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

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 and Mathias Chamaillard ()
Additional contact information
Sylvain Normand: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille
Nadine Waldschmitt: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille
Andreas Neerincx: University of Cambridge
Ruben Julio Martinez-Torres: University College London
Camille Chauvin: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille
Aurélie Couturier-Maillard: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille
Olivier Boulard: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille
Laetitia Cobret: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 933
Fawaz Awad: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 933
Ludovic Huot: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille
Andre Ribeiro-Ribeiro: University College London
Katja Lautz: University of Cologne
Richard Ruez: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille
Myriam Delacre: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille
Clovis Bondu: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille
Martin Guilliams: VIB Inflammation Research Center
Charlotte Scott: VIB Inflammation Research Center
Anthony Segal: University College London
Serge Amselem: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 933
David Hot: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille
Sonia Karabina: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 933
Erwin Bohn: Eberhard Karl Universitat Tuebingen
Bernhard Ryffel: CNRS, Orléans University, INEM, UMR 7355
Lionel F. Poulin: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille
Thomas A. Kufer: University of Hohenheim
Mathias Chamaillard: University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d′Infection et d′Immunité de Lille

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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 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.

Date: 2018
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DOI: 10.1038/s41467-018-07750-5

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