Affinage

NOD2

Nucleotide-binding oligomerization domain-containing protein 2 · UniProt Q9HC29

Length
1040 aa
Mass
115.3 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NOD2 is an intracellular innate immune pattern-recognition receptor that senses bacterial peptidoglycan and converts this detection into NF-κB- and MAPK-driven inflammatory and antibacterial responses, originally established through loss-of-function frameshift mutation (3020insC) that abrogates NF-κB activation (PMID:11385577). The proximal agonist is not muramyl dipeptide (MDP) itself but 6-O-phospho-MDP, generated when NAGK phosphorylates the N-acetylmuramic acid moiety; NAGK-deficient macrophages are completely defective in MDP sensing (PMID:36002575). Crystallographic analysis of ADP-bound NOD2 shows a closed, autoinhibited conformation maintained by inter-domain and nucleotide-mediated contacts within the NOD/NACHT domain (PMID:27283905). Upon activation, NOD2 signals through RIP2/RIPK2, whose K63-linked polyubiquitination by TRAF6/Ubc13 with TAK1, by the E3 ligase Pellino3, and by XIAP (via its BIR2 domain) drives downstream IKKγ ubiquitination and NF-κB/MAPK activation; RIP2 kinase activity is dispensable, serving instead to position the kinase domain for XIAP binding (PMID:17947236, PMID:23892723, PMID:29452636). Beyond canonical inflammation, NOD2 couples MDP sensing to ATG16L1-dependent autophagy for intracellular bacterial killing, and Crohn's-associated NOD2 variants impair this response (PMID:20637199). NOD2 also acts as a negative regulator, dampening Toll-like-receptor-driven NF-κB through induction of IRF4, a cross-regulatory function important for restraining colitis and colorectal tumorigenesis (PMID:19079230, PMID:28658623). NOD2 protein levels are tightly controlled by E3 ligases TRIM27 and Parkin, which catalyze K48-linked ubiquitination and proteasomal degradation, while p62/SQSTM1 stabilizes NOD2 oligomers (PMID:22829933, PMID:23437331, PMID:30378174). In vivo, NOD2 controls commensal bacterial load and crypt antibacterial killing in the terminal ileum, where its expression itself depends on the microbiota (PMID:19805227). Gain-of-function mutations in the NACHT domain cause Blau syndrome through ligand-independent, IFN-γ-primed NF-κB activation (PMID:25093298, PMID:28587749).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2001 High

    Established NOD2 as an innate immune sensor functioning upstream of NF-κB, with a disease-associated truncating mutation defining loss of function.

    Evidence NF-κB reporter assays comparing wild-type versus 3020insC mutant NOD2, plus genetic association analysis

    PMID:11385577

    Open questions at the time
    • Did not identify the precise physiological ligand
    • Did not define the downstream adaptor/effector cascade
  2. 2004 Medium

    Identified TAK1 as a NOD2-interacting kinase required for MDP-induced NF-κB, revealing reciprocal cross-talk via the LRR domain.

    Evidence Co-IP, dominant-negative TAK1, and NF-κB reporter assays in RICK-deficient fibroblasts

    PMID:15075345

    Open questions at the time
    • Mechanism of LRR-mediated inhibition not structurally resolved
    • Single-lab Co-IP without reciprocal genetic validation
  3. 2007 High

    Defined the ubiquitin-dependent core of NOD2 signaling, showing K63-linked polyubiquitination of RIP2 is required for IKKγ ubiquitination and NF-κB activation.

    Evidence In vitro ubiquitination assays, Co-IP, knockdown/dominant-negative in M. tuberculosis-infected and MDP-treated macrophages

    PMID:17947236

    Open questions at the time
    • Did not establish whether multiple E3 ligases act redundantly
    • Site-specific RIP2 ubiquitination not yet mapped
  4. 2007 Medium

    Showed NOD2 activation produces a specific chemokine output (CCL5/RANTES) through NF-κB rather than the interferon-β pathway.

    Evidence Murine macrophage MDP stimulation, CCL5 ELISA, NF-κB reporter, and in vivo injection

    PMID:17705131

    Open questions at the time
    • Scope of NOD2-driven chemokine repertoire not defined
    • Single-lab study
  5. 2009 High

    Reframed NOD2 as a negative regulator of innate immunity by showing MDP-induced IRF4 suppresses TLR-driven NF-κB and prevents experimental colitis.

    Evidence NOD2-deficient and transgenic mice, MDP stimulation, IRF4 analysis, DSS/TNBS colitis models

    PMID:19079230

    Open questions at the time
    • Mechanism by which NOD2 induces IRF4 not detailed
    • Cell-type-specific contributions not separated
  6. 2009 High

    Established an in vivo physiological role for NOD2 in controlling commensal load and crypt antibacterial killing, with a microbiota-dependent expression feedback loop.

    Evidence Nod2 knockout mice, terminal ileum bacterial quantification, in vitro crypt killing, germ-free reconstitution

    PMID:19805227

    Open questions at the time
    • Effector mechanism of crypt killing (e.g. specific antimicrobials) not resolved here
    • Direct link to human disease variants not tested
  7. 2010 High

    Connected NOD2 sensing to autophagy-mediated bacterial clearance via ATG16L1 and showed Crohn's variants impair this antibacterial arm.

