Alternative pathways driven by STING: From innate immunity to lipid metabolism

Vila, Isabelle K.; Guha, Soumyabrata; Kalucka, Joanna; Olagnier, David; Laguette, Nadine

doi:10.1016/j.cytogfr.2022.08.006

Cited by 7 publications

(5 citation statements)

References 184 publications

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“…Finally, this study also revealed that STING agonists can bind and modulate the enzymatic activity of FADS2. Thus, this work demonstrates the existence of a negative regulatory loop between STING and FADS2, opening many questions pertaining to their respective roles in human pathologies presenting with a chronic STINGassociated inflammation [14]. Interestingly, alleles of STING not competent for the induction of interferon responses have been documented in human populations.…”

Section: Sting In Fatty Acid Metabolism: An Unexpected Rolementioning

confidence: 80%

The unexpected role of the STING protein in lipid metabolism

Vila¹,

Laguette²

2023

Comptes Rendus. Biologies

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Detection of cytosolic pathological nucleic acids is a key step for the initiation of innate immune responses. In the past decade, the stimulator of interferon genes (STING) adaptor protein has emerged as a central platform enabling the activation of inflammatory responses in the presence of cytosolic DNAs. This has prompted a plethora of approaches aiming at modulating STING activation in order to boost or inhibit inflammatory responses. However, recent work has revealed that STING is also a direct regulator of metabolic homeostasis. In particular, STING regulates lipid metabolism directly, a function that is conserved throughout evolution. This indicates that STING targeting strategies must take into consideration potential metabolic side effects that may alter disease course, but also suggests that targeting STING may open the route to novel treatments for metabolic disorders.Here we discuss recent work describing the metabolic function of STING and the implications of these findings.Résumé. La détection des acides nucléiques pathologiques cytosoliques est une étape clé pour le déclenchement des réponses immunitaires innées. Au cours de la dernière décennie, la protéine adaptatrice STING (stimulator of interferon genes) est apparue comme une plateforme centrale permettant l'activation des réponses inflammatoires en présence d'ADN cytosolique. Cela a donné lieu à une multitude d'approches visant à moduler l'activation de STING afin de stimuler ou d'inhiber les réponses inflammatoires. Cependant, des travaux récents ont révélé que STING est également un régulateur direct de l'homéostasie métabolique. En particulier, STING régule directement le métabolisme des lipides, une fonction qui est conservée au cours de l'évolution. Cela indique que les stratégies de ciblage de STING doivent prendre en compte les effets secondaires métaboliques potentiels qui peuvent modifier l'évolution de la maladie, mais suggère également la possibilité que le ciblage de STING puisse ouvrir la voie à de nouvelles façons de traiter les pathologies présentant une composante métabolique. Nous discutons ici les travaux récents décrivant la fonction métabolique de STING et les implications de ces résultats.

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Section: Sting In Fatty Acid Metabolism: An Unexpected Rolementioning

confidence: 80%

The unexpected role of the STING protein in lipid metabolism

Vila¹,

Laguette²

2023

Comptes Rendus. Biologies

Self Cite

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“…The results showed increased expression of STING in cases of mild and moderate degrees of steatosis compared with the absence of steatosis. This finding is logical since in these patients, STING seems to inhibit lipid homeostasis, which triggers lipogenic and proinflammatory cascades [25,42]. Indeed, this function might be relevant in the first steps of lipid accumulation in the SS stage.…”

