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- Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens
Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens
Auteurs
Sylvain Normand, Nadine Waldschmitt, Andreas Neerincx, Ruben Julio Martinez-Torres, Camille Chauvin, Aurélie Couturier-Maillard, Olivier Boulard, Laetitia Cobret, Fawaz Awad, Ludovic Huot, Andre Ribeiro-Ribeiro, Katja Lautz, Richard Ruez, Myriam Delacre, Clovis Bondu, Martin Guilliams, Charlotte Scott, Anthony Segal, Serge Amselem, David Hot, Sonia Karabina, Erwin Bohn, Bernhard Ryffel, Lionel F. Poulin, Thomas A. Kufer, Mathias Chamaillard
Résumé
Abstract
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