ArticleThe Journal of biological chemistry2012
Proteasomal degradation of Nod2 protein mediates tolerance to bacterial cell wall components.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 90 citations in OpenAlex.
- Pathogenetic Therapy of Psoriasis by Muramyl Peptide.Frontiers in immunology · 2019Trial
- Multi-omics characterization of Yao syndrome identifies three pathophysiological axes and disease-specific divergence from Blau syndrome.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Histone demethylase JMJD2D promotes macrophage IL-12b expression and contributes to host defense againstFrontiers in cellular and infection microbiology · 2026Article
- Immunological analysis of Blau syndrome, a unique autoinflammatory state.Frontiers in immunology · 2026Review
- Clinical description, genetic analysis and characterization of two NLRP12 heterozygous VUS variants.Frontiers in immunology · 2026Article
- A Novel Role of Neutrophil Elastase in Podocyte Dysfunction Induced by High Glucose, PMA, and MDP.Journal of cellular physiology · 2025Article
- DUBA sustains the stability of NOD2 and RIPK2 to enhance innate immune responses.Cell death and differentiation · 2025Article
- Nucleotide-Binding Oligomerization Domain 2 in Signaling, Immunity, and Mycobacterial Infection.Immunity, inflammation and disease · 2025Review
- The Multiple Roles of Heat Shock Proteins in the Development of Inflammatory Bowel Disease.Current molecular medicine · 2025Review
- RIPK2 Is Crucial for the Microglial Inflammatory Response to Bacterial Muramyl Dipeptide but Not to Lipopolysaccharide.International journal of molecular sciences · 2024Article
- N4BP3 facilitates NOD2-MAPK/NF-κB pathway in inflammatory bowel disease through mediating K63-linked RIPK2 ubiquitination.Cell death discovery · 2024Article
- RIPK2 is crucial for the microglial inflammatory response to bacterial muramyl dipeptide but not to lipopolysaccharide.bioRxiv : the preprint server for biology · 2024Article
- Deubiquitination of RIPK2 by OTUB2 augments NOD2 signalling and protective effects in intestinal inflammation.Clinical and translational medicine · 2024Article
- NOD1 and NOD2: Essential Monitoring Partners in the Innate Immune System.Current issues in molecular biology · 2024Review
- Role and molecular mechanism of NOD2 in chronic non-communicable diseases.Journal of molecular medicine (Berlin, Germany) · 2024Review
- E3 ligase SOCS3 regulates NOD2 expression by ubiquitin proteasome system in lung cancer progression.Cellular oncology (Dordrecht, Netherlands) · 2024Article
- The Effects of Housing on Growth, Immune Function and Antioxidant Status of Young Female Lambs in Cold Conditions.Animals : an open access journal from MDPI · 2024Article
- Inhibition of specific signaling pathways rather than epigenetic silencing of effector genes is the leading mechanism of innate tolerance.Frontiers in immunology · 2023Article
- Multifaceted roles and regulation of nucleotide-binding oligomerization domain containing proteins.Frontiers in immunology · 2023Review
- NOD2 in monocytes negatively regulates macrophage development through TNFalpha.Frontiers in immunology · 2023Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The innate immune system serves as the first line of defense by detecting microbes and initiating inflammatory responses. Although both Toll-like receptor (TLR) and nucleotide binding domain and leucine-rich repeat (NLR) proteins are important for this process, their excessive activation is hazardous to hosts; thus, tight regulation is required. Endotoxin tolerance is refractory to repeated lipopolysaccharide (LPS) stimulation and serves as a host defense mechanism against septic shock caused by an excessive TLR4 response during gram-negative bacterial infection. Gram-positive bacteria as well as their cell wall components also induce shock. However, the mechanism underlying tolerance is not understood. Here, we show that activation of Nod2 by its ligand, muramyl dipeptide (MDP) in the bacterial cell wall, induces rapid degradation of Nod2, which confers MDP tolerance in vitro and in vivo. Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation. Upon MDP stimulation, Hsp90 rapidly dissociates from Nod2, which subsequently undergoes ubiquitination and proteasomal degradation. The SOCS-3 protein induced by Nod2 activation further facilitates this degradation process. Therefore, Nod2 protein stability is a key factor in determining responsiveness to MDP stimulation. This indicates that TLRs and NLRs induce a tolerant state through distinct molecular mechanisms that protect the host from septic shock.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.