iScience (Mar 2024)
Serine metabolism is crucial for cGAS-STING signaling and viral defense control in the gut
- Björn Becker,
- Felix Wottawa,
- Mohamed Bakr,
- Eric Koncina,
- Lisa Mayr,
- Julia Kugler,
- Guang Yang,
- Samuel J. Windross,
- Laura Neises,
- Neha Mishra,
- Danielle Harris,
- Florian Tran,
- Lina Welz,
- Julian Schwärzler,
- Zoltán Bánki,
- Stephanie T. Stengel,
- Go Ito,
- Christina Krötz,
- Olivia I. Coleman,
- Christian Jaeger,
- Dirk Haller,
- Søren R. Paludan,
- Richard Blumberg,
- Arthur Kaser,
- Luka Cicin-Sain,
- Stefan Schreiber,
- Timon E. Adolph,
- Elisabeth Letellier,
- Philip Rosenstiel,
- Johannes Meiser,
- Konrad Aden
Affiliations
- Björn Becker
- Luxembourg Institute of Health, Department of Cancer Research, Luxembourg, Luxembourg
- Felix Wottawa
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Mohamed Bakr
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Eric Koncina
- Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, Université du Luxembourg, Luxembourg, Luxembourg
- Lisa Mayr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Metabolism & Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
- Julia Kugler
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Guang Yang
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Samuel J. Windross
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Laura Neises
- Luxembourg Institute of Health, Department of Cancer Research, Luxembourg, Luxembourg
- Neha Mishra
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Danielle Harris
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Florian Tran
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Lina Welz
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Metabolism & Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
- Zoltán Bánki
- Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Innsbruck, Austria
- Stephanie T. Stengel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Go Ito
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Christina Krötz
- Luxembourg Institute of Health, Department of Cancer Research, Luxembourg, Luxembourg
- Olivia I. Coleman
- Chair of Nutrition and Immunology, TUM School of Life Sciences, Technical University of Munich, Luxembourg, Luxembourg
- Christian Jaeger
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Dirk Haller
- Chair of Nutrition and Immunology, TUM School of Life Sciences, Technical University of Munich, Luxembourg, Luxembourg; ZIEL-Institute for Food & Health, Technical University of Munich, 85354 Freising, Germany
- Søren R. Paludan
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Richard Blumberg
- Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Arthur Kaser
- Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, England, UK
- Luka Cicin-Sain
- Helmholtz Zentrum für Infektionsforschung, Braunschweig, Germany
- Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Timon E. Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Metabolism & Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
- Elisabeth Letellier
- Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, Université du Luxembourg, Luxembourg, Luxembourg
- Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Corresponding author
- Johannes Meiser
- Luxembourg Institute of Health, Department of Cancer Research, Luxembourg, Luxembourg; Corresponding author
- Konrad Aden
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Corresponding author
- Journal volume & issue
-
Vol. 27,
no. 3
p. 109173
Abstract
Summary: 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.
