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

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  • 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
    Technische Universität München, Chair of Nutrition and Immunology)

  • 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
    Inserm, UMR_S 933)

  • Fawaz Awad

    (Sorbonne Universités, UPMC Univ Paris 06, UMR_S 933
    Inserm, 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
    Ghent University)

  • Charlotte Scott

    (VIB Inflammation Research Center
    Ghent University)

  • Anthony Segal

    (University College London)

  • Serge Amselem

    (Sorbonne Universités, UPMC Univ Paris 06, UMR_S 933
    Inserm, 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
    Inserm, 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)

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.

Suggested Citation

  • Sylvain Normand & Nadine Waldschmitt & Andreas Neerincx & Ruben Julio Martinez-Torres & Camille Chauvin & Aurélie Couturier-Maillard & Olivier Boulard & Laetitia Cobret & Fawaz Awad & Ludovic Huot & A, 2018. "Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07750-5
    DOI: 10.1038/s41467-018-07750-5
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