{"gene":"CARD10","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2001,"finding":"CARD10 (BIMP1) was identified as a novel MAGUK/CARD family member that binds BCL10 and MALT1, forming a ternary complex (with BCL10 bridging BIMP1/MALT1 interaction), and activates NF-κB upstream of IκB kinases; a dominant-negative BIMP1 mutant inhibits NF-κB activation by anti-CD3 ligation, phorbol ester, and PKC expression.","method":"Co-immunoprecipitation, dominant-negative mutant expression, NF-κB reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, dominant-negative functional validation, replicated across stimuli","pmids":["11387339"],"is_preprint":false},{"year":2001,"finding":"CARD10 belongs to the membrane-associated guanylate kinase (MAGUK) family, binds BCL10 via its N-terminal CARD domain, and signals NF-κB activation; proposed to function as a molecular scaffold for assembly of a BCL10 signaling complex at plasma membranes.","method":"Co-immunoprecipitation, NF-κB reporter assays, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstrated by Co-IP, functional NF-κB activation established with domain mapping","pmids":["11259443"],"is_preprint":false},{"year":2004,"finding":"CARMA3 (CARD10) physically associates with IκB kinase γ/NEMO in lymphoid and non-lymphoid cells and participates in an inducible large molecular complex containing IKKγ/NEMO, BCL10, and IKKα/β; expression of the NEMO-binding region of CARMA3 exerts a dominant-negative effect on BCL10-mediated NF-κB activation.","method":"Co-immunoprecipitation, dominant-negative expression, NF-κB reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP in multiple cell types, dominant-negative functional validation","pmids":["15184390"],"is_preprint":false},{"year":2006,"finding":"CARMA3/BCL10/MALT1 complex mediates angiotensin II type 1 receptor (GPCR)-induced NF-κB activation in hepatocytes; blocking any of the three proteins via dominant-negative mutants, RNAi, or gene targeting abolishes Ang II-dependent NF-κB activation; pathway activates NF-κB through ubiquitination of IKKγ/NEMO.","method":"Dominant-negative mutants, RNAi, Bcl10 knockout mice, ubiquitination assay, NF-κB reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including genetic knockout, RNAi, and dominant-negatives; in vivo validation","pmids":["17101977"],"is_preprint":false},{"year":2007,"finding":"CARMA3 is required for GPCR-induced NF-κB activation; CARMA3 deficiency impairs GPCR-induced IKK kinase activity (but not IKKα/β phosphorylation); CARMA3 physically associates with NEMO/IKKγ and induces polyubiquitination of a protein associated with NEMO, likely by linking NEMO to TRAF6; TRAF6 deficiency also abrogates GPCR-induced NF-κB activation.","method":"CARMA3 knockout mice (gene targeting), Co-immunoprecipitation, IKK kinase assay, ubiquitination assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — genetic knockout with in vitro kinase assays and Co-IP; multiple orthogonal methods","pmids":["17438001"],"is_preprint":false},{"year":2007,"finding":"PKCα links LPA receptor signaling to CARMA3 in ovarian cancer cells; LPA stimulation activates PKCα and induces Ras-PKCα interaction; dominant-negative PKCα attenuates LPA-induced NF-κB activation and uPA upregulation; dominant-negative CARMA3 or siRNA knockdown of CARMA3/BCL10/MALT1 diminishes LPA-induced NF-κB activation, uPA upregulation, and invasion.","method":"Dominant-negative mutants, siRNA knockdown, NF-κB reporter assays, invasion assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (dominant-negatives + siRNA) in multiple cell lines","pmids":["17724468"],"is_preprint":false},{"year":2008,"finding":"The CXCL8/IL-8-CXCR2 axis activates NF-κB and up-regulates VEGF in endothelial cells via the CBM (CARMA3/BCL10/MALT1) complex, independently of HIF1α.","method":"Dominant-negative constructs, NF-κB reporter assays, Western blot, siRNA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — functional knockdown with defined readout, single lab","pmids":["19112107"],"is_preprint":false},{"year":2008,"finding":"CARMA3 is specifically expressed in human airway epithelial cells and mediates LPA-induced NF-κB activation and downstream expression of TSLP and CCL20; inhibition of CARMA3 reduces LPA-mediated NF-κB activity and cytokine production in bronchial epithelial cells.","method":"siRNA knockdown, NF-κB reporter assays, ELISA, qPCR","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — functional KD with specific cytokine readouts, single lab","pmids":["18757306"],"is_preprint":false},{"year":2008,"finding":"A20 negatively regulates CARMA3/BCL10/MALT1 signaling by its deubiquitylation activity; A20 perturbs assembly of the CARMA3-BCL10-IKKγ/NEMO complex, suppressing NF-κB activation.","method":"Co-immunoprecipitation, deubiquitylation assay, NF-κB reporter assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical complex disruption assay with mechanistic readout, single lab","pmids":["18349075"],"is_preprint":false},{"year":2009,"finding":"CXCL12/CXCR4 activates NF-κB through the CARMA3/BCL10/MALT1 (CBM) complex in oral squamous cell carcinoma cells; novel and atypical (but not classical) PKCs activate IKK through CXCR4; CBM complex inhibition significantly decreases SDF-1α-mediated invasion.","method":"Lentivirus-based knockdown, Western blot, EMSA, invasion assays","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 — functional KD with multiple readouts, single lab","pmids":["20695076"],"is_preprint":false},{"year":2010,"finding":"CARMA3/BCL10/MALT1 signalosome links PAR-1 (thrombin receptor, a GPCR) activation to IKK complex stimulation in endothelial cells; the CARMA3-containing signalosome relies on β-arrestin 2 (not PDK1) for assembly, distinguishing it from the CARMA1-containing lymphocyte signalosome; thrombin-dependent