Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens

Sylvain Normand (1) , Nadine Waldschmitt (1, 2) , Andre Neerincx (3) , Ruben Julio Martinez-Torres (4) , Camille Chauvin (1) , Aurélie Couturier-Maillard (1) , Olivier Boulard (1) , Laetitia Cobret (5, 6) , Fawaz Awad (5, 6) , Ludovic Huot (1) , Andre Ribeiro-Ribeiro (4) , Katja Lautz (7) , Richard Ruez (1) , Myriam Delacre (1) , Clovis Bondu (1) , Martin Guilliams (8) , Charlotte L. Scott (8) , Anthony Segal (4) , Serge Amselem (5, 6, 9) , David Hot (1) , Sonia Karabina (5, 6) , Erwin Bohn (10) , Bernhard Ryffel (11, 12) , Lionel Poulin (1) , Thomas A Kufer (13) , Mathias Chamaillard (1)

1 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
2 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
3 CAM - University of Cambridge [UK]
4 UCL - University College of London [London]
5 SU FM - Sorbonne Université - Faculté de Médecine
6 U933 - Maladies génétiques d'expression pédiatrique
7 University of Cologne
8 UGENT - Universiteit Gent = Ghent University
9 CHU Trousseau [APHP]
10 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
11 INEM - Immunologie et Neurogénétique Expérimentales et Moléculaires
12 UO - Université d'Orléans
13 University of Hohenheim

Mutations in the nucleotide-binding oligomerization domain protein 12 (NLRP12) cause recurrent episodes of serosal inflammation. Here we show that NLRP12 efficiently sequesters HSP90 and promotes K48-linked ubiquitination and degradation of NOD2 in response to bacterial muramyl dipeptide (MDP). This interaction is mediated by the linker-region proximal to the nucleotide-binding domain of NLRP12. Consequently, the disease-causing NLRP12 R284X mutation fails to repress MDP-induced NF-κB and subsequent activity of the JAK/STAT signaling pathway. While NLRP12 deficiency renders septic mice highly susceptible towards MDP, a sustained sensing of MDP through NOD2 is observed among monocytes lacking NLRP12. This loss of tolerance in monocytes results in greater colonization resistance towards Citrobacter rodentium. Our data show that this is a consequence of NOD2-dependent accumulation of inflammatory mononuclear cells that correlates with induction of interferon-stimulated genes. Our study unveils a relevant process of tolerance towards the gut microbiota that is exploited by an attaching/effacing enteric pathogen.

Domaines: Immunologie

Sylvain Normand, Nadine Waldschmitt, Andre Neerincx, Ruben Julio Martinez-Torres, Camille Chauvin, et al.. Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens. Nature Communications, 2018, 9, pp.5338. ⟨10.1038/s41467-018-07750-5⟩. ⟨hal-01976051⟩