Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 33; pp. E7768 - E7775
• Main Authors: Hansen, Anne Louise, Buchan, Gregory J., Rühl, Michael, Mukai, Kojiro, Salvatore, Sonia R., Ogawa, Emari, Andersen, Sidsel D., Iversen, Marie B., Thielke, Anne L., Gunderstofte, Camilla, Motwani, Mona, Møller, Charlotte T., Jakobsen, Andreas S., Fitzgerald, Katherine A., Roos, Jessica, Lin, Rongtuan, Maier, Thorsten J., Goldbach-Mansky, Raphaela, Miner, Cathrine A., Qian, Wei, Miner, Jonathan J., Rigby, Rachel E., Rehwinkel, Jan, Jakobsen, Martin R., Arai, Hiroyuki, Taguchi, Tomohiko, Schopfer, Francisco J., Olagnier, David, Holm, Christian K.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14-08-2018
• Series: PNAS Plus
• Subjects: Alkylation; Animals; Autoimmune Diseases of the Nervous System - genetics; Autoimmune Diseases of the Nervous System - metabolism; Autoimmune Diseases of the Nervous System - pathology; Biological Sciences; Chronic conditions; Cytosol; Deoxyribonucleic acid; DNA; DNA viruses; Fatty acids; Fatty Acids - metabolism; Fibroblasts; Genes; Genetic disorders; Herpes Simplex - genetics; Herpes Simplex - metabolism; Herpes Simplex - pathology; Herpesvirus 2, Human - metabolism; Humans; Inflammatory diseases; Inhibitors; Interferon; Interferon Type I - genetics; Interferon Type I - metabolism; Lipids; Lipoylation; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - metabolism; Lupus Erythematosus, Systemic - pathology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Nervous System Malformations - genetics; Nervous System Malformations - metabolism; Nervous System Malformations - pathology; Palmitoylation; PNAS Plus; RAW 264.7 Cells; Signal Transduction; Signaling; Stimulators; Systemic lupus erythematosus; Vascular diseases; Viral infections; Viruses; IFN; STING; nitro-fatty acids; palmitoylation; SAVI
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1806239115

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.