Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling
| Autor: | Charlotte Möller, Gregory J. Buchan, Francisco J. Schopfer, Rachel E. Rigby, Hiroyuki Arai, Jonathan J. Miner, Wei Qian, Anne L. Thielke, Camilla Gunderstofte, Martin R. Jakobsen, Jan Rehwinkel, Jessica Roos, Mona Motwani, Sonia R. Salvatore, Katherine A. Fitzgerald, Marie B. Iversen, Rongtuan Lin, Raphaela Goldbach-Mansky, Christian K. Holm, Michael Rühl, Kojiro Mukai, Thorsten J. Maier, Tomohiko Taguchi, Cathrine A. Miner, Andreas S. Jakobsen, Anne-Louise S. Hansen, Emari Ogawa, David Olagnier, Sidsel D. Andersen |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Autoimmune Diseases of the Nervous System/genetics Herpesvirus 2 Human medicine.disease_cause Mice chemistry.chemical_compound Immunology and Inflammation Interferon Type I/genetics Lupus Erythematosus Systemic palmitoylation nitro-fatty acids Mice Knockout Mutation Multidisciplinary Chemistry Fatty Acids Biological Sciences Lupus Erythematosus Systemic/genetics 3. Good health Herpes Simplex/genetics Fatty Acids/metabolism PNAS Plus Interferon Type I Nervous System Malformations/genetics Signal Transduction Lipoylation Herpesvirus 2 Human/metabolism Nervous System Malformations IFN Virus 03 medical and health sciences Autoimmune Diseases of the Nervous System Palmitoylation medicine Animals Humans ddc:610 Membrane Proteins/genetics Gene Membrane Proteins Herpes Simplex eye diseases Sting Cytosol SAVI RAW 264.7 Cells 030104 developmental biology Immunology Nitro DNA STING |
| Zdroj: | Hansen, A L, Buchan, G J, Rühl, M, Mukai, K, Salvatore, S R, Ogawa, E, Andersen, S D, Iversen, M B, Thielke, A L, Gunderstofte, C, Motwani, M, Møller, C T, Jakobsen, A S, Fitzgerald, K A, Roos, J, Lin, R, Maier, T J, Goldbach-Mansky, R, Miner, C A, Qian, W, Miner, J J, Rigby, R E, Rehwinkel, J, Jakobsen, M R, Arai, H, Taguchi, T, Schopfer, F J, Olagnier, D & Holm, C K 2018, ' Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling ', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 33, pp. E7768-E7775 . https://doi.org/10.1073/pnas.1806239115 Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Several chronic inflammatory conditions have recently been shown to depend on abnormally high activity of the signaling protein stimulator of IFN genes (STING). These conditions include examples from systemic lupus erythematosus, Aicardi–Goutiéres syndrome, and STING-associated vasculopathy with onset in infancy. The involvement of STING in these diseases points to an unmet demand to identify inhibitors of STING signaling, which could form the basis of anti-STING therapeutics. With this report, we identify distinct endogenously formed lipid species as potent inhibitors of STING signaling—and propose that these lipids could have pharmaceutical potential for treatment of STING-dependent inflammatory diseases. 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. |
| Databáze: | OpenAIRE |
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