monocyte-endothelial adhesion requires an intact endothelial CARMA3·BCL10·MALT1 signalosome.","method":"siRNA knockdown, Co-immunoprecipitation, NF-κB reporter assays, monocyte-endothelial adhesion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — mechanistic distinction from CARMA1 complex established with multiple methods; functional adhesion readout","pmids":["21041303"],"is_preprint":false},{"year":2010,"finding":"CARMA3/BCL10/MALT1 signalosome mediates angiotensin II type 1 receptor-dependent NF-κB activation in endothelial and vascular smooth muscle cells, driving pro-inflammatory vascular signaling; Bcl10-deficient mice are protected from angiotensin II-dependent atherosclerosis and aortic aneurysms.","method":"siRNA knockdown, dominant-negative constructs, Bcl10 knockout mice, in vivo atherosclerosis model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout in vivo, multiple cell types, replicated signaling mechanism","pmids":["20605784"],"is_preprint":false},{"year":2011,"finding":"CARMA3 is required for EGF receptor (RTK)-induced NF-κB activation; CARMA3 deficiency impairs IKK complex activation following EGF stimulation, reducing IκBα phosphorylation and NF-κB activation; CARMA3 and BCL10 contribute to EGFR-associated proliferation, survival, migration, invasion, and tumor growth in vivo.","method":"CARMA3 knockout cells, siRNA, NF-κB reporter, in vivo tumor xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — genetic KO and siRNA with in vivo tumor model and multiple mechanistic readouts","pmids":["21406399"],"is_preprint":false},{"year":2012,"finding":"miR-146a directly targets CARD10 and COPS8 mRNA (validated by luciferase assay and Western blot) in gastric cancer cells, inhibiting GPCR-mediated NF-κB activation and reducing LPA-induced cytokine/growth factor expression and monocyte attraction.","method":"Luciferase reporter assay, Western blot, qPCR, NF-κB reporter, miR-146a transfection","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — direct target validation with luciferase assay and functional NF-κB readout, single lab","pmids":["22992343"],"is_preprint":false},{"year":2014,"finding":"miR-146a induced by LPS directly targets CARD10 in human umbilical vein endothelial cells (validated by Ago2 RIP and luciferase assay); CARD10 knockdown inhibits p65 nuclear translocation and increases angiogenesis, placing CARD10 as a negative regulator of NF-κB-dependent impairment of angiogenesis in a negative feedback loop.","method":"Ago2 ribonucleoprotein immunoprecipitation, luciferase reporter assay, siRNA knockdown, p65 nuclear translocation assay, tube formation assay","journal":"Toxicological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — Ago2 RIP plus luciferase validation plus functional localization readout, single lab","pmids":["24863965"],"is_preprint":false},{"year":2014,"finding":"DEPDC7 (DEP domain-containing protein) binds to CARMA3 as a cellular binding partner; DEPDC7 shRNA-mediated knockdown impairs NF-κB activation following GPCR stimulation (in a CARMA3-dependent but CARMA1-independent manner), identifying DEPDC7 as a CARMA3-specific co-activator in the CBM complex pathway.","method":"Co-immunoprecipitation, shRNA knockdown, NF-κB reporter assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with functional KD validation, single lab","pmids":["25541973"],"is_preprint":false},{"year":2015,"finding":"CARMA3 promotes lung cancer stemness and metastasis by reducing NME2 levels through an NF-κB/miR-182 pathway; chromatin immunoprecipitation and luciferase assays demonstrate NF-κB-driven miR-182 expression that suppresses NME2, and CARMA3 inversely correlates with NME2 in patient samples.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, in vitro and in vivo metastasis assays","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus luciferase plus functional in vivo validation, single lab","pmids":["25906011"],"is_preprint":false},{"year":2015,"finding":"CARMA3 mediates NF-κB activation and suppresses P38 MAPK signaling in lung cancer cells; CARMA3 knockdown increases P38 phosphorylation while decreasing NF-κB nuclear p65, and P38 inhibitor (SB203580) reverses CARMA3-knockdown-induced migration inhibition and apoptosis, establishing reciprocal regulation between NF-κB and P38 MAPK downstream of CARMA3.","method":"siRNA knockdown, P38 inhibitor treatment, Western blot, flow cytometry, NF-κB reporter","journal":"Experimental and molecular pathology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and genetic epistasis with multiple mechanistic readouts, single lab","pmids":["26526492"],"is_preprint":false},{"year":2015,"finding":"CARMA3 depletion in pancreatic cancer cells inhibits EGF-induced NF-κB activation through a Bcl10-dependent mechanism; the effect of CARMA3 depletion on NF-κB signaling is significantly reduced in Bcl10-depleted cells, establishing Bcl10 as essential downstream mediator.","method":"siRNA knockdown (CARMA3 and Bcl10), NF-κB reporter assays, Western blot","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis by double-KD establishing pathway order, single lab","pmids":["24633921"],"is_preprint":false},{"year":2015,"finding":"CARMA3 is critical for the initiation of allergic airway inflammation via GPCR-induced NF-κB activation in airway epithelial cells; CARMA3-deficient AECs show decreased production of proasthmatic mediators in response to LPA, ATP, Alternaria alternata, and house dust mite; mice with CARMA3-deficient AECs have reduced airway eosinophilia, proinflammatory cytokines, and impaired dendritic cell maturation.","method":"CARMA3 conditional knockout mice, siRNA in primary human bronchial epithelial cells, cytokine ELISAs, in vivo allergic airway model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic conditional KO in vivo