    Evidence Gentamicin protection, confocal microscopy, RNAi of NOD2/ATG16L1, primary cells from genotyped donors

    PMID:20637199

    Open questions at the time
    • Molecular link between NOD2 and ATG16L1 recruitment not fully defined
    • Relative contribution of autophagy versus NF-κB arm not quantified
  8. 2012 Medium

    Identified TRIM27 as an E3 ligase that terminates NOD2 signaling via K48-linked ubiquitination and proteasomal degradation.

    Evidence Co-IP, ubiquitination assays, proteasome inhibition, reporter assays in HeLa

    PMID:22829933

    Open questions at the time
    • In vivo relevance not tested
    • Single-lab overexpression system
  9. 2013 High

    Added Pellino3 as a positive E3 ligase ubiquitinating RIP2 downstream of NOD2, with an in vivo colitis phenotype.

    Evidence Co-IP, in vitro ubiquitination, Pellino3 knockout mice, colitis models

    PMID:23892723

    Open questions at the time
    • Hierarchy among RIP2 E3 ligases (TRAF6, Pellino3, XIAP) unresolved
    • Ubiquitin chain linkage specificity not fully detailed
  10. 2013 Medium

    Showed p62/SQSTM1 positively regulates NOD2 by stabilizing oligomerization and preventing degradation.

    Evidence Co-IP, electron microscopy of NOD2-p62 complex, NF-κB reporter, cytokine ELISA

    PMID:23437331

    Open questions at the time
    • In vivo requirement not established
    • Single-lab study
  11. 2014 Medium

    Localized Blau syndrome gain-of-function mutations to the ATP/Mg2+-binding site and helical domain 1 of the NACHT domain, distinguishing NOD2 activation/regulation from NOD1.

    Evidence Mutational functional analysis of NOD2 constructs with comparative NOD1 mutagenesis

    PMID:25093298

    Open questions at the time
    • Structural mechanism inferred not directly visualized
    • Single-lab functional assays
  12. 2014 Medium

    Demonstrated post-transcriptional control of NOD2 by multiple miRNAs targeting its 3'UTR, with a disease-associated SNP modulating miRNA efficacy.

    Evidence 3'UTR luciferase reporters, miRNA mimics, NF-κB reporters in colonic epithelial cells

    PMID:24297055

    Open questions at the time
    • Physiological/in vivo relevance not tested
    • Relative dominance among the four miRNAs unclear
  13. 2014 Low

    Extended NOD2 signaling beyond immunity to inhibition of odontoblast differentiation via MKP-1-mediated MAPK inactivation.

    Evidence siRNA knockdown, differentiation and mineralization assays, MAPK/MKP-1 analysis in dental pulp cells

    PMID:24820666

    Open questions at the time
    • Single-lab cell-line study not independently confirmed
    • No in vivo validation
  14. 2016 High

    Provided the structural basis of NOD2 autoinhibition, showing an ADP-bound closed conformation whose interfaces are disrupted by Blau gain-of-function mutations.

    Evidence X-ray crystallography of ADP-bound rabbit NOD2 with mutational mapping

    PMID:27283905

    Open questions at the time
    • Active oligomeric (ligand-bound) state not captured
    • LRR-ligand engagement not visualized in this structure
  15. 2016 High

    Linked NOD2 to ER stress signaling, showing physical association with IRE1α/TRAF2 and requirement for ER-stress- and infection-induced inflammation.

    Evidence Genetic KO/KD cells, IRE1α kinase inhibitor, Brucella infection model, cytokine and NF-κB assays

    PMID:27007849

    Open questions at the time
    • Whether ER stress sensing requires peptidoglycan ligand unclear
    • Direct NOD2-IRE1α interaction interface not mapped
  16. 2017 Medium

    Demonstrated NOD2 suppresses colorectal tumorigenesis through IRF4-associated downregulation of TLR/NF-κB/MAPK/STAT3 signaling.

    Evidence Nod2-/- colorectal tumor model with in vitro MDP/TLR co-stimulation

    PMID:28658623

    Open questions at the time
    • Causal role of IRF4 in tumor suppression not directly tested
    • Epithelial versus immune cell contribution unresolved
  17. 2017 High

    Established causal, mutation-specific Blau syndrome mechanism: ligand-independent NF-κB activation requiring IFN-γ priming, reversible by isogenic CRISPR correction.

    Evidence Blau patient iPSC-derived macrophages, CRISPR isogenic correction/introduction, NF-κB and cytokine assays, RNA-seq

    PMID:28587749

    Open questions at the time
    • Mechanism of IFN-γ-driven NOD2 priming not fully dissected
    • Generalizability across Blau mutations not exhaustively tested
  18. 2018 High

    Defined XIAP as an essential RIP2 E3 ligase acting via its BIR2 domain and showed RIP2 kinase activity is dispensable, with the kinase domain conformation regulating XIAP binding.

