Affinage

CARD9

Caspase recruitment domain-containing protein 9 · UniProt Q9H257

Length
536 aa
Mass
62.2 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CARD9 is a myeloid-enriched cytosolic CARD-coiled-coil adaptor that couples innate pattern-recognition receptors to NF-κB and MAPK signaling, serving as the central transducer of antifungal immunity (PMID:16862125, PMID:19864672). It selectively binds the CARD of BCL10 through homophilic CARD-CARD interactions and self-associates via coiled-coil motifs to seed a CARD9-BCL10-MALT1 (CBM) signalosome (PMID:11053425); cryo-EM and crystallographic analysis show CARD9 is held in an autoinhibited state by an intramolecular CARD-coiled-coil interface whose disruption produces BCL10-templating filaments and hyperactivation (PMID:31296852). In myeloid cells CARD9 is the obligate BCL10-MALT1 linker (in place of CARMA1/CARD11) downstream of ITAM-coupled C-type lectin receptors—Dectin-1, Dectin-2, Dectin-3, and Mincle—and FcRγ/DAP12 receptors, where Syk-activated Vav GEFs and PKCδ converge on CARD9, the latter phosphorylating Thr231 to license CBM assembly and canonical NF-κB activation (PMID:17486093, PMID:22265677, PMID:27926862, PMID:25202022). This pathway drives proinflammatory and IL-23/Th17 cytokine programs essential for clearing Candida albicans (PMID:17450144), and germline loss-of-function mutations (Q295X) cause autosomal recessive chronic mucocutaneous candidiasis with deficient Th17 immunity (PMID:19864672). CARD9 additionally branches into NF-κB-independent outputs: it links Ras-GRF1 to H-Ras for ERK activation (PMID:25267792), cooperates with Nod2/RICK to drive p38 and JNK during intracellular infection (PMID:17187069), and assembles a cytosolic Rad50 complex for DNA-induced IL-1β (PMID:24777530). Its activity is set by post-translational control—OTUD1-mediated removal of K33-linked ubiquitin promotes CBM assembly (PMID:33789983, PMID:39118286), while Dok3-recruited PP1 dephosphorylates CARD9 to dampen signaling (PMID:31180338). The S12N variant aberrantly activates non-canonical RelB to produce IL-5 and type 2 responses (PMID:29777223). Beyond immune signaling, CARD9 shapes mucosal homeostasis by enabling microbiota tryptophan metabolism into AHR ligands driving IL-22 (PMID:27158904) and coordinating antifungal IgG responses (PMID:33548172).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2000 High

    Established CARD9's biochemical core: how it nucleates an NF-κB-activating complex, by showing selective CARD-CARD binding to BCL10 and coiled-coil self-association.

    Evidence Mammalian two-hybrid, co-IP of endogenous CARD9-BCL10, NF-κB reporter assay

    PMID:11053425

    Open questions at the time
    • No physiological receptor or upstream trigger identified
    • No structural basis for self-association
  2. 2006 High

    Placed CARD9 in a pathway by defining it as the essential transducer linking Dectin-1 to BCL10-MALT1 and antifungal NF-κB, distinct from TLR/MyD88 and CARMA1 routes.

    Evidence Card9−/− mice, zymosan/Dectin-1 stimulation, cytokine ELISA, genetic reconstitution

    PMID:16862125

    Open questions at the time
    • Mechanism of CARD9 activation downstream of receptor not resolved
    • Cell-type specificity not yet formalized
  3. 2006 High

    Revealed a parallel CARD9 output by showing it is required for Nod2-mediated p38/JNK (not NF-κB) activation against intracellular pathogens via inducible Nod2/RICK association.

    Evidence Card9−/− mice, co-IP with Nod2 and RICK, p38/JNK kinase assays, Listeria infection

    PMID:17187069

    Open questions at the time
    • Domain basis of Nod2 interaction unresolved (later revised)
    • How CARD9 selectively routes to MAPK vs NF-κB unknown
  4. 2007 High

    Generalized CARD9 as the myeloid counterpart of CARMA1, required for ITAM (FcRγ/DAP12)-driven NF-κB and TLR-induced MAPK, establishing cell-type-specific adaptor usage.

    Evidence Card9−/−, Card11−/−, Bcl10−/− mouse comparisons, co-IP, cytokine assays

    PMID:17450144 PMID:17486093

    Open questions at the time
    • Th17-driving cytokine circuit defined but transcriptional control unclear
  5. 2009 High

    Extended CARD9-BCL10 module to antiviral signaling, showing it is essential for RIG-I/MAVS-driven proinflammatory NF-κB but dispensable for inflammasome activation.

    Evidence Card9−/− and Bcl10−/− cells, RNA virus infection, NF-κB and IL-1β readouts, co-IP

    PMID:19915568

    Open questions at the time
    • Connection between RIG-I/MAVS and CARD9 recruitment not mechanistically resolved
  6. 2009 High

    Connected CARD9 to human disease, establishing that biallelic Q295X loss-of-function causes chronic mucocutaneous candidiasis with impaired Th17 immunity.

    Evidence Homozygosity mapping, Sanger sequencing, T cell phenotyping, reconstitution of Card9−/− myeloid cells

    PMID:19864672

    Open questions at the time
    • Molecular consequence of Q295X truncation on signalosome not defined at structural level
  7. 2010 High

    Refined receptor specificity by showing Dectin-2/hyphae use CARD9-BCL10 to drive IKK ubiquitination, dissecting it from Syk-driven IKK phosphorylation.

