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

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.

Single-Cell Transcriptome Profiling of Immune Cell Repertoire of the Atlantic Cod Which Naturally Lacks the Major Histocompatibility Class II System

“…Erythrocytes were identified by the high expression of multiple haemoglobin genes ( HBB ). Erythrocytes also expressed immune related genes, such as NACHT, LRR, and PYD domain-containing protein 12 ( NLRP12 ), a potent mitigator of inflammation ( 37 ). Expression of thrombospondin-1 ( THBS1 ), platelet glycoprotein Ib alpha chain ( GP1BA ), and thrombopoietin receptor ( MPL ) genes was used to identify the thrombocytes.…”

The Ubiquitin Code of NODs Signaling Pathways in Health and Disease

“…Consequently, SOCS3 negatively regulates NOD2 signaling. Akin to the previous study, Normand et al (53) found that NLRP12 directly interacted with NOD2 through its linker region (residues 200–224). Even if the specific NOD2 region involved in the interaction was not reported, they confirmed that NOD2 was found in complex with the heat-shock chaperon Hsp90.…”

NOD Signaling and Cell Death

“…NLRP12 activation leads to the sequestering of HSP90, which in turn promotes K48-linked ubiquitination and degradation of NOD2 in response to MDP. The significance of NLRP12 as a regulator of NOD2 signaling was highlighted by the finding that LPS-primed NLRP12-deficient mice are highly susceptible to secondary challenge by bacterial MDP (Normand et al, 2018).…”