    Evidence XIAP antagonists, RIP2 kinase inhibitors, ubiquitination-site mutagenesis, Co-IP, reporter and cytokine assays

    PMID:29452636

    Open questions at the time
    • Functional hierarchy with TRAF6/Pellino3 not reconciled
    • Structural basis of kinase-domain/BIR2 coupling not solved
  19. 2018 Medium

    Showed Parkin ubiquitylates and degrades NOD2 in astrocytes, linking NOD2 dysregulation to neuroinflammation and neuronal toxicity.

    Evidence Co-IP, ubiquitination assay, parkin/NOD2 siRNA, dopaminergic neuron co-culture rescue

    PMID:30378174

    Open questions at the time
    • In vivo neurodegeneration relevance not established
    • Single-lab study
  20. 2020 Medium

    Identified a non-immune, anti-tumor function of NOD2 in hepatocellular carcinoma through direct binding to the AMPKα-LKB1 complex and autophagy-mediated apoptosis.

    Evidence Co-IP, Nod2-/- HCC and xenograft models, AMPK pathway and proliferation/invasion assays

    PMID:32144252

    Open questions at the time
    • Whether this is peptidoglycan-ligand dependent unclear
    • Single-lab mechanistic study
  21. 2021 Medium

    Revealed NOD2 controls intestinal M-cell receptor expression, limiting retrograde transport of SIgA-pathogen complexes by suppressing Dectin-1 and Siglec-5.

    Evidence Human NOD2-deficient patients and mouse models, M-cell receptor expression and SIgA transport assays

    PMID:33431850

    Open questions at the time
    • Signaling pathway linking NOD2 to receptor repression undefined
    • Single study
  22. 2022 High

    Redefined the true NOD2 agonist by showing NAGK phosphorylates MDP to 6-O-phospho-MDP, which is required for NOD2 activation.

    Evidence Forward genetic screen, biochemical phosphorylation assay, mass spectrometry, NAGK-KO macrophages, active-site mutagenesis

    PMID:36002575

    Open questions at the time
    • Structural basis of 6-O-phospho-MDP recognition by NOD2 LRR not solved
    • Whether all NOD2 ligands require NAGK modification unclear
  23. 2022 Medium

    Showed Blau NACHT mutations paradoxically impair canonical RIPK2 signaling and IRF4-mediated cross-regulation, identifying IRF4 as the proximal mediator of NOD2 suppression of TLR/NF-κB in vivo.

    Evidence Blau mutant overexpression, reporter assays, colitis/arthritis models, lentiviral IRF4 rescue, patient macrophages

    PMID:36189261

    Open questions at the time
    • Reconciliation with gain-of-function inflammatory phenotype not fully clarified
    • Single-lab study
  24. 2022 Medium

    Demonstrated microbial DL-endopeptidase availability controls luminal NOD2 ligand levels, linking microbiome enzymatic activity to NOD2-dependent intestinal homeostasis.

    Evidence Metagenomics, active-site mutant control, NOD2-dependent colitis rescue, fecal transplant

    PMID:36049483

    Open questions at the time
    • Identity of the specific muropeptide species not fully defined
    • Single study
  25. 2022 Medium

    Extended NOD2 function to systemic physiology, showing intestinal epithelial NOD2 mediates microbiota-driven IGF-1 production and postnatal growth during undernutrition.

    Evidence Conditional and constitutive Nod2 KO mice, MDP/mifamurtide administration, IGF-1 measurement, germ-free models

    PMID:36821686

    Open questions at the time
    • Signaling pathway from epithelial NOD2 to IGF-1 not detailed
    • Single study
  26. 2022 Medium

    Identified a neuronal role for NOD2 in hypothalamic inhibitory neurons regulating appetite and body temperature in response to bacterial muropeptides.

    Evidence Nod2 KO mice, live brain imaging, muropeptide brain delivery, neuronal recording, food intake/temperature measurement

    PMID:35420957

    Open questions at the time
    • Downstream neuronal signaling pathway undefined
    • Sex-specific mechanism not explained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ligand-bound NOD2 transitions from the autoinhibited ADP-bound state to an active oligomer that recruits RIP2, and how the competing positive and negative ubiquitin E3 ligases are coordinated in time and tissue, remains unresolved.
  • No structure of the active, ligand-engaged NOD2 oligomer
  • Functional hierarchy among TRAF6, Pellino3, XIAP, TRIM27, and Parkin not integrated
  • Mechanism connecting NOD2 to ATG16L1, IRF4, and AMPK arms not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2 GO:0140299 molecular sensor activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 2 R-HSA-8953897 Cellular responses to stimuli 1
Partners
ERN1MAP3K7PARK2RIPK2SQSTM1TRAF6TRIM27XIAP