    Evidence siRNA knockdown of Dectin-1/2, co-IP, IKK ubiquitination assays, NF-κB reporter

    PMID:20538615

    Open questions at the time
    • Ubiquitin ligase mediating IKK modification not identified
  8. 2012 High

    Identified the molecular switch for CBM assembly: PKCδ phosphorylates CARD9 at Thr231 downstream of Syk to enable BCL10 recruitment and canonical NF-κB.

    Evidence Prkcd−/− mice, in vitro kinase assay, phosphosite mapping, co-IP, Candida infection

    PMID:22265677

    Open questions at the time
    • How Thr231 phosphorylation relieves autoinhibition not yet structurally explained
  9. 2014 High

    Defined an NF-κB-independent ERK branch in which CARD9 bridges Syk-phosphorylated Ras-GRF1 to H-Ras for proinflammatory ERK signaling.

    Evidence Co-IP of CARD9-RasGRF1-H-Ras, ERK kinase assays, Card9−/− cells, in vivo ERK inhibition

    PMID:25267792

    Open questions at the time
    • Structural basis of the trimeric complex unresolved
    • How CARD9 partitions between ERK and CBM outputs unclear
  10. 2014 High

    Uncovered a cytosolic DNA-sensing role: Rad50 directly binds CARD9 to form dsDNA-Rad50-CARD9 complexes generating pro-IL-1β.

    Evidence Co-IP of endogenous Rad50-CARD9, pulldowns, dsDNA transfection, Card9−/− cells, DNA virus model

    PMID:24777530

    Open questions at the time
    • Inflammasome coupling downstream of Rad50-CARD9 not fully defined
  11. 2014 Medium

    Revised the NOD2-CARD9 interaction model, mapping it to the NOD2 CARD-NACHT linker and NACHT domain rather than reciprocal CARDs.

    Evidence Pulldown/co-IP domain mapping with NOD2 and CARD9 truncation mutants

    PMID:24960071

    Open questions at the time
    • Single method type (pulldown mapping)
    • Functional consequence of revised interface not tested
  12. 2014 High

    Showed CARD9 drives transcriptional feed-forward by mediating Dectin-3-induced Mincle expression through CBM/NF-κB binding at the Mincle promoter.

    Evidence Dectin-3−/− and Card9−/− macrophages, ChIP at Mincle promoter, reporter assays

    PMID:25202022

    Open questions at the time
    • Cooperating transcription factors at Mincle locus not defined
  13. 2015 High

    Confirmed the ERK branch in humans by showing the hypomorphic Y91H mutation selectively impairs CARD9-RASGRF1 complex/GM-CSF responses while leaving CBM assembly intact.

    Evidence Co-IP of CARD9 with RASGRF1 and BCL10/MALT1, NF-κB/ERK assays in patient monocytes, clinical GM-CSF rescue

    PMID:26521038

    Open questions at the time
    • Why this axis is uniquely sensitive to Y91H not structurally explained
  14. 2016 High

    Defined upstream GEF activators, showing Vav1/2/3 are required to engage CARD9 across multiple CLRs, with triple-KO phenocopying Card9−/−.

    Evidence Vav1/2/3 triple-KO mice, NF-κB reporter and cytokine assays, Candida models

    PMID:27926862

    Open questions at the time
    • Direct biochemical link from Vav GEFs to CARD9 not mapped
  15. 2016 High

    Extended CARD9 to mucosal homeostasis, demonstrating it enables microbiota tryptophan-to-AHR-ligand metabolism that drives IL-22 and colitis recovery.

    Evidence Card9−/− mice, germ-free microbiota transfer, metabolomics, AHR agonist rescue, IL-22 measurement

    PMID:27158904

    Open questions at the time
    • Cell-intrinsic CARD9 events shaping microbiota composition not fully delineated
  16. 2018 High

    Defined a gain-of-function variant: S12N redirects CLR signaling to non-canonical RelB, driving IL-5 and type 2 immunity not seen with wild-type CARD9.

    Evidence CARD9 S12N knock-in mice, RelB activation assays, IL-5 ELISA, eosinophil recruitment, patient PBMCs

    PMID:29777223

    Open questions at the time
    • Structural basis by which S12N favors RelB not resolved
  17. 2018 Medium

    Linked CARD9 filament architecture to disease by showing R70W blocks BCL10/MALT1 interactions and CBM filament assembly at a CARD-CARD interface.

    Evidence Reporter assays, CBM co-IP, confocal imaging of BCL10 filaments, structural interface analysis

    PMID:30429846

    Open questions at the time
    • No in vitro reconstitution
    • Interface inference from modeling
  18. 2019 High

    Provided the structural framework: cryo-EM filament and autoinhibited crystal structures showing CARD-coiled-coil autoinhibition that, when disrupted, templates BCL10 filaments.

    Evidence Cryo-EM, crystal structure, in vitro filament reconstitution, gain-of-function mutagenesis with reporter assays

    PMID:31296852

    Open questions at the time
    • How physiological phosphorylation (Thr231) maps onto autoinhibition release not directly shown
  19. 2019 High

    Defined post-translational tuning by phosphatase: Dok3 recruits PP1 to dephosphorylate CARD9 and dampen NF-κB/JNK and antifungal immunity.

