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 Vol. 115; no. 33; pp. E7768 - E7775 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
National Academy of Sciences
14-08-2018
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| Series: | PNAS Plus |
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| Abstract | 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. |
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| AbstractList | 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. 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. |
| Author | Buchan, Gregory J. Holm, Christian K. Gunderstofte, Camilla Thielke, Anne L. Rehwinkel, Jan Rühl, Michael Jakobsen, Andreas S. Iversen, Marie B. Lin, Rongtuan Arai, Hiroyuki Rigby, Rachel E. Olagnier, David Andersen, Sidsel D. Maier, Thorsten J. Salvatore, Sonia R. Schopfer, Francisco J. Taguchi, Tomohiko Mukai, Kojiro Møller, Charlotte T. Roos, Jessica Qian, Wei Motwani, Mona Goldbach-Mansky, Raphaela Ogawa, Emari Miner, Jonathan J. Miner, Cathrine A. Jakobsen, Martin R. Hansen, Anne Louise Fitzgerald, Katherine A. |
| Author_xml | – sequence: 1 givenname: Anne Louise surname: Hansen fullname: Hansen, Anne Louise organization: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark – sequence: 2 givenname: Gregory J. surname: Buchan fullname: Buchan, Gregory J. organization: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213 – sequence: 3 givenname: Michael surname: Rühl fullname: Rühl, Michael organization: Department of Pharmaceutical Chemistry, Goethe University, 60438 Frankfurt am Main, Germany – sequence: 4 givenname: Kojiro surname: Mukai fullname: Mukai, Kojiro organization: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 113-0033 Tokyo, Japan – sequence: 5 givenname: Sonia R. surname: Salvatore fullname: Salvatore, Sonia R. organization: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213 – sequence: 6 givenname: Emari surname: Ogawa fullname: Ogawa, Emari organization: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 113-0033 Tokyo, Japan – sequence: 7 givenname: Sidsel D. surname: Andersen fullname: Andersen, Sidsel D. organization: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark – sequence: 8 givenname: Marie B. surname: Iversen fullname: Iversen, Marie B. organization: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark – sequence: 9 givenname: Anne L. surname: Thielke fullname: Thielke, Anne L. organization: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark – sequence: 10 givenname: Camilla surname: Gunderstofte fullname: Gunderstofte, Camilla organization: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark – sequence: 11 givenname: Mona surname: Motwani fullname: Motwani, Mona organization: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655 – sequence: 12 givenname: Charlotte T. surname: Møller fullname: Møller, Charlotte T. organization: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark – sequence: 13 givenname: Andreas S. surname: Jakobsen fullname: Jakobsen, Andreas S. organization: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark – sequence: 14 givenname: Katherine A. surname: Fitzgerald fullname: Fitzgerald, Katherine A. organization: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655 – sequence: 15 givenname: Jessica surname: Roos fullname: Roos, Jessica organization: Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany – sequence: 16 givenname: Rongtuan surname: Lin fullname: Lin, Rongtuan organization: Lady Davis Institute, Department of Medicine, McGill University, H3T 1E2 Montreal, QC, Canada – sequence: 17 givenname: Thorsten J. surname: Maier fullname: Maier, Thorsten J. organization: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark – sequence: 18 givenname: Raphaela surname: Goldbach-Mansky fullname: Goldbach-Mansky, Raphaela organization: Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20850 – sequence: 19 givenname: Cathrine A. surname: Miner fullname: Miner, Cathrine A. organization: Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 – sequence: 20 givenname: Wei surname: Qian fullname: Qian, Wei organization: Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 – sequence: 21 givenname: Jonathan J. surname: Miner fullname: Miner, Jonathan J. organization: Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 – sequence: 22 givenname: Rachel E. surname: Rigby fullname: Rigby, Rachel E. organization: Medical Research Council (MRC) Human Immunology Unit, University of Oxford, MRCWeatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Headington, OX3 9DS Oxford, United Kingdom – sequence: 23 givenname: Jan surname: Rehwinkel fullname: Rehwinkel, Jan organization: Medical Research Council (MRC) Human Immunology Unit, University of Oxford, MRCWeatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Headington, OX3 9DS Oxford, United Kingdom – sequence: 24 givenname: Martin R. surname: Jakobsen fullname: Jakobsen, Martin R. organization: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark – sequence: 25 givenname: Hiroyuki surname: Arai fullname: Arai, Hiroyuki organization: Japan Agency for Medical Research and Development (AMED)-Core Research for Evolutionary Medical Science and Technology (CREST), Japan Agency for Medical Research and Development, 100-0004 Tokyo, Japan – sequence: 26 givenname: Tomohiko surname: Taguchi fullname: Taguchi, Tomohiko organization: Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, 980-8578 Miyagi, Japan – sequence: 27 givenname: Francisco J. surname: Schopfer fullname: Schopfer, Francisco J. organization: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213 – sequence: 28 givenname: David surname: Olagnier fullname: Olagnier, David organization: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark – sequence: 29 givenname: Christian K. surname: Holm fullname: Holm, Christian K. organization: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30061387$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles Copyright © 2018 the Author(s). Published by PNAS. Copyright National Academy of Sciences Aug 14, 2018 Copyright © 2018 the Author(s). Published by PNAS. 2018 |
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| Keywords | IFN STING nitro-fatty acids palmitoylation SAVI |
| Language | English |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: A.L.H., T.J.M., T.T., F.J.S., D.O., and C.K.H. designed research; A.L.H., G.J.B., M.R., K.M., S.R.S., E.O., S.D.A., M.B.I., A.L.T., C.G., C.T.M., A.S.J., J. Roos, R.L., C.A.M., W.Q., J.J.M., T.T., F.J.S., D.O., and C.K.H. performed research; M.M., K.A.F., R.G.-M., R.E.R., J. Rehwinkel, M.R.J., H.A., T.T., and F.J.S. contributed new reagents/analytic tools; A.L.H., G.J.B., M.R., K.M., S.R.S., E.O., J. Roos, R.L., C.A.M., J.J.M., T.T., F.J.S., D.O., and C.K.H. analyzed data; and A.L.H., D.O., and C.K.H. wrote the paper. Edited by Daniel B. Stetson, University of Washington, Seattle, WA, and accepted by Editorial Board Member Ruslan Medzhitov July 3, 2018 (received for review April 11, 2018) |
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| Snippet | 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... Several chronic inflammatory conditions have recently been shown to depend on abnormally high activity of the signaling protein stimulator of IFN genes... |
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| SubjectTerms | 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 |
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| Title | Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling |
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