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 NOD2 frameshift mutation (3020insC) encodes a truncated protein deficient in NF-κB activation in response to bacterial lipopolysaccharides; wild-type NOD2 activates NF-κB in response to LPS, establishing NOD2 as an innate immune sensor upstream of NF-κB. Functional reporter assay (NF-κB activation) in cells expressing wild-type vs. mutant NOD2; genetic association analysis (TDT and case-control) Nature High 11385577
2007 NOD2 pathway activation by MDP or M. tuberculosis infection involves stable K63-linked polyubiquitination of RIP2 (RIPK2); this requires the E2-conjugating enzyme Ubc13, E3 ligase TRAF6, and kinase TAK1. RIP2 polyubiquitination is also required for IKKγ ubiquitination and downstream NF-κB activation. In vitro ubiquitination assays, co-immunoprecipitation, dominant-negative and knockdown approaches in macrophages infected with M. tuberculosis or treated with MDP The Journal of biological chemistry High 17947236
2004 TAK1 (MAP3K7) physically interacts with NOD2 and is required for NOD2-mediated NF-κB activation in response to MDP. Conversely, NOD2 inhibits TAK1-induced NF-κB activation through its LRR domain, revealing reciprocal cross-talk. The 3020insC LRR mutation reduces this inhibitory activity. Co-immunoprecipitation, dominant-negative TAK1 overexpression, reporter gene assays (NF-κB luciferase) in RICK-deficient embryonic fibroblasts and NOD2-expressing cells The Journal of biological chemistry Medium 15075345
2008 Beta-PIX and Rac1 GTPase interact with NOD2 upon MDP stimulation and mediate membrane recruitment of NOD2 and its negative regulation. Knockdown of beta-PIX or Rac1 increases NOD2-mediated NF-κB activation and IL-8 secretion, and abrogates NOD2 interaction with its negative regulator Erbin. Co-immunoprecipitation, RNA interference knockdown, Rac1 inhibitor treatment, IL-8 secretion and NF-κB activation assays in THP-1 cells and primary human monocytes Journal of immunology Medium 18684957
2010 ATG16L1 and NOD2 form part of an autophagy-dependent antibacterial pathway. MDP stimulation activates autophagy and increases intracellular killing of Salmonella in an ATG16L1- and NOD2-dependent manner. CD-associated NOD2 variants impair this MDP-mediated autophagy and bacterial killing response. Immunoblot, confocal microscopy, flow cytometry, reporter gene assay, gentamicin protection assay; RNAi knockdown of NOD2 and ATG16L1; primary macrophages and dendritic cells from genotyped donors Gastroenterology High 20637199
2012 TRIM27 acts as an E3 ubiquitin ligase that negatively regulates NOD2. TRIM27 physically interacts with NOD2 via the nucleotide-binding domain; NOD2 activation enhances this interaction. TRIM27-dependent K48-linked ubiquitination of NOD2 leads to proteasomal degradation of NOD2 and attenuation of NOD2-mediated pro-inflammatory signaling. Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor treatment, reporter gene assay; overexpression and knockdown in HeLa cells PloS one Medium 22829933
2013 Pellino3 E3 ubiquitin ligase directly binds RIP2 kinase and catalyzes its ubiquitination downstream of NOD2. Loss of Pellino3 attenuates NOD2-induced RIP2 ubiquitination, NF-κB activation, and MAPK signaling, and exacerbates experimental colitis in mice. Co-immunoprecipitation, in vitro ubiquitination assay, Pellino3 knockout mice, cytokine measurement, colitis models Nature immunology High 23892723
2013 p62/SQSTM1 positively regulates NOD2 signaling by associating with the nucleotide-binding domain of NOD2 through TRAF6-binding or ubiquitin-associated domains, stabilizing NOD2 oligomerization and preventing NOD2 degradation, thereby enhancing NF-κB and p38 MAPK activation and IL-1β/TNF-α production. Co-immunoprecipitation, electron microscopy of NOD2-p62 complex, reporter gene assay (NF-κB), cytokine ELISA, overexpression in macrophage-like cells PloS one Medium 23437331
2016 NOD2 (and NOD1) physically associate with IRE1α/TRAF2 at the ER membrane and are required for ER-stress-induced IL-6 production and NF-κB activation. ER stress inducers trigger NOD1/2-dependent inflammation; Brucella VceC-induced ER stress triggers NOD1/2- and RIP2-dependent inflammation that is blocked by IRE1α kinase inhibition. Genetic KO/KD cells, IRE1α kinase inhibitor, bacterial infection model (Brucella), cytokine ELISA, NF-κB reporter assay in mouse and human cells Nature High 27007849