with multiple functional readouts, replicated across species","pmids":["26041536"],"is_preprint":false},{"year":2016,"finding":"CARMA3 positively regulates MAVS-induced NF-κB activation during RNA virus infection; however, CARMA3 sequesters MAVS from forming high-molecular-weight aggregates, thereby suppressing TBK1/IRF3 activation and type I IFN production; following NF-κB activation, CARMA3 undergoes proteasome-dependent degradation, releasing MAVS to activate IRF3; CARMA3-deficient mice show reduced inflammation and enhanced viral clearance.","method":"CARMA3 knockout mice, Co-immunoprecipitation, sucrose gradient sedimentation (MAVS aggregate assay), proteasome inhibitor experiments, in vivo viral infection","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic KO in vivo, biochemical aggregate assay, proteasome-dependent degradation mechanism, multiple orthogonal methods","pmids":["26947079"],"is_preprint":false},{"year":2017,"finding":"AGTR1 (angiotensin II receptor) overexpression activates NF-κB via the CARMA3/BCL10/MALT1 (CBM) signalosome in breast cancer, driving both ligand-independent and ligand-dependent NF-κB activation, cancer cell proliferation, migration, invasion, and tumor angiogenesis.","method":"siRNA knockdown of CBM components, NF-κB reporter assays, in vitro proliferation/migration/invasion assays, endothelial angiogenesis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — functional KD with multiple cancer hallmark readouts, single lab","pmids":["29259013"],"is_preprint":false},{"year":2018,"finding":"CARD10 is a transcriptional target of CEBPE; CEBPE binds regulatory elements upstream of the murine Card10 locus (shown by ChIP); Card10 expression is significantly reduced in Cebpe knockout mice; silencing Card10 impairs granulopoiesis, demonstrating a role for CARD10 in granulocytic differentiation.","method":"ChIP, Cebpe knockout mice, siRNA knockdown in human cell line and murine primary cells, granulopoiesis assays","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus genetic KO mouse plus siRNA functional validation, single lab","pmids":["29773596"],"is_preprint":false},{"year":2018,"finding":"CARMA3 mediates A. alternata-induced allergic airway inflammation; CARMA3 interacts with inositol 1,4,5-trisphosphate receptors (IP3Rs) in airway epithelial cells, and inhibition of CARMA3 signaling reduces A. alternata-induced intracellular calcium release.","method":"Co-immunoprecipitation (CARMA3-IP3R interaction), CARMA3-deficient AEC mice, intracellular calcium measurement, in vivo allergic inflammation model","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — novel binding partner (IP3R) by Co-IP with functional calcium readout and in vivo validation, single lab","pmids":["29958012"],"is_preprint":false},{"year":2021,"finding":"CARD10 is the first identified MALT1 substrate in non-hematopoietic cells; MALT1 cleaves CARD10 at R587, dampening its capacity to activate NF-κB; preventing CARD10 cleavage in lung tumor cells increased basal IL-6 and extracellular matrix components in vitro and led to increased tumor growth in a mouse xenograft model, indicating CARD10 cleavage by MALT1 is a built-in mechanism controlling tumorigenicity.","method":"MALT1 cleavage assay (in vitro), site-directed mutagenesis (R587A), NF-κB reporter, cytokine ELISA, mouse xenograft model","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 1 — in vitro cleavage assay with mutagenesis, plus in vivo xenograft validation; multiple orthogonal methods","pmids":["33824280"],"is_preprint":false},{"year":2021,"finding":"CARMA3 promotes CRC motility and cancer stemness via a CARMA3/YAP/Slug signaling axis; CARMA3 activates NF-κB through YAP expression, which upregulates Slug (EMT transcription factor); genetic inhibition of YAP blocks CARMA3-mediated migration/invasion.","method":"siRNA/shRNA knockdown, NF-κB reporter, YAP inhibition, in vivo tumor model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis by sequential KD establishing pathway order, in vivo validation, single lab","pmids":["34885061"],"is_preprint":false},{"year":2022,"finding":"CARMA3 localizes to mitochondria in liver sinusoidal endothelial cells (LSECs); in Carma3-deficient LSECs, Con A treatment triggers increased mitochondrial damage and cell death, revealing a role for CARMA3 in maintaining mitochondrial integrity independent of its known NF-κB scaffolding function.","method":"Carma3 knockout mice, subcellular fractionation/co-localization (mitochondrial localization), in vitro LSEC injury assays, Con A hepatitis model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by fractionation with functional KO consequence, single lab; novel unexpected localization","pmids":["35831018"],"is_preprint":false},{"year":2024,"finding":"SHH signaling activates the CARD10-BCL10-MALT1 (CBM) complex formation in cardiomyocytes via PKCα; inhibition of PKCα attenuates CBM complex formation; disruption of the CBM complex prevents MALT1 from recruiting TRAF6, which triggers caspase-11-dependent pyroptosis in myocardial ischemia/reperfusion injury.","method":"PKCα inhibitor (pharmacological), siRNA knockdown, Co-immunoprecipitation (CBM complex), caspase-11 pyroptosis assay, mouse I/R model","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and genetic epistasis with biochemical complex assembly assay, in vivo model, single lab","pmids":["39343081"],"is_preprint":false},{"year":2024,"finding":"CARMA3 binds BCL10 and MALT1 to form a signalosome in nucleus pulposus cells; CARMA3 knockdown reduces CARMA3-BCL10-MALT1 signalosome-mediated NF-κB activation, decreasing MMP-3, MMP-13, ADAMTS-5, and caspase-3, and reversing intervertebral disc degeneration pathology.","method":"Co-immunoprecipitation (CARMA3-BCL10-MALT1 complex), siRNA knockdown, Western blot, in vivo