Section: Discussionmentioning

confidence: 94%

Expression of STING in Women with Morbid Obesity and Nonalcoholic Fatty Liver Disease

et al. 2023

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Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disease. Although mostly benign, this disease can evolve into nonalcoholic steatohepatitis (NASH). The stimulator of interferon genes (STING) plays an important role in the immune response against stressed cells, but this protein may also be involved in liver lipogenesis and microbiota composition. In this study, the role of STING in NAFLD was evaluated by RT–qPCR to analyze STING mRNA abundance and by immunohistochemical analysis to evaluate protein expression in liver biopsies from a cohort composed of 69 women with morbid obesity classified according to their liver involvement (normal liver, n = 27; simple steatosis (SS), n = 26; NASH, n = 16). The results showed that STING mRNA expression in the liver increases with the occurrence of NAFLD, specifically in the SS stage in which the degree of steatosis is mild or moderate. Protein analysis corroborated these results. Positive correlations were observed among hepatic STING mRNA abundance and gamma-glutamyl transferase and alkaline phosphatase levels, hepatic Toll-like receptor 9 expression and some circulating microbiota-derived bile acids. In conclusion, STING may be involved in the outcome and progression of NAFLD and may be related to hepatic lipid metabolism. However, further studies are needed to confirm these findings.

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“…Recently, accumulating evidence suggests the reciprocal modulation between STING and lipid metabolism. [ 31 , 32 ] Since RIFSP‐2 directly restrained SCD1 and modulated neutral lipid droplets, we further investigated whether alteration of lipid profiles by RIFSP‐2 interfered with STING activation in response to irradiation. Volcano plot of lipid class reflected that administration of RIFSP‐2 resulted in obvious change of cardiolipins (CL), diglyceride (DG), lyso‐phosphatidylcholine (LPC), lyso‐phosphatidylethanolamine (LPE), monogalactosyldiacylglycerols (MGDG), methylphosphocholine (MePC), phosphatidylcholines (PC), phosphatidylethanolamines (PE), phosphatidylethanol (PEt), phosphatidylmethanol (PMe) and triglyceride (TG) (Figure 4E ).…”

Section: Resultsmentioning

confidence: 99%

A Frog Skin‐Derived Peptide Targeting SCD1 Exerts Radioprotective Effects Against Skin Injury by Inhibiting STING‐Mediated Inflammation

Geng,

Zhong,

Yang

et al. 2024

Advanced Science

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The extensive application of nuclear technology has increased the potential of uncontrolled radiation exposure to the public. Since skin is the largest organ, radiation‐induced skin injury remains a serious medical concern. Organisms evolutionally develop distinct strategies to protect against environment insults and the related research may bring novel insights into therapeutics development. Here, 26 increased peptides are identified in skin tissues of frogs (Pelophylax nigromaculatus) exposed to electron beams, among which four promoted the wound healing of irradiated skin in rats. Specifically, radiation‐induced frog skin peptide‐2 (RIFSP‐2), from histone proteolysis exerted membrane permeability property, maintained cellular homeostasis, and reduced pyroptosis of irradiated cells with decreased TBK1 phosphorylation. Subsequently, stearyl‐CoA desaturase 1 (SCD1) is identified, a critical enzyme in biogenesis of monounsaturated fatty acids (MUFAs) as a direct target of RIFSP‐2 based on streptavidin‐biotin system. The lipidomic analysis further assured the restrain of MUFAs biogenesis by RIFSP‐2 following radiation. Moreover, the decreased MUFA limited radiation‐induced and STING‐mediated inflammation response. In addition, genetic depletion or pharmacological inhibition of STING counteracted the decreased pyroptosis by RIFSP‐2 and retarded tissue repair process. Altogether, RIFSP‐2 restrains radiation‐induced activation of SCD1‐MUFA‐STING axis. Thus, the stress‐induced amphibian peptides can be a bountiful source of novel radiation mitigators.

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Alternative pathways driven by STING: From innate immunity to lipid metabolism

Cited by 7 publications

References 184 publications

The unexpected role of the STING protein in lipid metabolism

The unexpected role of the STING protein in lipid metabolism

Expression of STING in Women with Morbid Obesity and Nonalcoholic Fatty Liver Disease

A Frog Skin‐Derived Peptide Targeting SCD1 Exerts Radioprotective Effects Against Skin Injury by Inhibiting STING‐Mediated Inflammation

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