2016 Crystal structure of rabbit NOD2 in an ADP-bound inactive closed conformation reveals that subdomains in the NOD domain are closely packed via ADP-mediated and inter-domain interactions. Blau syndrome/EOS gain-of-function mutations map to NOD subdomain interfaces and likely disrupt inter-domain interactions to facilitate conformational change to the active form; CD mutations are distributed throughout the protein affecting oligomer formation and ligand binding. X-ray crystallography of ADP-bound NOD2; mutational mapping Nature communications High 27283905
2018 XIAP ubiquitinates RIP2 downstream of NOD2, and the XIAP-RIP2 interaction (via XIAP BIR2 domain) is required for NOD2-mediated NF-κB and MAPK activation and cytokine production. RIP2 kinase activity is dispensable for NOD2 signaling; rather, the RIP2 kinase domain conformation regulates XIAP-BIR2 binding. Specific lysine residues on RIP2 serve as XIAP-dependent ubiquitination sites required for pathway signaling. XIAP antagonists, RIP2 kinase inhibitors, mutagenesis of RIP2 ubiquitination sites, co-immunoprecipitation, NF-κB reporter and cytokine production assays Molecular cell High 29452636
2018 Parkin E3 ubiquitin ligase directly interacts with and ubiquitylates NOD2, leading to reduced NOD2 protein levels in astrocytes. Parkin-deficient astrocytes show elevated NOD2 and exaggerated ER stress, JNK activation, and cytokine release; NOD2 knockdown in parkin-deficient astrocytes suppresses these inflammatory defects and protects neighboring neurons. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown of parkin and NOD2, co-culture with dopaminergic neurons, cytokine ELISA Glia Medium 30378174
2022 N-acetylglucosamine kinase (NAGK) is required for MDP (muramyl dipeptide) activation of NOD2. NAGK phosphorylates the N-acetylmuramic acid moiety of MDP at the C6 hydroxyl position, generating 6-O-phospho-MDP, which is the actual NOD2 agonist. Unmodified MDP does not constitutively activate NOD2; NAGK-deficient macrophages are completely defective in MDP sensing. Forward genetic screen, biochemical phosphorylation assay, mass spectrometry identification of 6-O-phospho-MDP, NAGK knockout macrophages, active-site mutagenesis Nature High 36002575
2014 Blau syndrome gain-of-function NOD2 mutations cluster at two locations in the NACHT domain: the ATP/Mg2+-binding site and helical domain 1. These polymorphisms likely dysregulate ATP hydrolysis and NOD2 autoinhibition, respectively. Complementary mutations in NOD1 do not mirror the NOD2 hyperactivation phenotype, indicating distinct activation/regulation mechanisms for NOD1 and NOD2. Mutational analysis of NOD2 constructs in functional assays; comparative NOD1 mutagenesis FEBS letters Medium 25093298
2009 NOD2 activation by MDP ordinarily downregulates responses to Toll-like receptor stimulation via induction of IRF4. Cells and mice lacking NOD2 mount increased TLR responses. Administration of MDP to normal mice induces IRF4 and prevents experimental colitis, placing NOD2 as a negative regulator of TLR-driven NF-κB activation through IRF4. NOD2-deficient mice, MDP stimulation assays, NOD2 transgenic mice (increased NOD2 function), IRF4 expression analysis, experimental colitis models (DSS, TNBS) Mucosal immunology High 19079230
2022 Blau syndrome NOD2 mutations in the nucleotide-binding domain reduce canonical RIPK2-mediated NF-κB activation and impair NOD2-mediated cross-regulation of TLR responses. IRF4 upregulation is defective in cells bearing Blau NOD2 mutations, identifying IRF4 as the proximal mediator of NOD2 cross-regulatory suppression of NF-κB. In vivo, mice bearing Blau mutations fail to suppress colitis or arthritis in response to MDP. Overexpression of Blau NOD2 mutants in HEK293 cells, reporter assays, experimental colitis and arthritis models, lentiviral IRF4 transduction rescue, IRF4 expression in patient-derived macrophages Frontiers in immunology Medium 36189261
2017 NOD2 suppresses colorectal tumorigenesis via downregulation of TLR signaling pathways. In vitro, NOD2 activation by MDP inhibits TLR-mediated NF-κB and MAPK activation, associated with induction of IRF4. Nod2-deficient mice show higher NF-κB, ERK, and STAT3 activation during colitis and colorectal tumorigenesis. Nod2-/- mouse colorectal tumorigenesis model, in vitro MDP stimulation with TLR co-stimulation, NF-κB/MAPK/STAT3 activation assays, IRF4 expression analysis Cell reports Medium 28658623
2009 Nod2 is required for controlling commensal bacterial load in the intestinal terminal ileum. Nod2-deficient mice harbor increased commensal bacteria and have diminished ability to prevent intestinal colonization by pathogens. Intestinal crypts from Nod2-/- mice are unable to kill bacteria effectively in vitro. Nod2 expression in the terminal ileum is dependent on the presence of commensal bacteria, establishing a feedback regulatory mechanism. Nod2 knockout mice, bacterial quantification from terminal ilea, in vitro crypt bacterial killing assay, germ-free mouse reconstitution Proceedings of the National Academy of Sciences of the United States of America High 19805227
