STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses

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Vila, Isabelle | Chamma, Hanane | Steer, Alizée | Saccas, Mathilde | Taffoni, Clara | Turtoi, Evgenia | Reinert, Line | Hussain, Saqib | Marines, Johanna | Jin, Lei | Bonnefont, Xavier | Hubert, Mathieu | Schwartz, Olivier | Paludan, Soren | van Simaeys, Gaetan | Doumont, Gilles | Sobhian, Bijan | Vlachakis, Dimitrios | Turtoi, Andrei | Laguette, Nadine

Edité par CCSD ; Elsevier -

International audience. Concerted alteration of immune and metabolic homeostasis underlies several inflammation-related pathologies, ranging from metabolic syndrome to infectious diseases. Here, we explored the coordination of nucleic acid-dependent inflammatory responses and metabolic homeostasis. We reveal that the STING (stimulator of interferon genes) protein regulates metabolic homeostasis through inhibition of the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in polyunsaturated fatty acid (PUFA) desaturation. STING ablation and agonist-mediated degradation increased FADS2-associated desaturase activity and led to accumulation of PUFA derivatives that drive thermogenesis. STING agonists directly activated FADS2-dependent desaturation, promoting metabolic alterations. PUFAs in turn inhibited STING, thereby regulating antiviral responses and contributing to resolving STING-associated inflammation. Thus, we have unveiled a negative regulatory feedback loop between STING and FADS2 that fine-tunes inflammatory responses. Our results highlight the role of metabolic alterations in human pathologies associated with aberrant STING activation and STING-targeting therapies.

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