2: IFITM3 is S-palmitoylated on membrane-proximal cysteine residues.
Figure 3: Palmitoylation-dependent clustering of IFITM3 in the ER.
Figure 4: Antiviral activity of IFITM3 is regulated by palmitoylation.

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Acknowledgements

J.S.Y. is a postdoctoral fellow of the Irving Institute Fellowship Program of the Cancer Research Institute. Y.-Y.Y. was supported in part by the Anderson Cancer Center postdoctoral fellowship. G.C. acknowledges the Weill-Cornell/Rockefeller/Sloan-Kettering Tri-institutional Program in Chemical Biology. The authors would like to thank A. Li for technical support. T.M.M. is supported by grant AI041111 and C.B.L. is supported by grant AI083284-01, both from the US National Institute of Allergy and Infectious Diseases of the US National Institutes of Health. H.C.H. acknowledges support from The Rockefeller University, Ellison Medical Foundation, Irma T. Hirschl and Monique Weill-Caulier Trust, Lerner Trust and the US National Institute of Drug Abuse of the US National Institutes of Health (1R21DA025751-01).

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Authors and Affiliations

  1. The Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, New York, USA

    Jacob S Yount, Yu-Ying Yang, Guillaume Charron & Howard C Hang

  2. Department of Microbiology, The Mount Sinai School of Medicine, New York, New York, USA

    Bruno Moltedo, Thomas M Moran & Carolina B López

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  1. Jacob S Yount
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Contributions

J.S.Y. conceived the study, designed and performed experiments, interpreted data and co-wrote the manuscript; Y.-Y.Y. and G.C. synthesized reagents for palmitoylome profiling studies; B.M., C.B.L. and T.M.M. provided reagents and expertise on influenza virus infections; H.C.H. conceived the study, designed experiments, interpreted data and co-wrote the manuscript.

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Correspondence to Howard C Hang.

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The authors declare no competing financial interests.

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Yount, J., Moltedo, B., Yang, YY. et al. Palmitoylome profiling reveals S-palmitoylation–dependent antiviral activity of IFITM3. Nat Chem Biol 6, 610–614 (2010). https://doi.org/10.1038/nchembio.405

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