rat IDD model","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP demonstrating complex formation with functional KD readout in vivo, single lab","pmids":["38607566"],"is_preprint":false},{"year":2025,"finding":"CARMA3 suppresses myofibroblast activation by inhibiting STAT1 phosphorylation in cardiac fibroblasts; CARMA3 physically interacts with STAT1 in response to pressure overload; CARMA3-knockout mice show increased STAT1 phosphorylation, exacerbated myofibroblast differentiation, collagen production, and cardiac fibrosis.","method":"Co-immunoprecipitation (CARMA3-STAT1 interaction), CARMA3 knockout mice (TAC and Ang II models), proteomic analysis, flow cytometry","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP of novel binding partner plus genetic KO with in vivo phenotype, single lab","pmids":["41053092"],"is_preprint":false}],"current_model":"CARD10 (CARMA3) is a CARD-MAGUK scaffold protein that assembles the CARMA3-BCL10-MALT1 (CBM) signalosome downstream of GPCRs, RTKs (EGFR), and innate immune sensors (RIG-I/MAVS), recruits NEMO/IKKγ and TRAF6 to drive canonical NF-κB activation via IKK complex polyubiquitination, and is itself feedback-regulated by MALT1-mediated cleavage at R587 and by proteasomal degradation following viral activation, with additional non-NF-κB roles including mitochondrial integrity maintenance in endothelial cells, STAT1 phosphorylation suppression in cardiac fibroblasts, and IP3R-mediated calcium signaling in airway epithelium."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of CARD10 as a MAGUK-family scaffold that binds BCL10 and MALT1 to activate NF-κB established the existence of a non-lymphocyte CBM signalosome and its core molecular architecture.","evidence":"Co-immunoprecipitation, domain deletion mapping, dominant-negative expression, and NF-κB reporter assays in multiple cell types","pmids":["11387339","11259443"],"confidence":"High","gaps":["Upstream receptor inputs not yet defined","Endogenous stoichiometry and oligomerization state unknown","No structural model of the CARD10–BCL10 interface"]},{"year":2004,"claim":"Demonstrating that CARD10 physically associates with NEMO/IKKγ in an inducible complex with BCL10 and IKKα/β revealed how the CBM signalosome engages the IKK complex to transmit NF-κB activation signals.","evidence":"Reciprocal co-immunoprecipitation in lymphoid and non-lymphoid cells, dominant-negative NEMO-binding region expression","pmids":["15184390"],"confidence":"High","gaps":["Ubiquitin chain type mediating IKK activation not specified","Direct vs. bridged interaction between CARD10 and NEMO not resolved"]},{"year":2007,"claim":"Genetic knockout studies established that CARD10 is essential for GPCR-induced NF-κB activation and showed that TRAF6 is recruited to NEMO via CARD10 to catalyze polyubiquitination, defining the pathway from receptor to IKK activation.","evidence":"CARMA3 knockout mice, IKK kinase assays, ubiquitination assays, co-immunoprecipitation, and PKCα epistasis with dominant-negatives in ovarian cancer cells","pmids":["17438001","17101977","17724468"],"confidence":"High","gaps":["Direct PKC phosphorylation site on CARD10 not mapped","Relationship to alternative ubiquitin ligases (e.g., cIAP1/2) not tested"]},{"year":2010,"claim":"Discovery that β-arrestin 2 (not PDK1) mediates CBM signalosome assembly downstream of GPCRs distinguished the CARD10 pathway from the CARMA1-dependent lymphocyte signalosome and linked it to vascular inflammation and atherosclerosis.","evidence":"siRNA knockdown and co-IP in endothelial cells for β-arrestin 2 dependence; Bcl10 knockout mice protected from Ang II-induced atherosclerosis and aortic aneurysms","pmids":["21041303","20605784"],"confidence":"High","gaps":["β-arrestin 2 binding site on CARD10 not mapped","Whether β-arrestin 2 acts as adaptor or conformational activator is unresolved"]},{"year":2011,"claim":"Extension of CARD10 function to RTK signaling showed that EGFR activates NF-κB through the CBM signalosome, broadening CARD10's role beyond GPCRs to receptor tyrosine kinase-driven oncogenesis.","evidence":"CARMA3 knockout cells, siRNA, NF-κB reporter, and in vivo tumor xenograft","pmids":["21406399"],"confidence":"High","gaps":["How EGFR signals to CARD10 (direct phosphorylation vs. intermediate PKC) not determined","Generality to other RTKs untested"]},{"year":2015,"claim":"Conditional knockout of CARD10 in airway epithelial cells demonstrated its non-redundant requirement for allergic airway inflammation, establishing the CBM signalosome as a critical innate epithelial signaling node for proasthmatic mediator production.","evidence":"CARMA3 conditional knockout mice, primary human bronchial epithelial cell siRNA, in vivo allergen challenge models with multiple stimuli","pmids":["26041536"],"confidence":"High","gaps":["Relative contributions of NF-κB versus calcium signaling arms in airway inflammation not dissected","Therapeutic window for CARD10 inhibition in asthma not assessed"]},{"year":2016,"claim":"Revealing that CARD10 sequesters MAVS from forming high-molecular-weight aggregates to suppress TBK1/IRF3 activation while simultaneously promoting MAVS-dependent NF-κB uncovered a dual regulatory role and a proteasome-dependent degradation switch during antiviral signaling.","evidence":"CARMA3 knockout mice, sucrose gradient sedimentation for MAVS aggregation, proteasome inhibitor experiments, in vivo viral infection","pmids":["26947079"],"confidence":"High","gaps":["Ubiquitin ligase responsible for CARD10 proteasomal targeting not identified","Whether CARD10–MAVS interaction is direct or BCL10-bridged not resolved"]},{"year":2018,"claim":"Identification of CARD10 interaction with IP3 receptors in airway epithelial cells revealed a non-NF-κB function in calcium signaling, expanding