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

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 interferon...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 2018-08, Vol.115 (33), p.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:	Article
Language:	eng
Subjects:	Alkylation Animals Autoimmune diseases 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 Infections 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 Medical treatment 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
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Summary:	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.
ISSN:	0027-8424 1091-6490