open access publication

Article, 2024

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

iScience, ISSN 2589-0042, Volume 27, 3, Page 109173, 10.1016/j.isci.2024.109173

Contributors

Becker, Björn 0000-0003-0057-8622 [1] Wottawa, Felix 0000-0002-0625-8649 [2] Bakr, Mohamed [2] Koncina, Eric [3] Mayr, Lisa [4] Kugler, Julia [2] Yang, Guang [2] Windross, Samuel Joseph [5] Neises, Laura 0000-0002-5435-2277 [1] Mishra, Neha 0000-0002-7436-1066 [2] Harris, Danielle [2] Tran, Florian [2] Welz, Lina [2] Schwärzler, Julian 0000-0001-9939-7324 [4] Bánki, Zoltán 0000-0002-3826-5800 [4] Stengel, Stephanie T [2] Ito, Go [6] Krötz, Christina [1] Coleman, Olivia I [7] Jaeger, Christian [3] Haller, Dirk [7] [8] Paludan, Søren Riis 0000-0001-9180-4060 [5] Blumberg, Richard Steven [9] [10] Kaser, Arthur [11] [12] Cicin-Sain, Luka 0000-0003-3978-778X [13] Schreiber, Stefan [2] Adolph, Timon Erik 0000-0002-4736-830X [4] Letellier, Elisabeth 0000-0001-8242-9393 [3] Rosenstiel, Philip Caspar 0000-0002-9692-8828 (Corresponding author) [2] Meiser, Johannes 0000-0002-9093-6210 (Corresponding author) [1] Aden, Konrad A 0000-0003-3482-7316 (Corresponding author) [2]

Affiliations

  1. [1] Luxembourg Institute of Health
    2. [NORA names: Luxembourg; Europe, EU; OECD];
  2. [2] University Hospital Schleswig-Holstein
    3. [NORA names: Germany; Europe, EU; OECD];
  3. [3] University of Luxembourg
    4. [NORA names: Luxembourg; Europe, EU; OECD];
  4. [4] Innsbruck Medical University
    5. [NORA names: Austria; Europe, EU; OECD];
  5. [5] Aarhus University
    6. [NORA names: AU Aarhus University; University; Denmark; Europe, EU; Nordic; OECD];

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.

Keywords

ER stress, GSH, IBD, IBD severity, NADPH, NADPH metabolism, STING function, acid uptake, amino, amino acid uptake, bacterial infections, bowel disease, cGAS-STING, cGAS-STING signaling, causality, cells, chronic ER stress, chronic relapsing inflammation, control, data, dataset, defense control, disease, endoplasmic reticulum, enteritis, epithelial cells, epithelial responses, experimental enteritis, function, gastrointestinal tract, gut, gut inflammation, immune response, infection, inflammation, inflammatory bowel disease, innate immune response, intestinal epithelial cells, intestinal inflammation, limitations, metabolic consequences, metabolic phenotype, metabolism, mitochondrial one-carbon metabolism, model, molecular causality, one-carbon metabolism, pathophysiology, pathophysiology of IBD, patient datasets, patients, phenotype, polarization, relapsing inflammation, response, reticulum, serine, serine limitation, serine metabolism, severity, signal, stress, therapy, therapy response, tract, uptake, virus, virus control

Funders

  • FWF Austrian Science Fund
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • European Research Council
  • Deutsche Forschungsgemeinschaft
  • Federal Ministry of Education and Research
  • Wilhelm Sander Stiftung
  • Else Kröner-Fresenius-Stiftung
  • Fonds National de la Recherche
  • European Commission
  • Federal Ministry of Food and Agriculture

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