the mechanistic repertoire of the scaffold beyond inflammatory transcription.","evidence":"Co-immunoprecipitation of CARMA3–IP3R, intracellular calcium measurement, CARMA3-deficient AEC mice","pmids":["29958012"],"confidence":"Medium","gaps":["Binding interface between CARD10 and IP3R not mapped","Whether calcium regulation requires BCL10/MALT1 or is independent unknown","Single-lab finding awaits independent replication"]},{"year":2021,"claim":"Discovery that MALT1 cleaves CARD10 at R587 to dampen NF-κB signaling identified the first non-hematopoietic MALT1 substrate and revealed a built-in negative feedback mechanism controlling tumor-promoting inflammation.","evidence":"In vitro MALT1 cleavage assay, R587A mutagenesis, NF-κB reporter, cytokine ELISA, mouse xenograft tumor growth","pmids":["33824280"],"confidence":"High","gaps":["Whether cleavage generates a dominant-negative fragment or simply inactivates CARD10 not fully resolved","Kinetics of cleavage relative to signalosome disassembly unknown"]},{"year":2022,"claim":"Localization of CARD10 to mitochondria in liver sinusoidal endothelial cells and its requirement for mitochondrial integrity independent of NF-κB revealed a previously unsuspected organelle-level function.","evidence":"Subcellular fractionation and co-localization in LSECs, CARMA3 knockout mice, Con A hepatitis model","pmids":["35831018"],"confidence":"Medium","gaps":["Mitochondrial binding partners and targeting signal not identified","Mechanism by which CARD10 preserves mitochondrial integrity unknown","Single-lab observation in one cell type"]},{"year":2025,"claim":"Demonstration that CARD10 physically interacts with STAT1 to suppress its phosphorylation in cardiac fibroblasts uncovered an NF-κB-independent anti-fibrotic mechanism, expanding CARD10's functional scope to JAK-STAT regulation.","evidence":"Co-immunoprecipitation of CARD10–STAT1, CARMA3 knockout mice subjected to TAC and Ang II pressure overload, proteomics","pmids":["41053092"],"confidence":"Medium","gaps":["Domain on CARD10 mediating STAT1 interaction not mapped","Whether STAT1 suppression is direct (sequestration) or involves a phosphatase intermediary unknown","Single-lab finding"]},{"year":null,"claim":"Key unresolved questions include the structural basis of CARD10 signalosome assembly, the identity of the E3 ubiquitin ligase targeting CARD10 for proteasomal degradation during antiviral signaling, whether the mitochondrial and calcium-signaling functions operate through BCL10/MALT1 or represent independent scaffolding modes, and the direct PKC phosphorylation site(s) on CARD10 that activate the signalosome.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of CARD10 or the CBM signalosome","PKC phosphorylation site on CARD10 not mapped in any system","Relative physiological importance of NF-κB-dependent vs. -independent functions not compared in a single genetic model"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,3,4,10,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[20,29]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,10]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[26]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3,4,5,10,11,12,20,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,19,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[27]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,16,21,24,25]}],"complexes":["CARMA3-BCL10-MALT1 (CBM) signalosome"],"partners":["BCL10","MALT1","NEMO","TRAF6","MAVS","STAT1","ITPR1","DEPDC7"],"other_free_text":[]},"mechanistic_narrative":"CARD10 (CARMA3) is a CARD-domain-containing MAGUK scaffold protein that assembles the CARMA3–BCL10–MALT1 (CBM) signalosome to activate canonical NF-κB signaling downstream of G protein-coupled receptors, receptor tyrosine kinases (EGFR), and innate immune sensors (RIG-I/MAVS). CARD10 binds BCL10 via its CARD domain and recruits NEMO/IKKγ and TRAF6 to drive IKK complex polyubiquitination and NF-κB nuclear translocation; in the GPCR context, β-arrestin 2 is required for signalosome assembly, distinguishing it mechanistically from the lymphocyte CARMA1 complex [PMID:11387339, PMID:17438001, PMID:21041303]. The pathway is negatively regulated by MALT1-mediated cleavage of CARD10 at R587, by A20 deubiquitylase activity disrupting the CBM–NEMO complex, and by proteasomal degradation of CARD10 following viral infection [PMID:33824280, PMID:18349075, PMID:26947079]. Beyond NF-κB scaffolding, CARD10 maintains mitochondrial integrity in endothelial cells, interacts with IP3 receptors to regulate calcium signaling in airway epithelium, and suppresses STAT1 phosphorylation in cardiac fibroblasts [PMID:35831018, PMID:29958012, PMID:41053092]."},"prefetch_data":{"uniprot":{"accession":"Q9BWT7","full_name":"Caspase recruitment domain-containing protein 10","aliases":["CARD-containing MAGUK protein 3","Carma 3"],"length_aa":1032,"mass_kda":115.9,"function":"Scaffold protein that plays an important role in mediating the activation of NF-kappa-B via BCL10 or EGFR","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9BWT7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CARD10","classification":"Not 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CARD10","url":"https://www.omim.org/entry/607209"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, dominant-negative functional validation, replicated across stimuli\",\n      \"pmids\": [\"11387339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CARD10 belongs to the membrane-associated guanylate kinase (MAGUK) family, binds BCL10 via its N-terminal CARD domain, and signals NF-κB activation; proposed to function as a molecular scaffold for assembly of a BCL10 signaling complex at plasma membranes.