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 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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Author:Anne-Louise Smidt Hansen, Gregory J. Buchan, Michael Rühl, Kojiro Mukai, Sonia R. Salvatore, Emari Ogawa, Sidsel 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 Jürgen Maier, Raphaela Goldbach-Mansky, Cathrine A. Miner, Wei Qian, Jonathan Miner, Rachel Rigby, Jan Rehwinkel, Martin R. Jakobsen, Hiroyuki Arai, Tomohiko Taguchi, Francisco J. Schopfer, David Olagnier, Christian K. Holm
URN:urn:nbn:de:hebis:30:3-483539
DOI:https://doi.org/10.1073/pnas.1806239115
ISSN:1091-6490
ISSN:0027-8424
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30061387
Parent Title (English):Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Acad. of Sciences
Place of publication:Washington, DC
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/07/30
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/11/27
Tag:IFN; SAVI; STING; nitro-fatty acids; palmitoylation
Volume:115
Issue:33
Page Number:8
First Page:E7768
Last Page:E7775
Note:
This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND)
HeBIS-PPN:440087430
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0