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

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

  • iScience. 2024 Feb 8;27(3):109173. doi: 10.1016/j.isci.2024.109173.
Björn Becker 1,  Felix Wottawa 2,  Mohamed Bakr 2,  Eric Koncina 3,  Lisa Mayr 4,  Julia Kugler 2,  Guang Yang 2,  Samuel J Windross 5,  Laura Neises 1,  Neha Mishra 2,  Danielle Harris 2,  Florian Tran 2 6,  Lina Welz 2 6,  Julian Schwärzler 4,  Zoltán Bánki 7,  Stephanie T Stengel 2,  Go Ito 8,  Christina Krötz 1,  Olivia I Coleman 9,  Christian Jaeger 10,  Dirk Haller 9 11,  Søren R Paludan 5,  Richard Blumberg 12,  Arthur Kaser 13,  Luka Cicin-Sain 14,  Stefan Schreiber 2 6,  Timon E Adolph 4,  Elisabeth Letellier 3,  Philip Rosenstiel 2,  Johannes Meiser 1,  Konrad Aden 2 6
Affiliations

Affiliations

  • 1 Luxembourg Institute of Health, Department of Cancer Research, Luxembourg, Luxembourg.
  • 2 Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
  • 3 Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, Université du Luxembourg, Luxembourg, Luxembourg.
  • 4 Department of Internal Medicine I, Gastroenterology, Hepatology, Metabolism & Endocrinology, Medical University of Innsbruck, Innsbruck, Austria.
  • 5 Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • 6 Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
  • 7 Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Innsbruck, Austria.
  • 8 Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
  • 9 Chair of Nutrition and Immunology, TUM School of Life Sciences, Technical University of Munich, Luxembourg, Luxembourg.
  • 10 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
  • 11 ZIEL-Institute for Food & Health, Technical University of Munich, 85354 Freising, Germany.
  • 12 Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 13 Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, England, UK.
  • 14 Helmholtz Zentrum für Infektionsforschung, Braunschweig, Germany.
PMID: 38496294 DOI: 10.1016/j.isci.2024.109173
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

Microbial metabolism; Virology.

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