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

Nat Commun 2018 12 17;9(1):5338. Epub 2018 Dec 17.

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.

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.

Download full-text PDF

Source
http://www.nature.com/articles/s41467-018-07750-5
Publisher Site
http://dx.doi.org/10.1038/s41467-018-07750-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297353PMC
December 2018
49 Reads

Publication Analysis

Top Keywords

degradation nod2
8
nlrp12
7
septic mice
4
mice highly
4
renders septic
4
deficiency renders
4
pathway nlrp12
4
highly susceptible
4
nlrp12 deficiency
4
mdp sustained
4
nod2 observed
4
observed monocytes
4
mdp nod2
4
sensing mdp
4
signaling pathway
4
sustained sensing
4
susceptible mdp
4
activity jak/stat
4
consequently disease-causing
4
disease-causing nlrp12
4

References

(Supplied by CrossRef)

I Jeru et al.
Proc. Natl Acad. Sci. USA 2008

Z Ye et al.
Mol. Cell. Biol. 2008

KL Williams et al.
J. Biol. Chem. 2005

IC Allen et al.
Immunity 2012

MH Zaki et al.
Cancer Cell. 2011

GI Vladimer et al.
Immunity 2012

JB Kaper et al.
Nat. Rev. Microbiol. 2004

R Mundy et al.
Cell Microbiol. 2005

LF Poulin et al.
Vet. Microbiol. 2017

YG Kim et al.
Immunity 2008

Similar Publications