    Evidence Dok3−/− mice, co-IP of Dok3-PP1-CARD9, phosphorylation and activation assays, Candida model

    PMID:31180338

    Open questions at the time
    • Target residue(s) dephosphorylated by PP1 not mapped
  20. 2019 High

    Expanded CARD9 into tissue-specific and pathological roles: microglial CARD9 drives IL-1β/CXCL1 and neutrophil recruitment in CNS candidiasis, and DC CARD9 amplifies autoimmunity in Lyn-deficiency.

    Evidence Microglia- and DC-specific conditional Card9 KO mice, cytokine ELISA, colitis/autoimmunity models, p38 assays

    PMID:30996332 PMID:31594855

    Open questions at the time
    • Tissue-specific differences in CARD9 wiring not mechanistically separated
  21. 2019 High

    Revealed non-signalosome functions: CARD9 supports neutrophil mitochondrial function/survival and protects cardiomyocytes from apoptosome formation via CARD-domain binding to Apaf-1.

    Evidence Conditional Card9 KO mice with Seahorse profiling and apoptosis assays; co-IP of CARD9-Apaf-1 with domain mapping, caspase assays, I/R model

    PMID:31212066 PMID:36167663

    Open questions at the time
    • Apaf-1 finding is Medium-confidence single-lab co-IP
    • Mechanism connecting CARD9 to neutrophil mitochondrial regulation unclear
  22. 2020 Medium

    Identified an autophagy-promoting role: CARD9 binds Rubicon in cardiomyocytes to enhance UVRAG-Beclin1-PI3KC3 and Rab7-dependent autophagosome maturation.

    Evidence Co-IP of CARD9-Rubicon, Rubicon siRNA rescue, LC3/p62 and autophagy flux assays, Card9−/− I/R model

    PMID:32248306

    Open questions at the time
    • Single-lab co-IP
    • Whether this is myeloid-relevant or cardiomyocyte-restricted unclear
  23. 2021 High

    Established ubiquitin-based positive regulation: OTUD1 directly deubiquitinates CARD9 (removing K33-linked chains) to promote CBM assembly and NF-κB/MAPK output.

    Evidence Co-IP of OTUD1-CARD9, in vitro and linkage-specific deubiquitination assays, Otud1−/− and myeloid-specific KO mice, Candida and cardiac stress models

    PMID:33789983 PMID:39118286

    Open questions at the time
    • E3 ligase adding K33 chains to CARD9 not identified
  24. 2021 High

    Connected CARD9 to humoral immunity, showing CARD9+CX3CR1+ macrophages coordinate antifungal IgG against gut mycobiota, impaired in CARD9-deficient patients.

    Evidence Card9−/− mice, fungal colonization, germinal center analysis, antibody profiling, human patient validation

