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

• Published in: Cell metabolism Vol. 34; no. 1; pp. 125 - 139.e8
• Main Authors: Vila, Isabelle K., Chamma, Hanane, Steer, Alizée, Saccas, Mathilde, Taffoni, Clara, Turtoi, Evgenia, Reinert, Line S., Hussain, Saqib, Marines, Johanna, Jin, Lei, Bonnefont, Xavier, Hubert, Mathieu, Schwartz, Olivier, Paludan, Soren R., Van Simaeys, Gaetan, Doumont, Gilles, Sobhian, Bijan, Vlachakis, Dimitrios, Turtoi, Andrei, Laguette, Nadine
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.01.2022; Elsevier; Cell Press
• Subjects: Cellular Biology; cGAS; cytosolic DNA; delta-6 Desaturase; FADS2; Fatty Acid Desaturases - genetics; Fatty Acid Desaturases - metabolism; Fatty Acids, Unsaturated - metabolism; Humans; Inflammation; interferon responses; Life Sciences; Lipid Metabolism; Metabolic Syndrome; metabolism; nucleic acid immunity; polyunsaturated fatty acids; STING; FADS2; delta-6 Desaturase; inflammation; polyunsaturated fatty acids; cGAS; nucleic acid immunity; STING; metabolism; cytosolic DNA; interferon responses
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2021.12.007

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. [Display omitted] •STING inhibits FADS2-dependent desaturation of PUFAs and LC-PUFAs•STING activation leads to upregulation of FADS2-associated desaturase activity•STING agonists activate FADS2-dependent PUFA and LC-PUFA desaturation•PUFAs inhibit STING-dependent inflammatory responses The stimulator of interferon genes (STING) is a central regulator of nucleic acid-associated inflammatory responses. Here, Vila et al. discover that STING regulates polyunsaturated fatty acid (PUFA) metabolism, and in turn, PUFAs inhibit STING-dependent inflammation. This cross-regulation is central to the maintenance of metabolic homeostasis.