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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-Goutières 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.

Original publication

DOI

10.1073/pnas.1806239115

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

14/08/2018

Volume

115

Pages

E7768 - E7775

Keywords

IFN, SAVI, STING, nitro-fatty acids, palmitoylation, Animals, Autoimmune Diseases of the Nervous System, Fatty Acids, Herpes Simplex, Herpesvirus 2, Human, Humans, Interferon Type I, Lipoylation, Lupus Erythematosus, Systemic, Membrane Proteins, Mice, Mice, Knockout, Nervous System Malformations, RAW 264.7 Cells, Signal Transduction