    PMID:33548172

    Open questions at the time
    • Signaling events linking CARD9 to GC/B-cell help not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CARD9's physiological phosphorylation, K33-deubiquitination, and receptor-specific inputs are integrated to release autoinhibition and select among the CBM, ERK, MAPK, and apoptotic/autophagic outputs remains unresolved.
  • No structure of phosphorylated/activated CARD9 in receptor context
  • Quantitative rules governing output selection unknown
  • E3 ligase counterpart of OTUD1 unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
APAF1BCL10MALT1NOD2OTUD1RAD50RASGRF1RIPK2
Complex memberships
CARD9-BCL10-MALT1 (CBM) signalosomedsDNA-Rad50-CARD9 complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 CARD9 is a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10 via homophilic CARD-CARD interactions, self-associates through coiled-coil motifs, and activates NF-κB when expressed in cells. Endogenous CARD9 was found constitutively associated with BCL10, indicating a pre-existing signaling complex. Mammalian two-hybrid analysis, co-immunoprecipitation of endogenous proteins, NF-κB reporter assay The Journal of biological chemistry High 11053425
2006 CARD9 is an essential transducer of Dectin-1 signaling in myeloid cells. CARD9 couples Dectin-1 (an ITAM-related innate receptor for fungal β-glucan/zymosan) to BCL10-MALT1-mediated canonical NF-κB activation, mediating cytokine production and innate anti-fungal immunity. CARD9 is dispensable for TLR/MyD88-induced responses and for antigen receptor signaling that uses CARMA1 as the BCL10-MALT1 linker. Card9−/− mouse generation, zymosan/Dectin-1 stimulation assays, NF-κB reporter assays, cytokine ELISA, genetic reconstitution Nature High 16862125
2006 CARD9 is required for Nod2-mediated activation of p38 and JNK (but not NF-κB) in macrophages responding to intracellular pathogens. CARD9 inducibly associates with both Nod2 and the serine-threonine kinase RICK (RIPK2) after bacterial or viral infection. Card9−/− mouse generation, co-immunoprecipitation of CARD9 with Nod2 and RICK, kinase activation assays (p38, JNK), Listeria monocytogenes infection model Nature immunology High 17187069
2007 CARD9 (not CARMA1/CARD11) is required for NF-κB activation downstream of ITAM-associated receptors (FcRγ and DAP12) on myeloid cells, and for TLR-induced MAPK activation in dendritic cells. CARD9 forms a complex with BCL10 in myeloid cells analogous to the CARMA1-BCL10-MALT1 complex in lymphocytes, establishing cell-type-specific adaptor usage for ITAM signaling. Card9−/−, Card11−/−, Bcl10−/− mouse comparisons; NF-κB activation assays; co-immunoprecipitation; cytokine production assays Nature immunology High 17486093
2007 Dectin-1-Syk-CARD9 signaling induces DC maturation and secretion of IL-6, TNF, and IL-23 (but little IL-12), and is required for CARD9-dependent Th17 responses to Candida albicans infection in vivo. Card9−/− mice, Candida albicans infection model, cytokine ELISA, T cell differentiation assays, dectin-1 agonist adjuvant experiments Nature immunology High 17450144
2009 RIG-I-mediated NF-κB activation during RNA virus infection requires MAVS and a CARD9-BCL10 complex, establishing CARD9-BCL10 as an essential module downstream of RIG-I for proinflammatory (but not inflammasome) signaling. RIG-I-triggered inflammasome activation proceeds independently of CARD9. Card9−/− and Bcl10−/− cells, RNA virus infection assays, NF-κB reporter assays, IL-1β production measurement, co-immunoprecipitation Nature immunology High 19915568
2009 A homozygous Q295X loss-of-function mutation in CARD9 causes autosomal recessive susceptibility to chronic mucocutaneous candidiasis, associated with low Th17 cell numbers. Genetic reconstitution of CARD9-deficient myeloid cells showed the Q295X allele impairs dectin-1-induced innate signaling. Homozygosity mapping, Sanger sequencing, T cell phenotyping, genetic reconstitution of Card9−/− myeloid cells The New England journal of medicine High 19864672
2010 CARD9 mediates Dectin-2-induced IκBα kinase (IKK) ubiquitination to activate NF-κB in response to C. albicans hyphae, while Syk regulates IKK phosphorylation. Hyphal stimulation specifically induces CARD9 association with BCL10 via Dectin-2 (not Dectin-1). siRNA knockdown of Dectin-1 and Dectin-2, NF-κB reporter assay, co-immunoprecipitation of CARD9-BCL10, ubiquitination assays on IKK The Journal of biological chemistry High 20538615
2012 Protein kinase C-δ (PKCδ) is activated downstream of Dectin-1-Syk signaling and phosphorylates CARD9 at Thr231, which is required for CARD9-BCL10 complex assembly and canonical NF-κB activation. Prkcd−/− but not PKCα-, PKCβ-, or PKCθ-deficient DCs are defective in innate responses to Dectin-1, Dectin-2, and Mincle. Prkcd−/− mice, in vitro kinase assay, CARD9 phosphorylation mapping, co-immunoprecipitation of CARD9-BCL10, Candida albicans infection model Immunity High 22265677
