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

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Date
2018-12-17
Author
Normand, Sylvain
Waldschmitt, Nadine
Neerincx, Andreas
Martinez-Torres, Ruben Julio
Chauvin, Camille
Couturier-Maillard, Aurélie
Boulard, Olivier
Cobret, Laetitia
Awad, Fawaz
Huot, Ludovic
Ribeiro-Ribeiro, Andre
Lautz, Katja
Ruez, Richard
Delacre, Myriam
Bondu, Clovis
Guilliams, Martin
Scott, Charlotte
Segal, Anthony
Amselem, Serge
Hot, David
Karabina, Sonia
Bohn, Erwin
Ryffel, Bernhard
Poulin, Lionel F.
Kufer, Thomas A.
Chamaillard, Mathias
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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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https://dspace.alquds.edu/handle/20.500.12213/4919
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