\",\n      \"method\": \"Co-immunoprecipitation, NF-κB reporter assays, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated by Co-IP, functional NF-κB activation established with domain mapping\",\n      \"pmids\": [\"11259443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CARMA3 (CARD10) physically associates with IκB kinase γ/NEMO in lymphoid and non-lymphoid cells and participates in an inducible large molecular complex containing IKKγ/NEMO, BCL10, and IKKα/β; expression of the NEMO-binding region of CARMA3 exerts a dominant-negative effect on BCL10-mediated NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative expression, NF-κB reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP in multiple cell types, dominant-negative functional validation\",\n      \"pmids\": [\"15184390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CARMA3/BCL10/MALT1 complex mediates angiotensin II type 1 receptor (GPCR)-induced NF-κB activation in hepatocytes; blocking any of the three proteins via dominant-negative mutants, RNAi, or gene targeting abolishes Ang II-dependent NF-κB activation; pathway activates NF-κB through ubiquitination of IKKγ/NEMO.\",\n      \"method\": \"Dominant-negative mutants, RNAi, Bcl10 knockout mice, ubiquitination assay, NF-κB reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including genetic knockout, RNAi, and dominant-negatives; in vivo validation\",\n      \"pmids\": [\"17101977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CARMA3 is required for GPCR-induced NF-κB activation; CARMA3 deficiency impairs GPCR-induced IKK kinase activity (but not IKKα/β phosphorylation); CARMA3 physically associates with NEMO/IKKγ and induces polyubiquitination of a protein associated with NEMO, likely by linking NEMO to TRAF6; TRAF6 deficiency also abrogates GPCR-induced NF-κB activation.\",\n      \"method\": \"CARMA3 knockout mice (gene targeting), Co-immunoprecipitation, IKK kinase assay, ubiquitination assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic knockout with in vitro kinase assays and Co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"17438001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PKCα links LPA receptor signaling to CARMA3 in ovarian cancer cells; LPA stimulation activates PKCα and induces Ras-PKCα interaction; dominant-negative PKCα attenuates LPA-induced NF-κB activation and uPA upregulation; dominant-negative CARMA3 or siRNA knockdown of CARMA3/BCL10/MALT1 diminishes LPA-induced NF-κB activation, uPA upregulation, and invasion.\",\n      \"method\": \"Dominant-negative mutants, siRNA knockdown, NF-κB reporter assays, invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (dominant-negatives + siRNA) in multiple cell lines\",\n      \"pmids\": [\"17724468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The CXCL8/IL-8-CXCR2 axis activates NF-κB and up-regulates VEGF in endothelial cells via the CBM (CARMA3/BCL10/MALT1) complex, independently of HIF1α.\",\n      \"method\": \"Dominant-negative constructs, NF-κB reporter assays, Western blot, siRNA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional knockdown with defined readout, single lab\",\n      \"pmids\": [\"19112107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CARMA3 is specifically expressed in human airway epithelial cells and mediates LPA-induced NF-κB activation and downstream expression of TSLP and CCL20; inhibition of CARMA3 reduces LPA-mediated NF-κB activity and cytokine production in bronchial epithelial cells.\",\n      \"method\": \"siRNA knockdown, NF-κB reporter assays, ELISA, qPCR\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional KD with specific cytokine readouts, single lab\",\n      \"pmids\": [\"18757306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A20 negatively regulates CARMA3/BCL10/MALT1 signaling by its deubiquitylation activity; A20 perturbs assembly of the CARMA3-BCL10-IKKγ/NEMO complex, suppressing NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitylation assay, NF-κB reporter assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical complex disruption assay with mechanistic readout, single lab\",\n      \"pmids\": [\"18349075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CXCL12/CXCR4 activates NF-κB through the CARMA3/BCL10/MALT1 (CBM) complex in oral squamous cell carcinoma cells; novel and atypical (but not classical) PKCs activate IKK through CXCR4; CBM complex inhibition significantly decreases SDF-1α-mediated invasion.\",\n      \"method\": \"Lentivirus-based knockdown, Western blot, EMSA, invasion assays\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional KD with multiple readouts, single lab\",\n      \"pmids\": [\"20695076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CARMA3/BCL10/MALT1 signalosome links PAR-1 (thrombin receptor, a GPCR) activation to IKK complex stimulation in endothelial cells; the CARMA3-containing signalosome relies on β-arrestin 2 (not PDK1) for assembly, distinguishing it from the CARMA1-containing lymphocyte signalosome; thrombin-dependent monocyte-endothelial adhesion requires an intact endothelial CARMA3·BCL10·MALT1 signalosome.\",\n      \"method\": \"siRNA knockdown, Co-immunoprecipitation, NF-κB reporter assays, monocyte-endothelial adhesion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic distinction from CARMA1 complex established with multiple methods; functional adhesion readout\",\n      \"pmids\": [\"21041303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CARMA3/BCL10/MALT1 signalosome mediates angiotensin II type 1 receptor-dependent NF-κB activation in endothelial and vascular smooth muscle cells, driving pro-inflammatory vascular signaling; Bcl10-deficient mice are protected from angiotensin II-dependent atherosclerosis and aortic aneurysms.