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

Cell Metab. 2022 Jan 4;34(1):125-139.e8. doi: 10.1016/j.cmet.2021.12.007.

Abstract

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.

Keywords: FADS2; STING; cGAS; cytosolic DNA; delta-6 Desaturase; inflammation; interferon responses; metabolism; nucleic acid immunity; polyunsaturated fatty acids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Fatty Acid Desaturases* / genetics
  • Fatty Acid Desaturases* / metabolism
  • Fatty Acids, Unsaturated / metabolism
  • Humans
  • Inflammation
  • Lipid Metabolism
  • Metabolic Syndrome*

Substances

  • Fatty Acids, Unsaturated
  • Fatty Acid Desaturases