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

Anne Louise Hansen, Gregory J. Buchan, Michael Rühl, Kojiro Mukai, Sonia R. Salvatore, Emari Ogawa, Sidsel D. Andersen, Marie B. Iversen, Anne L. Thielke, Camilla Gunderstofte, Mona Motwani, Charlotte T. Møller, Andreas S. Jakobsen, Katherine A. Fitzgerald, Jessica Roos, Rongtuan Lin, Thorsten J. Maier, Raphaela Goldbach-Mansky, Cathrine A. Miner, Wei QianJonathan J. Miner, Rachel E. Rigby, Jan Rehwinkel, Martin R. Jakobsen, Hiroyuki Arai, Tomohiko Taguchi, Francisco J. Schopfer, David Olagnier, Christian K. Holm

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E7768-E7775
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number33
DOIs
Publication statusPublished - 2018 Aug 14

Keywords

  • IFN
  • Nitro-fatty acids
  • Palmitoylation
  • SAVI
  • STING

ASJC Scopus subject areas

  • General

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