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Serine metabolism is crucial for cGAS-STING signaling and viral defense control in the gut.

ABSTRACT: Inflammatory bowel diseases are characterized by the chronic relapsing inflammation of the gastrointestinal tract. While the molecular causality between endoplasmic reticulum (ER) stress and intestinal inflammation is widely accepted, the metabolic consequences of chronic ER stress on the pathophysiology of IBD remain unclear. By using in vitro, in vivo models, and patient datasets, we identified a distinct polarization of the mitochondrial one-carbon metabolism and a fine-tuning of the amino acid uptake in intestinal epithelial cells tailored to support GSH and NADPH metabolism upon ER stress. This metabolic phenotype strongly correlates with IBD severity and therapy response. Mechanistically, we uncover that both chronic ER stress and serine limitation disrupt cGAS-STING signaling, impairing the epithelial response against viral and bacterial infection and fueling experimental enteritis. Consequently, the antioxidant treatment restores STING function and virus control. Collectively, our data highlight the importance of serine metabolism to allow proper cGAS-STING signaling and innate immune responses upon gut inflammation.

SUBMITTER: Becker B

PROVIDER: S-EPMC10943449 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Serine metabolism is crucial for cGAS-STING signaling and viral defense control in the gut.

Becker Björn B Wottawa Felix F Bakr Mohamed M Koncina Eric E Mayr Lisa L Kugler Julia J Yang Guang G Windross Samuel J SJ Neises Laura L Mishra Neha N Harris Danielle D Tran Florian F Welz Lina L Schwärzler Julian J Bánki Zoltán Z Stengel Stephanie T ST Ito Go G Krötz Christina C Coleman Olivia I OI Jaeger Christian C Haller Dirk D Paludan Søren R SR Blumberg Richard R Kaser Arthur A Cicin-Sain Luka L Schreiber Stefan S Adolph Timon E TE Letellier Elisabeth E Rosenstiel Philip P Meiser Johannes J Aden Konrad K

iScience 20240208 3

Inflammatory bowel diseases are characterized by the chronic relapsing inflammation of the gastrointestinal tract. While the molecular causality between endoplasmic reticulum (ER) stress and intestinal inflammation is widely accepted, the metabolic consequences of chronic ER stress on the pathophysiology of IBD remain unclear. By using <i>in vitro</i>, <i>in vivo</i> models, and patient datasets, we identified a distinct polarization of the mitochondrial one-carbon metabolism and a fine-tuning o ...[more]

PMID: 38496294

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Project description:The intestinal mucosa is constantly exposed to commensal microbes, opportunistic pathogens, toxins, luminal components and other environmental stimuli. The intestinal mucosa consists of multiple differentiated cellular and extracellular components that form a critical barrier, but is also equipped for efficient absorption of nutrients. Combination of genetic susceptibility and environmental factors are known as critical components involved in the pathogenesis of intestinal diseases. The innate immune system plays a critical role in the recognition and elimination of potential threats by detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). This host defense is facilitated by pattern recognition receptors (PRRs), in which the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has gained attention due to its role in sensing host and foreign double-stranded DNA (dsDNA) as well as cyclic dinucleotides (CDNs) produced by bacteria. Upon binding with dsDNA, cGAS converts ATP and GTP to cyclic GMP-AMP (cGAMP), which binds to STING and activates TANK binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3), inducing type I interferon (IFN) and nuclear factor kappa B (NF-κB)-mediated pro-inflammatory cytokines, which have diverse effects on innate and adaptive immune cells and intestinal epithelial cells (IECs). However, opposite perspectives exist regarding the role of the cGAS-STING pathway in different intestinal diseases. Activation of cGAS-STING signaling is associated with worse clinical outcomes in inflammation-associated diseases, while it also plays a critical role in protection against tumorigenesis and certain infections. Therefore, understanding the context-dependent mechanisms of the cGAS-STING pathway in the physiopathology of the intestinal mucosa is crucial for developing therapeutic strategies targeting the cGAS-STING pathway. This review aims to provide insight into recent findings of the protective and detrimental roles of the cGAS-STING pathway in intestinal diseases.

Dataset Information

Serine metabolism is crucial for cGAS-STING signaling and viral defense control in the gut.

Publications

Serine metabolism is crucial for cGAS-STING signaling and viral defense control in the gut.

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