2. Academic Validation
  3. 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

  • Nat Commun. 2018 Dec 17;9(1):5338. doi: 10.1038/s41467-018-07750-5.
Sylvain Normand 1,  Nadine Waldschmitt 1 2,  Andreas 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 9,  Charlotte Scott 8 9,  Anthony Segal 4,  Serge Amselem 5 6,  David Hot 1,  Sonia Karabina 5 6,  Erwin Bohn 10,  Bernhard Ryffel 11,  Lionel F Poulin 1,  Thomas A Kufer 12,  Mathias Chamaillard 13
Affiliations

Affiliations

  • 1 University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France.
  • 2 Technische Universität München, Chair of Nutrition and Immunology, 85350, Freising-Weihenstephan, Germany.
  • 3 Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
  • 4 Division of Medicine, University College London, WC1E 6BT, London, UK.
  • 5 Sorbonne Universités, UPMC Univ Paris 06, UMR_S 933, F-75012, Paris, France.
  • 6 Inserm, UMR_S 933, F-75012, Paris, France.
  • 7 Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
  • 8 Laboratory of Immunoregulation, VIB Inflammation Research Center, 9052, Ghent, Belgium.
  • 9 Department of Internal Medicine, Ghent University, Ghent, 9000, Belgium.
  • 10 Interfakultaeres Institut für Mikrobiologie und Infektionsmedizin, Eberhard Karl Universitat Tuebingen, 72076, Tuebingen, Germany.
  • 11 CNRS, Orléans University, INEM, UMR 7355, F-45071, Orléans, France.
  • 12 Department of Immunology, Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
  • 13 University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France. [email protected].
PMID: 30559449 DOI: 10.1038/s41467-018-07750-5
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.

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