Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 4, Pages 1994-2003Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1902788117
Keywords
LGR5 intestinal stem cells; NOD2; ROS; autophagy; muramyl dipeptide
Categories
Funding
- European Research Council [339579-DECRYPT]
- French National Research Agency (ANR) [17-CE14-0022]
- Poste d'Accueil INSERM
- Soutien pour la Formation a la Recherche Translationnelle en Cancerologie (ITMO Cancer, INCa-Plan Cancer 2014-2019, Allocation) [ASC17040JSA]
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The nucleotide-binding oligomerization domain-containing protein 2 (NOD2) agonist muramyl dipeptide (MDP), a peptidoglycan motif common to all bacteria, supports leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)(+) intestinal stem cell (ISC) survival through NOD2 activation upon an otherwise lethal oxidative stress-mediated signal. However, the underlying protective mechanisms remain unknown. Here, using irradiation as stressor and primarily murine-derived intestinal organoids as a model system, we show that MDP induced a significant reduction of total and mitochondrial reactive oxygen species (ROS) within ISCs, which was associated with mitophagy induction. ATG16L1 knockout (KO) and NOD2 KO organoids did not benefit from the MDP-induced cytoprotection. We confirmed the MDP-dependent induction of ISC mitophagy upon stress in vivo. These findings elucidate the NOD2-mediated mechanism of cytoprotection involving the clearance of the lethal excess of ROS molecules through mitophagy, triggered by the coordinated activation of NOD2 and ATG16L1 by a nuclear factor kappa B (NF-kappa B)-independent pathway.
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