2014 CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras. Syk-dependent phosphorylation of Ras-GRF1 enables it to recruit and activate H-Ras through a complex with CARD9, leading to downstream ERK activation and proinflammatory responses. This ERK pathway is independent of CARD9-mediated NF-κB activation. Co-immunoprecipitation of CARD9-RasGRF1-H-Ras complex, ERK kinase assays, Card9−/− macrophages/DCs, ERK inhibitor in vivo survival experiments The Journal of experimental medicine High 25267792
2014 Cytosolic Rad50 directly interacts with CARD9. Transfection of dsDNA or DNA virus infection induces formation of dsDNA-Rad50-CARD9 signaling complexes that activate NF-κB and generate pro-IL-1β. Primary cells lacking Rad50 or CARD9 exhibit defective DNA-induced IL-1β production. Co-immunoprecipitation of endogenous Rad50-CARD9, pulldown assays, dsDNA transfection assay, Card9−/− primary cells and mice, DNA virus infection model Nature immunology High 24777530
2014 The interaction between NOD2 and CARD9 is mediated not by the CARDs of each protein as previously proposed, but by two sites on NOD2: the CARD-NACHT linker region and the NACHT domain itself. Pulldown and co-immunoprecipitation mapping experiments using truncation and domain mutants of NOD2 and CARD9 FEBS letters Medium 24960071
2015 A hypomorphic CARD9 p.Y91H mutation impairs the ability of CARD9 to complex with RASGRF1, leading to impaired NF-κB and ERK activation in monocytes and defective GM-CSF responses. CARD9-BCL10-MALT1 complex formation is intact in these patients, demonstrating that the CARD9/RASGRF1/ERK/GM-CSF axis is distinct from the CBM complex pathway. Co-immunoprecipitation of CARD9 with RASGRF1 and BCL10/MALT1, NF-κB and ERK activation assays in patient monocytes, clinical GM-CSF rescue The Journal of allergy and clinical immunology High 26521038
2016 Vav1, Vav2, and Vav3 GEF proteins are key activators of the CARD9 pathway downstream of Dectin-1, Dectin-2, and Mincle, required for NF-κB control and proinflammatory gene transcription. Vav1/2/3−/− mice phenocopy Card9−/− animals with extreme fungal susceptibility. Vav1/2/3 triple-KO mice, NF-κB reporter assays, cytokine production assays, Candida infection models Cell reports High 27926862
2018 The CARD9 S12N variant (rs4077515) mediates CLR-induced activation of the non-canonical NF-κB subunit RelB, leading to IL-5 production in alveolar macrophages and type 2 immune responses with eosinophil recruitment. Wild-type CARD9 does not activate RelB or induce IL-5 in this context. CARD9S12N knock-in mice, NF-κB subunit activation assays (RelB), IL-5 ELISA, eosinophil recruitment assays, patient PBMC studies Nature immunology High 29777223
2018 The CARD9 R70W mutation prevents NF-κB activation by blocking productive interactions with BCL10 and MALT1, thereby preventing assembly of the filamentous CARD9-BCL10-MALT1 (CBM) signalosome. Structural analysis maps R70 to the interface between successive CARD domains in CARD9 filaments. Reporter assays, co-immunoprecipitation of CBM complex, confocal imaging of BCL10 filament assemblies, structural analysis of CARD domain interface Frontiers in immunology Medium 30429846
2019 Cryo-EM structure of the CARD9 filament and crystal structure of an autoinhibited CARD9 fragment (CARD-coiled-coil interface) were determined. Autoinhibition is mediated by an extensive intramolecular interface between the CARD and coiled-coil domains. Disruption of this interface leads to hyperactivation in cells and formation of BCL10-templating filaments in vitro. CARD9 and CARD11 share similar but distinct autoinhibition mechanisms. Cryo-EM structure determination, crystal structure, in vitro filament reconstitution, gain-of-function mutagenesis with NF-κB reporter assays in cells Nature communications High 31296852
2019 CARD9 in microglia promotes IL-1β production (via both transcriptional regulation of Il1b and inflammasome activation) and CXCL1 production in response to CNS Candida infection, driving CXCR2+ neutrophil recruitment. Microglia-specific Card9 deletion impairs IL-1β and CXCL1 production and increases fungal proliferation in the CNS. Microglia-specific Card9 conditional KO mice, IL-1β and CXCL1 ELISA, neutrophil recruitment quantification, CNS Candida infection model, p38 kinase assays Nature immunology High 30996332
2019 Dok3 recruits protein phosphatase 1 (PP1) to dephosphorylate CARD9, dampening downstream NF-κB and JNK activation and antifungal immune responses in neutrophils. Dok3 deficiency enhances phagocytosis, cytokine production, and survival against Candida albicans infection. Dok3−/− mice, co-immunoprecipitation of Dok3-PP1-CARD9, CARD9 phosphorylation assays, NF-κB/JNK activation assays, in vivo Candida infection model The Journal of clinical investigation High 31180338
2019 CARD9 in dendritic cells is required for development of autoimmune disease in Lyn-deficient mice via a CD11b-Syk-PKCδ-CARD9 pathway. In the absence of Lyn, this pathway is amplified, leading to increased TLR-induced production of inflammatory cytokines. Dendritic cell-specific CARD9 deletion reversed autoimmunity and experimental colitis in Lyn-deficient mice. Cell-type-specific (DC-specific) Card9 KO, co-immunoprecipitation, cytokine assays, DSS and IL-10-deficiency colitis models Science signaling High 31594855
