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
Date
2018-12-17
Authors
Normand, Sylvain
Waldschmitt, Nadine
Neerincx, Andreas
Martinez-Torres, Ruben Julio
Chauvin, Camille
Couturier-Maillard, Aurélie
Boulard, Olivier
Cobret, Laetitia
Awad, Fawaz
Huot, Ludovic
Journal Title
Journal ISSN
Volume Title
Publisher
Springer
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 nucleotidebinding
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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Citation
Normand, S., Waldschmitt, N., Neerincx, A. et al. Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens. Nat Commun 9, 5338 (2018) doi:10.1038/s41467-018-07750-5