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

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DOI

  • Anne Louise Hansen
  • Gregory J Buchan, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213.
  • ,
  • Michael Rühl, Department of Pharmaceutical Chemistry, Goethe University, 60438 Frankfurt am Main, Germany.
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  • Kojiro Mukai, Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 113-0033 Tokyo, Japan.
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  • Sonia R Salvatore, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213.
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  • Emari Ogawa, Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 113-0033 Tokyo, Japan.
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  • Sidsel D Andersen
  • Marie B Iversen
  • Anne L Thielke
  • Camilla Gunderstofte
  • Mona Motwani, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655.
  • ,
  • Charlotte T Møller
  • Andreas S Jakobsen
  • ,
  • Katherine A Fitzgerald, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655.
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  • Jessica Roos, Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
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  • Rongtuan Lin, Department of Medicine, Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, QC, H3T 1E2, Canada. rongtuan.lin@mcgill.ca.
  • ,
  • Thorsten J Maier
  • Raphaela Goldbach-Mansky, Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20850.
  • ,
  • Cathrine A Miner, Department of Neurology, Washington University in St. Louis School of Medicine, St Louis, MO, 63110, USA.
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  • Wei Qian, Department of Neurology, Washington University in St. Louis School of Medicine, St Louis, MO, 63110, USA.
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  • Jonathan J Miner, Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
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  • Rachel E Rigby, Medical Research Council (MRC) Human Immunology Unit, University of Oxford, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Headington, OX3 9DS Oxford, United Kingdom.
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  • Jan Rehwinkel, Medical Research Council (MRC) Human Immunology Unit, University of Oxford, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Headington, OX3 9DS Oxford, United Kingdom.
  • ,
  • Martin R Jakobsen
  • Hiroyuki Arai, 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.
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  • Tomohiko Taguchi, AMED-Precursory Research for Innovative Medical Care (PRIME), Japan Agency for Medical Research and Development, 100-0004 Tokyo, Japan.
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  • Francisco J Schopfer, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213.
  • ,
  • David Olagnier
  • Christian K Holm

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 languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue33
Pages (from-to)E7768-E7775
Number of pages8
ISSN0027-8424
DOIs
Publication statusPublished - 14 Aug 2018

    Research areas

  • Animals, Autoimmune Diseases of the Nervous System/genetics, Fatty Acids/metabolism, Herpes Simplex/genetics, Herpesvirus 2, Human/metabolism, Humans, Interferon Type I/genetics, Lipoylation, Lupus Erythematosus, Systemic/genetics, Membrane Proteins/genetics, Mice, Mice, Knockout, Nervous System Malformations/genetics, RAW 264.7 Cells, Signal Transduction

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