The bacterial receptor NOD2 mediates LGR5+ intestinal stem cells protection against irradiation via mitophagy activation

Abstract Background The NOD2 agonist muramyl-dipeptide (MDP), a peptidoglycan motif common to all bacteria, supports LGR5+ intestinal stem cells (ISCs) survival through NOD2 activation upon an otherwise lethal oxidative-stress-mediated signal. Yet the underlying protective mechanisms remains unknown. Methods Irradiation was used as stressor and primarily murine-derived intestinal organoids as a model system. Results MDP induced a strong reduction of total and mitochondrial reactive oxygen species (ROS) within ISCs, which was associated with mitophagy induction. ATG16L1 KO and NOD2 KO organoids did not benefit from the MDP-induced cytoprotection. We showed the MDP-dependent induction of ISC mitophagy upon stress in vivo. Conclusions In LGR5+ ISCs, NOD2 allows irradiation-generated ROS clearance through ATG16L1-activated mitophagy. Legal entity responsible for the study The authors. Funding This work was supported by European Research Council (ERC) advanced grant 339579-DECRYPT to P.J.S and by French National Research Agency (ANR) grant 17-CE14-0022 (i-Stress) to P.S.. A.L. was personally funded by: i) Poste d’Accueil INSERM and ii) Soutien pour la formation a la recherche translationnelle en cancerologie (ITMO Cancer, INCa - Plan Cancer 2014-2019, allocation number: ASC17040JSA). Disclosure All authors have declared no conflicts of interest.