2022 NOD2 in intestinal epithelial cells is necessary for LpWJL bacteria-mediated IGF-1 production and postnatal growth promotion in malnourished conventional animals. Muramyl dipeptide and mifamurtide (MDP analogs) are sufficient as NOD2 ligands to stimulate animal growth during undernutrition. Conditional and constitutive Nod2 knockout mice, MDP and mifamurtide administration, IGF-1 measurement, germ-free and conventional malnourished mouse models Science Medium 36821686
2022 In mice, NOD2 is expressed in hypothalamic inhibitory neurons and is activated by muropeptides reaching the brain. Activation of neuronal NOD2 by bacterial peptidoglycan-derived muropeptides regulates appetite and body temperature control, primarily in females. Nod2 knockout mice, live brain imaging, peptidoglycan/muropeptide brain delivery, neuronal activity recording, food intake and body temperature measurement Science Medium 35420957
2021 NOD2 deficiency increases retrograde transport of secretory IgA (SIgA)-pathogen complexes through intestinal M cells by upregulating Dectin-1 and Siglec-5 expression. NOD2 normally downregulates these M cell receptors to limit SIgA retrograde transport. NOD2-deficient human patients and mouse models, M cell receptor expression analysis, SIgA transport assays, receptor KD experiments Nature communications Medium 33431850
2020 NOD2 exerts anti-tumor effects in hepatocellular carcinoma by directly binding the AMPKα-LKB1 complex, activating AMPK signaling, and triggering autophagy-mediated apoptosis. NOD2 also enhances chemosensitivity to sorafenib, lenvatinib, and 5-FU through AMPK pathway activation. Co-immunoprecipitation of NOD2 with AMPKα-LKB1, Nod2-/- mouse HCC model, xenograft model, in vitro proliferation and invasion assays, AMPK pathway activation assays Cell death & disease Medium 32144252
2022 Gut microbial DL-endopeptidase increases the level of NOD2 ligand (muropeptides) in the intestinal lumen. Administration of active DL-endopeptidase, but not an active-site mutant, alleviates colitis via the NOD2 pathway. This establishes that microbially-generated NOD2 ligand availability is a mechanism linking microbiome composition to NOD2-dependent intestinal homeostasis. Metagenomic analysis, active-site DL-endopeptidase mutant control, colitis mouse models (NOD2-dependent rescue), fecal microbiota transplant Cell host & microbe Medium 36049483
2007 Activation of NOD2 by its agonist MDP induces CCL5/RANTES secretion from murine macrophages through the NF-κB pathway, not through the interferon-β pathway. In vivo, intraperitoneal injection of NOD2 agonists causes rapid CCL5 secretion into the bloodstream. Murine macrophage stimulation with Nod2 agonists, CCL5 ELISA, NF-κB promoter reporter assay, IFN-β pathway analysis, in vivo peritoneal injection model European journal of immunology Medium 17705131
2014 NOD2 stimulation by MDP inhibits odontoblast differentiation of human dental pulp cells through increased MKP-1 protein expression and subsequent dephosphorylation/inactivation of MAPKs required for differentiation. NOD2 siRNA knockdown reverses MDP-mediated inhibition of differentiation. siRNA knockdown of NOD2, ALP activity assay, mineralization assay, MAPK phosphorylation analysis, MKP-1 expression analysis in human dental pulp cells Journal of dental research Low 24820666
2017 iPSC-derived macrophages with Blau syndrome NOD2 mutations show IFN-γ-dependent, ligand-independent NF-κB activation and proinflammatory cytokine production. IFN-γ acts as a priming signal by upregulating NOD2 expression, and correction of the NOD2 mutation by CRISPR-Cas9 normalizes inflammatory responses. Blau syndrome-specific iPSC derivation, CRISPR-Cas9 isogenic correction and introduction of NOD2 mutation, iPSC differentiation to macrophages, NF-κB activation assays, cytokine measurements, RNA-seq The Journal of allergy and clinical immunology High 28587749
2014 miR-192, miR-495, miR-512, and miR-671 directly suppress NOD2 expression by targeting its 3'UTR, thereby suppressing MDP-mediated NF-κB activation and IL-8/CXCL3 expression in colonic epithelial cells. A SNP (rs3135500) in the NOD2 3'UTR reduces miR-192 effectiveness. Luciferase reporter constructs with NOD2 3'UTR, miRNA mimic transfection, qRT-PCR, NF-κB reporter assays in HCT116 cells Inflammatory bowel diseases Medium 24297055

