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Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection
Stephen E Girardin1, Ivo G Boneca, Jérôme Viala
1Unité de Pathogénie Microbienne Moléculaire, INSERM U389, Paris Cedex 15, France.
Abstract:
Nod2 activates the NF-kappaB pathway following intracellular stimulation by bacterial products. Recently, mutations in Nod2 have been shown to be associated with Crohn's disease, suggesting a role for bacteria-host interactions in the etiology of this disorder. We show here that Nod2 is a general sensor of peptidoglycan through the recognition of muramyl dipeptide (MDP), the minimal bioactive peptidoglycan motif common to all bacteria. Moreover, the 3020insC frameshift mutation, the most frequent Nod2 variant associated with Crohn's disease patients, fully abrogates Nod2-dependent detection of peptidoglycan and MDP. Together, these results impact on the understanding of Crohn's disease development. Additionally, the characterization of Nod2 as the first pathogen-recognition molecule that detects MDP will help to unravel the well known biological activities of this immunomodulatory compound.
Insights
NOD2 (Nucleotide-binding oligomerization domain-containing protein 2) detects bacterial peptidoglycan via muramyl dipeptide (MDP). A common Crohn's disease mutation in NOD2 prevents this detection, impacting disease understanding.
Area of Science:
- Microbiology
- Immunology
- Genetics
Background:
- NOD2 (Nucleotide-binding oligomerization domain-containing protein 2) is an intracellular receptor involved in immune responses to bacterial products.
- Mutations in NOD2 are linked to Crohn's disease, suggesting a role for bacterial interactions in its development.
Purpose of the Study:
- To identify the specific bacterial component recognized by NOD2.
- To investigate the functional impact of a common NOD2 mutation found in Crohn's disease patients.
Main Methods:
- Biochemical assays to test NOD2 recognition of bacterial peptidoglycan components.
- Analysis of the NOD2 3020insC frameshift mutation's effect on peptidoglycan and muramyl dipeptide (MDP) detection.
Main Results:
- NOD2 recognizes muramyl dipeptide (MDP), a common motif in bacterial peptidoglycan, acting as a general sensor for bacteria.
- The 3020insC mutation, frequently observed in Crohn's disease, completely abolishes NOD2's ability to detect peptidoglycan and MDP.
Conclusions:
- NOD2 functions as a key sensor for bacterial peptidoglycan via MDP recognition.
- The identified NOD2 mutation disrupts this sensing mechanism, contributing to the understanding of Crohn's disease pathogenesis.
- This study characterizes NOD2 as the first identified MDP-detecting pathogen-recognition molecule, aiding research into MDP's biological functions.