Department of Medicine, Division of Infectious Diseases and Immunology
Biochemical Phenomena, Metabolism, and Nutrition | Immune System Diseases | Immunology and Infectious Disease
The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi-Goutieres syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory diseases.
IFN, SAVI, STING, nitro-fatty acids, palmitoylation
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Copyright © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
DOI of Published Version
Proc Natl Acad Sci U S A. 2018 Aug 14;115(33):E7768-E7775. doi: 10.1073/pnas.1806239115. Epub 2018 Jul 30. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America Inc.
Hansen AL, Motwani M, Fitzgerald KA, Holm CK. (2018). Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling. Open Access Publications by UMMS Authors. https://doi.org/10.1073/pnas.1806239115. Retrieved from https://escholarship.umassmed.edu/oapubs/3533
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.