Innate immune receptor NOD2 mediates LGR5 + intestinal stem cell protection against ROS cytotoxicity via mitophagy stimulation

Antonin Levy (1, 2, 3, 4) , Aline Stedman (2) , Eric Deutsch (4, 1) , Françoise Donnadieu (2) , Herbert W Virgin (5) , Philippe Sansonetti (2, 6) , Giulia Nigro (2)

1 RaMo-IT - Radiothérapie Moléculaire et Innovation Thérapeutique
2 Pathogénie microbienne moléculaire
3 ED562 - BioSPC - École Doctorale Bio Sorbonne Paris Cité [Paris]
4 Département de radiothérapie [Gustave Roussy]
5 Washington University School of Medicine in St. Louis
6 Collège de France - Chaire Microbiologie et Maladies infectieuses

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 κB (NF-κB)-independent pathway.

Mots clés: LGR5 intestinal stem cells; NOD2; ROS; autophagy; muramyl dipeptide

Domaines: Biologie cellulaire

Antonin Levy, Aline Stedman, Eric Deutsch, Françoise Donnadieu, Herbert W Virgin, et al.. Innate immune receptor NOD2 mediates LGR5 + intestinal stem cell protection against ROS cytotoxicity via mitophagy stimulation. Proceedings of the National Academy of Sciences of the United States of America, 2020, 117 (4), pp.1994-2003. ⟨10.1073/pnas.1902788117⟩. ⟨pasteur-02546675⟩