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

Abstract

Summary 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.

Effects and associated transcriptomic landscape changes of methamphetamine on immune cells

“…It is a regulatory node in cholesterol biosynthesis, and may promote cell proliferation [ 41 ]. FADS2 (fatty acid desaturase 2) may be involved in the coordination of inflammatory responses and metabolic homeostasis [ 42 ]. LSS (lanosterol synthase) catalyzes the conversion of (S)-2,3 oxidosqualene to lanosterol and catalyzes the first step in the biosynthesis of cholesterol, and may play a protective role in the early stages of oxidative stress [ 43 ].…”

The curious case of TMEM120A: Mechanosensor, fat regulator, or antiviral defender?

“…[ 57 ] Moreover, a recent study showed that PUFA (polyunsaturated fatty acid) can inhibit STING. [ 58 ] Collectively, these studies revealed the link between fatty acid metabolism and STING trafficking. Recently, we identified TMEM120A as a positive regulator of STING trafficking from the ER to ERGIC.…”

Protocol to induce and assess cGAS-STING pathway activation in vitro

“…This protocol below, used in Vila et al. ( Vila et al., 2022 ) describes the following steps: (i) preparation of dsDNA probes from synthetic ssDNA ( Stetson and Medzhitov, 2006 ), (ii) transfection of dsDNA in murine mouse embryonic fibroblasts (MEFs), and (iii) visualization of the activation of the cGAS-STING pathway by western blot and RT-qPCR. This protocol is the standard protocol used to verify cGAS-STING pathway activation in murine and human cell lines in our laboratory.…”

“…The protocol can be applied to investigate cGAS-STING signaling in both murine and human cell lines. For complete details on the use and execution of this protocol, please refer to Vila et al. (2022) .…”

“…For complete details on the use and execution of this protocol, please refer to Vila et al. (2022) .…”