\",\n      \"method\": \"siRNA knockdown, dominant-negative constructs, Bcl10 knockout mice, in vivo atherosclerosis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout in vivo, multiple cell types, replicated signaling mechanism\",\n      \"pmids\": [\"20605784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CARMA3 is required for EGF receptor (RTK)-induced NF-κB activation; CARMA3 deficiency impairs IKK complex activation following EGF stimulation, reducing IκBα phosphorylation and NF-κB activation; CARMA3 and BCL10 contribute to EGFR-associated proliferation, survival, migration, invasion, and tumor growth in vivo.\",\n      \"method\": \"CARMA3 knockout cells, siRNA, NF-κB reporter, in vivo tumor xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and siRNA with in vivo tumor model and multiple mechanistic readouts\",\n      \"pmids\": [\"21406399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-146a directly targets CARD10 and COPS8 mRNA (validated by luciferase assay and Western blot) in gastric cancer cells, inhibiting GPCR-mediated NF-κB activation and reducing LPA-induced cytokine/growth factor expression and monocyte attraction.\",\n      \"method\": \"Luciferase reporter assay, Western blot, qPCR, NF-κB reporter, miR-146a transfection\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation with luciferase assay and functional NF-κB readout, single lab\",\n      \"pmids\": [\"22992343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-146a induced by LPS directly targets CARD10 in human umbilical vein endothelial cells (validated by Ago2 RIP and luciferase assay); CARD10 knockdown inhibits p65 nuclear translocation and increases angiogenesis, placing CARD10 as a negative regulator of NF-κB-dependent impairment of angiogenesis in a negative feedback loop.\",\n      \"method\": \"Ago2 ribonucleoprotein immunoprecipitation, luciferase reporter assay, siRNA knockdown, p65 nuclear translocation assay, tube formation assay\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Ago2 RIP plus luciferase validation plus functional localization readout, single lab\",\n      \"pmids\": [\"24863965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DEPDC7 (DEP domain-containing protein) binds to CARMA3 as a cellular binding partner; DEPDC7 shRNA-mediated knockdown impairs NF-κB activation following GPCR stimulation (in a CARMA3-dependent but CARMA1-independent manner), identifying DEPDC7 as a CARMA3-specific co-activator in the CBM complex pathway.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, NF-κB reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with functional KD validation, single lab\",\n      \"pmids\": [\"25541973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CARMA3 promotes lung cancer stemness and metastasis by reducing NME2 levels through an NF-κB/miR-182 pathway; chromatin immunoprecipitation and luciferase assays demonstrate NF-κB-driven miR-182 expression that suppresses NME2, and CARMA3 inversely correlates with NME2 in patient samples.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, in vitro and in vivo metastasis assays\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus luciferase plus functional in vivo validation, single lab\",\n      \"pmids\": [\"25906011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CARMA3 mediates NF-κB activation and suppresses P38 MAPK signaling in lung cancer cells; CARMA3 knockdown increases P38 phosphorylation while decreasing NF-κB nuclear p65, and P38 inhibitor (SB203580) reverses CARMA3-knockdown-induced migration inhibition and apoptosis, establishing reciprocal regulation between NF-κB and P38 MAPK downstream of CARMA3.\",\n      \"method\": \"siRNA knockdown, P38 inhibitor treatment, Western blot, flow cytometry, NF-κB reporter\",\n      \"journal\": \"Experimental and molecular pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic epistasis with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"26526492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CARMA3 depletion in pancreatic cancer cells inhibits EGF-induced NF-κB activation through a Bcl10-dependent mechanism; the effect of CARMA3 depletion on NF-κB signaling is significantly reduced in Bcl10-depleted cells, establishing Bcl10 as essential downstream mediator.\",\n      \"method\": \"siRNA knockdown (CARMA3 and Bcl10), NF-κB reporter assays, Western blot\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis by double-KD establishing pathway order, single lab\",\n      \"pmids\": [\"24633921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CARMA3 is critical for the initiation of allergic airway inflammation via GPCR-induced NF-κB activation in airway epithelial cells; CARMA3-deficient AECs show decreased production of proasthmatic mediators in response to LPA, ATP, Alternaria alternata, and house dust mite; mice with CARMA3-deficient AECs have reduced airway eosinophilia, proinflammatory cytokines, and impaired dendritic cell maturation.\",\n      \"method\": \"CARMA3 conditional knockout mice, siRNA in primary human bronchial epithelial cells, cytokine ELISAs, in vivo allergic airway model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic conditional KO in vivo with multiple functional readouts, replicated across species\",\n      \"pmids\": [\"26041536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CARMA3 positively regulates MAVS-induced NF-κB activation during RNA virus infection; however, CARMA3 sequesters MAVS from forming high-molecular-weight aggregates, thereby suppressing TBK1/IRF3 activation and type I IFN production; following NF-κB activation, CARMA3 undergoes proteasome-dependent degradation, releasing MAVS to activate IRF3; CARMA3-deficient mice show reduced inflammation and enhanced viral clearance.