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

par Vila, Isabelle;Chamma, Hanane;Steer, Alizée;Saccas, Mathilde;Taffoni, Clara;Turtoi, Evgenia;Reinert, Line Sinnathamby;Hussain, Saqib;Marines, Johanna;Jin, Lei;Bonnefont, Xavier;Hubert, Mathieu;Schwartz, Olivier;Paludan, Søren Riis;Van Simaeys, Gaëtan ;Doumont, Gilles ;Sobhian, Bijan;Vlachakis, Dimitrios;Turtoi, Andrei;Laguette, Nadine
Référence Cell Metabolism, 34, 1, page (125-139.e8)
Publication Publié, 2022-01

Article révisé par les pairs

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Résumé :

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.