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 3800 11385577
2014 NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 649 25526305
2006 Signalling pathways and molecular interactions of NOD1 and NOD2. Nature reviews. Immunology 645 16493424
2009 Nod2 is required for the regulation of commensal microbiota in the intestine. Proceedings of the National Academy of Sciences of the United States of America 458 19805227
2016 NOD1 and NOD2 signalling links ER stress with inflammation. Nature 433 27007849
1998 Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1. Proceedings of the National Academy of Sciences of the United States of America 321 9636179
2010 ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn's disease pathogenesis. Gastroenterology 302 20637199
2012 NOD1 and NOD2 Signaling in Infection and Inflammation. Frontiers in immunology 220 23162548
2007 NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2. The Journal of biological chemistry 189 17947236
2011 Crohn's disease: NOD2, autophagy and ER stress converge. Gut 167 21252204
2020 NOD1 and NOD2 in inflammatory and infectious diseases. Immunological reviews 158 32677123
2018 NOD1 and NOD2 in inflammation, immunity and disease. Archives of biochemistry and biophysics 157 30578751
2005 NOD2 and Crohn's disease: loss or gain of function? Immunity 155 15963781
2018 NOD2 and inflammation: current insights. Journal of inflammation research 143 29483781
2022 Bacterial sensing via neuronal Nod2 regulates appetite and body temperature. Science (New York, N.Y.) 142 35420957
2014 Blau syndrome, the prototypic auto-inflammatory granulomatous disease. Pediatric rheumatology online journal 137 25136265
2012 Roles of NOD1 (NLRC1) and NOD2 (NLRC2) in innate immunity and inflammatory diseases. Bioscience reports 136 22908883
2016 Crystal structure of NOD2 and its implications in human disease. Nature communications 135 27283905
2017 Genetics of inflammatory bowel disease: beyond NOD2. The lancet. Gastroenterology & hepatology 132 28404137
2017 Nod2: The intestinal gate keeper. PLoS pathogens 129 28253332
2012 TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation. PloS one 104 22829933
2005 Blau syndrome mutation of CARD15/NOD2 in sporadic early onset granulomatous arthritis. The Journal of rheumatology 103 15693102
2012 Blau syndrome, clinical and genetic aspects. Autoimmunity reviews 101 22884558
2018 Disruption of XIAP-RIP2 Association Blocks NOD2-Mediated Inflammatory Signaling. Molecular cell 98 29452636
2004 The NOD2 3020insC mutation and the risk of colorectal cancer. Cancer research 95 14996717
2013 Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis. Nature immunology 93 23892723
2015 Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease. RMD open 91 26509073
2022 Gut microbial DL-endopeptidase alleviates Crohn's disease via the NOD2 pathway. Cell host & microbe 87 36049483
2017 NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways. Cell reports 85 28658623
2006 Functional consequences of NOD2 (CARD15) mutations. Inflammatory bowel diseases 85 16804402
2013 Mouse Paneth cell antimicrobial function is independent of Nod2. Gut 84 23512834
2007 Nod1 and Nod2 in innate immunity and human inflammatory disorders. Biochemical Society transactions 84 18031249
2014 NOD2 expression is regulated by microRNAs in colonic epithelial HCT116 cells. Inflammatory bowel diseases 79 24297055
2014 Insights into the molecular basis of the NOD2 signalling pathway. Open biology 78 25520185
2007 Inflammatory bowel disease genetics: Nod2. Annual review of medicine 78 16987083
2014 Caveats and truths in genetic, clinical, autoimmune and autoinflammatory issues in Blau syndrome and early onset sarcoidosis. Autoimmunity reviews 75 25182201
2004 Reciprocal cross-talk between Nod2 and TAK1 signaling pathways. The Journal of biological chemistry 75 15075345
1999 Genetic analysis in Italian families with inflammatory bowel disease supports linkage to the IBD1 locus--a GISC study. European journal of human genetics : EJHG 74 10439963
1998 Evidence of linkage of the inflammatory bowel disease susceptibility locus on chromosome 16 (IBD1) to ulcerative colitis. Journal of medical genetics 71 9541106
2008 The molecular basis of NOD2 susceptibility mutations in Crohn's disease. Mucosal immunology 70 19079230
2023 Microbe-mediated intestinal NOD2 stimulation improves linear growth of undernourished infant mice. Science (New York, N.Y.) 69 36821686
2007 Nod1 and Nod2 induce CCL5/RANTES through the NF-kappaB pathway. European journal of immunology 69 17705131
2009 NOD2-associated diseases: Bridging innate immunity and autoinflammation. Clinical immunology (Orlando, Fla.) 68 19467619
2005 A new CARD15 mutation in Blau syndrome. European journal of human genetics : EJHG 66 15812565
2019 RICK/RIP2 is a NOD2-independent nodal point of gut inflammation. International immunology 64 31132297
2010 The protein Nod2: an innate receptor more complex than previously assumed. Biochemical pharmacology 64 20643110
2020 Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation. Annals of the rheumatic diseases 62 32647028
2006 CARD15/NOD2 mutations in Crohn's disease. Annals of the New York Academy of Sciences 61 17057186
2022 Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation. Nature 60 36002575
2020 NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway. Cell death & disease 60 32144252
2011 Blau syndrome revisited. Current opinion in rheumatology 59 21788900
2000 Linkage heterogeneity for the IBD1 locus in Crohn's disease pedigrees by disease onset and severity. Gastroenterology 58 11113069
2008 Beta-PIX and Rac1 GTPase mediate trafficking and negative regulation of NOD2. Journal of immunology (Baltimore, Md. : 1950) 55 18684957
