Sting orchestrates the crosstalk between polyunsaturated fatty acids metabolism and inflammatory responses

Abstract

SummaryInflammatory disorders are major health issues in which immune function and metabolic homeostasis are concertedly altered. Yet, the molecular mechanisms coordinating innate and metabolic pathways in homeostatic conditions are poorly understood. Here, we unveil a negative regulatory feedback loop involving the Stimulator of interferon genes (Sting) and the Fatty acid desaturase 2 (Fads2). At steady state, Sting regulates FA metabolism by repressing the activity of the Fads2 enzyme responsible for the desaturation of polyunsaturated FAs (PUFAs). Importantly, Sting activation increased Fads2 activity, while antagonizing Fads2 enhanced Sting activation, promoting the establishment of an anti-viral state. Remarkably, the cross-regulation between Sting and Fads2 is mediated by the cyclic GMP-AMP (cGAMP) Sting agonist and PUFAs. Indeed, we found that PUFAs inhibit Sting activation, while Sting agonists bind Fads2. Thus, our study identifies Sting as a master regulator of FA metabolism, and PUFAs as modulators of Sting-dependent inflammation. The interplay between Fads2 and Sting determines the fine-tuning of inflammatory responses, but comes at the expense of metabolic alterations, which are critical to consider in human pathologies associated with aberrant Sting activation.

The commonTMEM173 HAQ, AQalleles rescue CD4 T cellpenia, restore T-regs, and preventSAVI (N153S)inflammatory disease in mice

“…Thus, besides preventing cell death, additional mechanism by the AQ allele, e.g. fatty acid metabolism 37,69 , is involved in curing SAVI.…”

Ferroptosis: Iron-mediated cell death linked to disease pathogenesis

“…In addition to metabolic and antioxidant dimensions, ferroptosis regulation is also influenced by immunerelated signaling cascades. Specifically, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) [21] , JAK-STAT1 [22][23] , TGF-β1-Smad3 signaling pathways have been implicated in the delicate orchestration of ferroptosis [24] . This interplay underscores the complex interplay among metabolism, redox biology, and immunity in shaping the fate of cells undergoing ferroptosis.…”

“…The main substrate of lipid peroxidation, PUFAs, are also closely associated with cGAS-STING signaling transduction. Through molecular docking analysis and in vitro experiments, Vila et al demonstrated that PUFAs specifically bond to the cGAMP-binding domain of STING, thereby blocking downstream TBK1 and IRF3 phosphorylation and inhibiting STING-mediated inflammatory response [21] . Additionally, STING may impede the formation of PUFAs by inhibiting the fatty acid desaturase 2-associated desaturation activity [21] , thereby hindering the occurrence of ferroptosis [64] .…”

“…Through molecular docking analysis and in vitro experiments, Vila et al demonstrated that PUFAs specifically bond to the cGAMP-binding domain of STING, thereby blocking downstream TBK1 and IRF3 phosphorylation and inhibiting STING-mediated inflammatory response [21] . Additionally, STING may impede the formation of PUFAs by inhibiting the fatty acid desaturase 2-associated desaturation activity [21] , thereby hindering the occurrence of ferroptosis [64] . In summary, intracellular lipid peroxidation substrates and products may impede the cGAS-STING signaling pathway, while STING may hinder ferroptosis by disrupting the PUFA synthesis.…”

Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes

“…First, multiple post-translational modifications influence signaling output (42)(43)(44). Second, STING can be directly activated by bacterial cyclic di-nucleotides (45,46), while its activation is skewed by alternative di-nucleotides (16) or other metabolites (47). Third, co-sensors, co-factors and alternative upstream STING activators have been described, that can operate in cell type-specific manners (23,(48)(49)(50).…”