2019 CARD9 in neutrophils mediates mitochondrial function; loss of CARD9 causes mitochondrial dysfunction with increased reactive oxygen species production and premature neutrophil apoptosis, particularly in oxidative environments. This impaired neutrophil survival reduces tissue fungal containment and increases susceptibility to intestinal inflammation. Neutrophil-specific and epithelial-specific conditional Card9 KO mice, DSS colitis model, Seahorse bioenergetics profiling, apoptosis assays, proteomics, in vivo fungal infection model Gut High 36167663
2020 CARD9 interacts directly with Rubicon (a negative regulator of autophagy) in cardiomyocytes, and this interaction enhances UVRAG-Beclin1-PI3KC3 interaction and UVRAG-Vps16-mediated Rab7 activation to promote autophagosome formation, maturation, and endocytosis. CARD9 overexpression increases autophagic flux; CARD9 loss impairs autophagy and worsens myocardial I/R injury. Co-immunoprecipitation of CARD9-Rubicon, Rubicon siRNA rescue, LC3 lipidation and p62 assays, autophagy flux assays (BafA1/3-MA), CARD9−/− mice in I/R model Basic research in cardiology Medium 32248306
2019 CARD9 protects cardiomyocytes from mitochondria-dependent apoptosis by interacting with Apaf-1 via its CARD domain, suppressing caspase-9 activation and apoptosome formation under oxidative stress. Co-immunoprecipitation of CARD9-Apaf-1, CARD domain deletion mutants, caspase-3 and -9 activation assays, CARD9−/− mice in I/R model, TUNEL staining Free radical biology & medicine Medium 31212066
2021 OTUD1 deubiquitinase directly interacts with CARD9 and removes polyubiquitin chains from CARD9, promoting canonical NF-κB and MAPK pathway activation in the context of antifungal immunity. OTUD1 deficiency impairs CARD9-mediated cytokine production and increases fungal susceptibility in vivo. Co-immunoprecipitation of OTUD1-CARD9, deubiquitination assay in vitro, Otud1−/− mice, NF-κB/MAPK activation assays, Candida infection model Journal of immunology High 33789983
2024 OTUD1 removes K33-linked ubiquitin from CARD9 (without affecting CARD9 stability) to promote assembly of the CARD9-BCL10-MALT1 (CBM) complex in macrophages, resulting in NF-κB activation and inflammatory gene expression in the context of isoproterenol-induced cardiac stress. Co-immunoprecipitation of OTUD1-CARD9, ubiquitin linkage-specific deubiquitination assays, CBM complex pull-down, myeloid-specific KO mice, NF-κB reporter assays Clinical and translational medicine High 39118286
2021 Antifungal IgG production by gut commensal fungi depends on CARD9 and CARD9+CX3CR1+ macrophages. In individuals with CARD9 loss-of-function mutations, antifungal IgG responses are impaired, revealing a role for CARD9 in coordinating innate-to-adaptive humoral immunity against mycobiota. Card9−/− mice, fungal colonization models, germinal center B cell analysis, systemic antibody profiling, human patient CARD9 mutation analysis, macrophage-specific functional assays Cell High 33548172
2014 CARD9 mediates Dectin-3-induced Mincle expression via the CARD9-BCL10-MALT1 complex and NF-κB (but not NFAT) activation. NF-κB binds the Mincle promoter, and CARD9- or Dectin-3-deficient macrophages fail to upregulate Mincle in response to TDM (mycobacterial trehalose 6,6'-dimycolate). Dectin-3−/− and Card9−/− bone marrow-derived macrophages, NF-κB/NFAT reporter assays, chromatin immunoprecipitation of NF-κB at Mincle promoter, cytokine ELISA, immunization experiments The Journal of biological chemistry High 25202022
2016 CARD9 promotes recovery from colitis partly by enabling the gut microbiota to metabolize tryptophan into aryl hydrocarbon receptor (AHR) ligands, which promote IL-22 production. Transfer of Card9−/− microbiota to germ-free wild-type recipients increases colitis susceptibility, and the Card9−/− microbiota fails to produce AHR ligands from tryptophan. Card9−/− mice, germ-free recipient microbiota transfer, metabolomics (tryptophan metabolites), AHR agonist treatment, Lactobacillus inoculation, IL-22 measurement Nature medicine High 27158904
2011 AIRE forms a transient complex with phosphorylated Syk and CARD9 at the cell membrane after Dectin-1 ligation, participating in the Dectin-1 signaling pathway to support TNF-α production. Reducing AIRE expression in THP-1 cells decreases TNF-α release after Dectin-1 ligation. Co-immunoprecipitation of AIRE-pSyk-CARD9, confocal microscopy of AIRE-Dectin-1 co-localization, siRNA knockdown, PBMC stimulation assays from APECED patients The Journal of allergy and clinical immunology Medium 21962774
2014 CARD9 promotes metastasis-associated macrophage polarization through NF-κB activation. Tumor cell-secreted VEGF activates Syk in macrophages, which is necessary for formation of the CARD9-BCL10-MALT1 complex. Card9−/− bone marrow promotes less liver metastasis of colon carcinoma cells. Card9−/− bone marrow transplantation, co-immunoprecipitation of CARD9-BCL10-MALT1, NF-κB activation assays, VEGF/Syk pathway inhibition, in vivo metastasis model Cell death and differentiation Medium 24722209