2003 Ocular manifestations in Blau syndrome associated with a CARD15/Nod2 mutation. Ophthalmology 55 14522785
2018 Parkin targets NOD2 to regulate astrocyte endoplasmic reticulum stress and inflammation. Glia 51 30378174
2020 Extracellular Histone H3 Induces Pyroptosis During Sepsis and May Act Through NOD2 and VSIG4/NLRP3 Pathways. Frontiers in cellular and infection microbiology 49 32432055
2014 Nod2 and Rip2 contribute to innate immune responses in mouse neutrophils. Immunology 49 24766550
2014 NOD2 polymorphisms associated with cancer risk: a meta-analysis. PloS one 48 24586700
2012 Ubiquitination and phosphorylation in the regulation of NOD2 signaling and NOD2-mediated disease. Biochimica et biophysica acta 48 22522061
2021 NOD2 deficiency increases retrograde transport of secretory IgA complexes in Crohn's disease. Nature communications 47 33431850
2007 NOD2/CARD15 disease associations other than Crohn's disease. Inflammatory bowel diseases 46 17206682
2017 Pluripotent stem cell models of Blau syndrome reveal an IFN-γ-dependent inflammatory response in macrophages. The Journal of allergy and clinical immunology 45 28587749
2023 NOD2 in Crohn's Disease-Unfinished Business. Journal of Crohn's & colitis 44 36006803
2023 Cell membrane-camouflaged bufalin targets NOD2 and overcomes multidrug resistance in pancreatic cancer. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 44 37647746
2006 NOD2: ethnic and geographic differences. World journal of gastroenterology 44 16773683
2005 Induction and localization of NOD2 protein in human endothelial cells. Cellular immunology 41 16288731
2005 Blau syndrome and related genetic disorders causing childhood arthritis. Current rheumatology reports 41 16303101
2017 Nod2 and Nod2-regulated microbiota protect BALB/c mice from diet-induced obesity and metabolic dysfunction. Scientific reports 39 28373658
2014 NOD2 contributes to Porphyromonas gingivalis-induced bone resorption. Journal of dental research 38 25239844
2019 Role of NOD1/NOD2 receptors in Fusobacterium nucleatum mediated NETosis. Microbial pathogenesis 37 30940608
2003 Lessons to be learned from the NOD2 gene in Crohn's disease. European journal of gastroenterology & hepatology 37 12840668
2014 Freund's adjuvant, NOD2 and mycobacteria. Current opinion in microbiology 35 25483349
2021 Distinguishing Blau Syndrome from Systemic Sarcoidosis. Current allergy and asthma reports 34 33560445
2014 Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators. FEBS letters 33 25093298
2022 Blau syndrome NOD2 mutations result in loss of NOD2 cross-regulatory function. Frontiers in immunology 31 36189261
2004 IBD1 and IBD3 determine location of Crohn's disease in the Spanish population. Inflammatory bowel diseases 31 15626888
2016 The effect of NOD2 on the microbiota in Crohn's disease. Current opinion in biotechnology 30 27035071
2004 NOD2/CARD15: relevance in clinical practice. Best practice & research. Clinical gastroenterology 29 15157828
2022 SARS-CoV-2/COVID-19 and its relationship with NOD2 and ubiquitination. Clinical immunology (Orlando, Fla.) 28 35513305
2021 Mediators of Metabolism: An Unconventional Role for NOD1 and NOD2. International journal of molecular sciences 28 33503814
2018 Using genes to triangulate the pathophysiology of granulomatous autoinflammatory disease: NOD2, PLCG2 and LACC1. International immunology 26 29538758
2013 p62/SQSTM1 enhances NOD2-mediated signaling and cytokine production through stabilizing NOD2 oligomerization. PloS one 26 23437331
2006 Blau syndrome associated with a CARD15/NOD2 mutation. American journal of ophthalmology 25 17157607
2014 NOD2 Mediates Odontoblast Differentiation and RANKL Expression. Journal of dental research 24 24820666
2020 NOD2 Influences Trajectories of Intestinal Microbiota Recovery After Antibiotic Perturbation. Cellular and molecular gastroenterology and hepatology 23 32289499
2020 Ocular manifestations of Blau syndrome. Current opinion in ophthalmology 23 33009086
2009 Genotyping for NOD2 genetic variants and crohn disease: a metaanalysis. Clinical chemistry 23 19713276
2023 Implications of combined NOD2 and other gene mutations in autoinflammatory diseases. Frontiers in immunology 21 37928541
2022 Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis. Frontiers in immunology 21 35711422
2017 Gene mutations and clinical phenotypes in Chinese children with Blau syndrome. Science China. Life sciences 21 28639104
2017 The NOD2 receptor is crucial for immune responses towards New World Leishmania species. Scientific reports 21 29123157
2016 NOD2 mutations and colorectal cancer - Where do we stand? World journal of gastrointestinal surgery 21 27152134
2016 The role of NOD1 and NOD2 in host defense against chlamydial infection. FEMS microbiology letters 21 27421958
2013 Blau syndrome-associated uveitis and the NOD2 gene. Seminars in ophthalmology 21 24010719
2021 NOD2 deficiency confers a pro-tumorigenic macrophage phenotype to promote lung adenocarcinoma progression. Journal of cellular and molecular medicine 20 34268854
2020 Nod2 protects mice from inflammation and obesity-dependent liver cancer. Scientific reports 20 33239685
2007 NOD2 and defensins: translating innate to adaptive immunity in Crohn's disease. Journal of endotoxin research 20 17621555
2019 NOD2 Supports Crypt Survival and Epithelial Regeneration after Radiation-Induced Injury. International journal of molecular sciences 18 31480799
2018 The bromodomain-containing protein Ibd1 links multiple chromatin-related protein complexes to highly expressed genes in Tetrahymena thermophila. Epigenetics & chromatin 18 29523178
2014 NOD2 gene mutations in ulcerative colitis: useless or misunderstood? International journal of colorectal disease 18 24651958

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