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nature medicine 1167 27158904
2007 Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nature immunology 954 17450144
2006 Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 700 16862125
2009 A homozygous CARD9 mutation in a family with susceptibility to fungal infections. The New England journal of medicine 636 19864672
2009 Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nature immunology 438 19915568
2006 The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nature immunology 357 17187069
2013 Deep dermatophytosis and inherited CARD9 deficiency. The New England journal of medicine 301 24131138
2007 The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nature immunology 297 17486093
2012 Syk kinase-coupled C-type lectin receptors engage protein kinase C-δ to elicit Card9 adaptor-mediated innate immunity. Immunity 225 22265677
2000 CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B. The Journal of biological chemistry 202 11053425
2019 CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment. Nature immunology 194 30996332
2011 The role of Syk/CARD9 coupled C-type lectins in antifungal immunity. European journal of immunology 180 21267996
2015 CARD9-Dependent Neutrophil Recruitment Protects against Fungal Invasion of the Central Nervous System. PLoS pathogens 170 26679537
2018 SYK-CARD9 Signaling Axis Promotes Gut Fungi-Mediated Inflammasome Activation to Restrict Colitis and Colon Cancer. Immunity 169 30231985
2021 Human gut mycobiota tune immunity via CARD9-dependent induction of anti-fungal IgG antibodies. Cell 166 33548172
2018 The Adaptor Protein CARD9 Protects against Colon Cancer by Restricting Mycobiota-Mediated Expansion of Myeloid-Derived Suppressor Cells. Immunity 164 30231984
2010 The adaptor molecule CARD9 is essential for tuberculosis control. The Journal of experimental medicine 164 20351059
2016 Extrapulmonary Aspergillus infection in patients with CARD9 deficiency. JCI insight 137 27777981
2018 Inherited CARD9 Deficiency: Invasive Disease Caused by Ascomycete Fungi in Previously Healthy Children and Adults. Journal of clinical immunology 131 30136218
2013 Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology 126 23732773
2014 Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production. Nature immunology 125 24777530
2018 Human CARD9: A Critical Molecule of Fungal Immune Surveillance. Frontiers in immunology 122 30127791
2014 CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity. The Journal of experimental medicine 119 25267792
2010 CARD9 mediates dectin-2-induced IkappaBalpha kinase ubiquitination leading to activation of NF-kappaB in response to stimulation by the hyphal form of Candida albicans. The Journal of biological chemistry 104 20538615
2014 C-type lectin receptor dectin-3 mediates trehalose 6,6'-dimycolate (TDM)-induced Mincle expression through CARD9/Bcl10/MALT1-dependent nuclear factor (NF)-κB activation. The Journal of biological chemistry 103 25202022
2016 Mechanistic Insights into the Role of C-Type Lectin Receptor/CARD9 Signaling in Human Antifungal Immunity. Frontiers in cellular and infection microbiology 100 27092298
2015 Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection. PLoS pathogens 96 25621893
2009 CARD9 versus CARMA1 in innate and adaptive immunity. Trends in immunology 91 19359218
2008 CARD9 signaling in the innate immune response. Annals of the New York Academy of Sciences 90 19076343
2017 Oxidized Low-Density Lipoprotein Immune Complex Priming of the Nlrp3 Inflammasome Involves TLR and FcγR Cooperation and Is Dependent on CARD9. Journal of immunology (Baltimore, Md. : 1950) 89 28130494
2020 CARD9 promotes autophagy in cardiomyocytes in myocardial ischemia/reperfusion injury via interacting with Rubicon directly. Basic research in cardiology 84 32248306
2016 Chronic and Invasive Fungal Infections in a Family with CARD9 Deficiency. Journal of clinical immunology 82 26961233
2018 Frequency and Geographic Distribution of CARD9 Mutations in Patients With Severe Fungal Infections. Frontiers in microbiology 72 30369919
2015 A homozygous CARD9 mutation in a Brazilian patient with deep dermatophytosis. Journal of clinical immunology 70 26044242
2015 Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians. The Journal of allergy and clinical immunology 70 26521038
2017 Impaired Specific Antifungal Immunity in CARD9-Deficient Patients with Phaeohyphomycosis. The Journal of investigative dermatology 68 29080677
2021 Dectin-1 limits autoimmune neuroinflammation and promotes myeloid cell-astrocyte crosstalk via Card9-independent expression of Oncostatin M. Immunity 63 33581044
2018 Molecular and physiological roles of the adaptor protein CARD9 in immunity. Cell death & disease 63 29352133
2018 Dectin-1-Syk-CARD9 Signaling Pathway in TB Immunity. Frontiers in immunology 63 29487599
2016 Vav Proteins Are Key Regulators of Card9 Signaling for Innate Antifungal Immunity. Cell reports 63 27926862
2011 Genetic variation in the dectin-1/CARD9 recognition pathway and susceptibility to candidemia. The Journal of infectious diseases 62 21881131
2018 CARD9S12N facilitates the production of IL-5 by alveolar macrophages for the induction of type 2 immune responses. Nature immunology 60 29777223
2010 Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene. Genes and immunity 60 20463747
2008 Cell type-specific regulation of ITAM-mediated NF-kappaB activation by the adaptors, CARMA1 and CARD9. Journal of immunology (Baltimore, Md. : 1950) 58 18606643
2016 Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye. Journal of immunology (Baltimore, Md. : 1950) 57 26921309
2014 An ITAM-Syk-CARD9 signalling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells. Nature communications 56 24806599
2011 Proinflammatory protein CARD9 is essential for infiltration of monocytic fibroblast precursors and cardiac fibrosis caused by Angiotensin II infusion. American journal of hypertension 56 21436792
2020 Ganoderma lucidum polysaccharide (GLP) enhances antitumor immune response by regulating differentiation and inhibition of MDSCs via a CARD9-NF-κB-IDO pathway. Bioscience reports 55 32530032
2016 CARD9 knockout ameliorates myocardial dysfunction associated with high fat diet-induced obesity. Journal of molecular and cellular cardiology 55 26900039
2022 CARD9 Signaling, Inflammation, and Diseases. Frontiers in immunology 53 35432375
2021 TREM (Triggering Receptor Expressed on Myeloid Cells)-1 Inhibition Attenuates Neuroinflammation via PKC (Protein Kinase C) δ/CARD9 (Caspase Recruitment Domain Family Member 9) Signaling Pathway After Intracerebral Hemorrhage in Mice. Stroke 52 33947214
2022 Triptolide promotes autophagy to inhibit mesangial cell proliferation in IgA nephropathy via the CARD9/p38 MAPK pathway. Cell proliferation 51 35733381
2014 Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization. Cell death and differentiation 49 24722209
2011 Targeting Syk-Card9-activating C-type lectin receptors by vaccine adjuvants: findings, implications and open questions. Immunobiology 48 21742403
2005 Overexpression of caspase recruitment domain (CARD) membrane-associated guanylate kinase 1 (CARMA1) and CARD9 in primary gastric B-cell lymphoma. Cancer 47 16177990
2017 Zinc rescues obesity-induced cardiac hypertrophy via stimulating metallothionein to suppress oxidative stress-activated BCL10/CARD9/p38 MAPK pathway. Journal of cellular and molecular medicine 45 28158919
2022 CARD9 in neutrophils protects from colitis and controls mitochondrial metabolism and cell survival. Gut 41 36167663
2018 A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation. Frontiers in immunology 41 30429846
2011 The role of Syk/CARD9-coupled C-type lectin receptors in immunity to Mycobacterium tuberculosis infections. Clinical & developmental immunology 41 21274433
2015 Evidence for TLR4 and FcRγ-CARD9 activation by cholera toxin B subunit and its direct bindings to TREM2 and LMIR5 receptors. Molecular immunology 39 26021803
2015 Delinking CARD9 and IL-17: CARD9 Protects against Candida tropicalis Infection through a TNF-α-Dependent, IL-17-Independent Mechanism. Journal of immunology (Baltimore, Md. : 1950) 39 26336150
2019 Structures of autoinhibited and polymerized forms of CARD9 reveal mechanisms of CARD9 and CARD11 activation. Nature communications 38 31296852
2019 The multifaceted role of CARD9 in inflammatory bowel disease. Journal of cellular and molecular medicine 38 31696662
2019 Dok3-protein phosphatase 1 interaction attenuates Card9 signaling and neutrophil-dependent antifungal immunity. The Journal of clinical investigation 36 31180338
2017 Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence. Gut 35 28790160
2020 CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis. mBio 34 31911495
2020 The adaptor protein CARD9, from fungal immunity to tumorigenesis. American journal of cancer research 34 32905547
2023 Macrophage CARD9 mediates cardiac injury following myocardial infarction through regulation of lipocalin 2 expression. Signal transduction and targeted therapy 33 37828006
2016 Card9- and MyD88-Mediated Gamma Interferon and Nitric Oxide Production Is Essential for Resistance to Subcutaneous Coccidioides posadasii Infection. Infection and immunity 33 26857574
2015 CARD9 deficiencies linked to impaired neutrophil functions against Phialophora verrucosa. Mycopathologia 33 25790941
2019 CARD9 inhibits mitochondria-dependent apoptosis of cardiomyocytes under oxidative stress via interacting with Apaf-1. Free radical biology & medicine 32 31212066
2019 The CARD9-Associated C-Type Lectin, Mincle, Recognizes La Crosse Virus (LACV) but Plays a Limited Role in Early Antiviral Responses against LACV. Viruses 31 30917612
2019 CARD9 prevents lung cancer development by suppressing the expansion of myeloid-derived suppressor cells and IDO production. International journal of cancer 31 31008530
2019 Phaeohyphomycosis caused by Phialophora americana with CARD9 mutation and 20-year literature review in China. Mycoses 30 31271673
2021 S-Layer From Lactobacillus brevis Modulates Antigen-Presenting Cell Functions via the Mincle-Syk-Card9 Axis. Frontiers in immunology 29 33732234
2016 Moraxella catarrhalis induces CEACAM3-Syk-CARD9-dependent activation of human granulocytes. Cellular microbiology 29 27038042
2016 Impairment of Immune Response against Dematiaceous Fungi in Card9 Knockout Mice. Mycopathologia 29 27421992
2020 Inherited CARD9 Deficiency in a Patient with Both Exophiala spinifera and Aspergillus nomius Severe Infections. Journal of clinical immunology 28 31940125
2020 CARD9-Associated Dectin-1 and Dectin-2 Are Required for Protective Immunity of a Multivalent Vaccine against Coccidioides posadasii Infection. Journal of immunology (Baltimore, Md. : 1950) 27 32358020
2019 CARD9 mediates dendritic cell-induced development of Lyn deficiency-associated autoimmune and inflammatory diseases. Science signaling 27 31594855
2024 Card9/neutrophil signalling axis promotes IL-17A-mediated ankylosing spondylitis. Annals of the rheumatic diseases 26 37813481
2020 Physiological and Pathological Functions of CARD9 Signaling in the Innate Immune System. Current topics in microbiology and immunology 26 32415389
2020 The role and mechanism of CARD9 gene polymorphism in diseases. Biomedical journal 26 34690098
2021 Talaromyces Marneffei Infection in an HIV-Negative Child with a CARD9 Mutation in China: A Case Report and Review of the Literature. Mycopathologia 24 34224076
2020 Primary Cutaneous Aspergillosis in a Patient with CARD9 Deficiency and Aspergillus Susceptibility of Card9 Knockout Mice. Journal of clinical immunology 24 33180249
2017 Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism. Clinical and experimental immunology 24 28763100
2023 Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy. Nature communications 23 37528097
2017 Novel bi-allelic splice mutations in CARD9 causing adult-onset Candida endophthalmitis. Mycoses 23 28984994
2021 OTUD1 Regulates Antifungal Innate Immunity through Deubiquitination of CARD9. Journal of immunology (Baltimore, Md. : 1950) 22 33789983
2016 CARD9 as a potential target in cardiovascular disease. Drug design, development and therapy 22 27920495
2015 Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity. Scientific reports 22 26627732
2017 Card9 controls Dectin-1-induced T-cell cytotoxicity and tumor growth in mice. European journal of immunology 21 28295265
2015 CARD9 mediates necrotic smooth muscle cell-induced inflammation in macrophages contributing to neointima formation of vein grafts. Cardiovascular research 21 26243429
2015 Determination of IL1 R2, ANTXR2, CARD9, and SNAPC4 single nucleotide polymorphisms in Iranian patients with ankylosing spondylitis. Rheumatology international 20 26590821
2018 The essential function of CARD9 in diet-induced inflammation and metabolic disorders in mice. Journal of cellular and molecular medicine 19 29575791
2014 Interaction between NOD2 and CARD9 involves the NOD2 NACHT and the linker region between the NOD2 CARDs and NACHT domain. FEBS letters 19 24960071
2024 Macrophage OTUD1-CARD9 axis drives isoproterenol-induced inflammatory heart remodelling. Clinical and translational medicine 18 39118286
2022 The combination of gemcitabine and ginsenoside Rh2 enhances the immune function of dendritic cells against pancreatic cancer via the CARD9-BCL10-MALT1 / NF-κB pathway. Clinical immunology (Orlando, Fla.) 18 36581220
2020 Invasive Saprochaete capitata Infection in a Patient with Autosomal Recessive CARD9 Deficiency and a Review of the Literature. Journal of clinical immunology 18 32020378
2011 Autoimmune regulator (AIRE) contributes to Dectin-1-induced TNF-α production and complexes with caspase recruitment domain-containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1. The Journal of allergy and clinical immunology 18 21962774

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