\",\n      \"method\": \"CARMA3 knockout mice, Co-immunoprecipitation, sucrose gradient sedimentation (MAVS aggregate assay), proteasome inhibitor experiments, in vivo viral infection\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in vivo, biochemical aggregate assay, proteasome-dependent degradation mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"26947079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AGTR1 (angiotensin II receptor) overexpression activates NF-κB via the CARMA3/BCL10/MALT1 (CBM) signalosome in breast cancer, driving both ligand-independent and ligand-dependent NF-κB activation, cancer cell proliferation, migration, invasion, and tumor angiogenesis.\",\n      \"method\": \"siRNA knockdown of CBM components, NF-κB reporter assays, in vitro proliferation/migration/invasion assays, endothelial angiogenesis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional KD with multiple cancer hallmark readouts, single lab\",\n      \"pmids\": [\"29259013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARD10 is a transcriptional target of CEBPE; CEBPE binds regulatory elements upstream of the murine Card10 locus (shown by ChIP); Card10 expression is significantly reduced in Cebpe knockout mice; silencing Card10 impairs granulopoiesis, demonstrating a role for CARD10 in granulocytic differentiation.\",\n      \"method\": \"ChIP, Cebpe knockout mice, siRNA knockdown in human cell line and murine primary cells, granulopoiesis assays\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus genetic KO mouse plus siRNA functional validation, single lab\",\n      \"pmids\": [\"29773596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARMA3 mediates A. alternata-induced allergic airway inflammation; CARMA3 interacts with inositol 1,4,5-trisphosphate receptors (IP3Rs) in airway epithelial cells, and inhibition of CARMA3 signaling reduces A. alternata-induced intracellular calcium release.\",\n      \"method\": \"Co-immunoprecipitation (CARMA3-IP3R interaction), CARMA3-deficient AEC mice, intracellular calcium measurement, in vivo allergic inflammation model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel binding partner (IP3R) by Co-IP with functional calcium readout and in vivo validation, single lab\",\n      \"pmids\": [\"29958012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CARD10 is the first identified MALT1 substrate in non-hematopoietic cells; MALT1 cleaves CARD10 at R587, dampening its capacity to activate NF-κB; preventing CARD10 cleavage in lung tumor cells increased basal IL-6 and extracellular matrix components in vitro and led to increased tumor growth in a mouse xenograft model, indicating CARD10 cleavage by MALT1 is a built-in mechanism controlling tumorigenicity.\",\n      \"method\": \"MALT1 cleavage assay (in vitro), site-directed mutagenesis (R587A), NF-κB reporter, cytokine ELISA, mouse xenograft model\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro cleavage assay with mutagenesis, plus in vivo xenograft validation; multiple orthogonal methods\",\n      \"pmids\": [\"33824280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CARMA3 promotes CRC motility and cancer stemness via a CARMA3/YAP/Slug signaling axis; CARMA3 activates NF-κB through YAP expression, which upregulates Slug (EMT transcription factor); genetic inhibition of YAP blocks CARMA3-mediated migration/invasion.\",\n      \"method\": \"siRNA/shRNA knockdown, NF-κB reporter, YAP inhibition, in vivo tumor model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis by sequential KD establishing pathway order, in vivo validation, single lab\",\n      \"pmids\": [\"34885061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CARMA3 localizes to mitochondria in liver sinusoidal endothelial cells (LSECs); in Carma3-deficient LSECs, Con A treatment triggers increased mitochondrial damage and cell death, revealing a role for CARMA3 in maintaining mitochondrial integrity independent of its known NF-κB scaffolding function.\",\n      \"method\": \"Carma3 knockout mice, subcellular fractionation/co-localization (mitochondrial localization), in vitro LSEC injury assays, Con A hepatitis model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by fractionation with functional KO consequence, single lab; novel unexpected localization\",\n      \"pmids\": [\"35831018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SHH signaling activates the CARD10-BCL10-MALT1 (CBM) complex formation in cardiomyocytes via PKCα; inhibition of PKCα attenuates CBM complex formation; disruption of the CBM complex prevents MALT1 from recruiting TRAF6, which triggers caspase-11-dependent pyroptosis in myocardial ischemia/reperfusion injury.\",\n      \"method\": \"PKCα inhibitor (pharmacological), siRNA knockdown, Co-immunoprecipitation (CBM complex), caspase-11 pyroptosis assay, mouse I/R model\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic epistasis with biochemical complex assembly assay, in vivo model, single lab\",\n      \"pmids\": [\"39343081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CARMA3 binds BCL10 and MALT1 to form a signalosome in nucleus pulposus cells; CARMA3 knockdown reduces CARMA3-BCL10-MALT1 signalosome-mediated NF-κB activation, decreasing MMP-3, MMP-13, ADAMTS-5, and caspase-3, and reversing intervertebral disc degeneration pathology.\",\n      \"method\": \"Co-immunoprecipitation (CARMA3-BCL10-MALT1 complex), siRNA knockdown, Western blot, in vivo rat IDD model\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP demonstrating complex formation with functional KD readout in vivo, single lab\",\n      \"pmids\": [\"38607566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CARMA3 suppresses myofibroblast activation by inhibiting STAT1 phosphorylation in cardiac fibroblasts; CARMA3 physically interacts with STAT1 in response to pressure overload; CARMA3-knockout mice show increased STAT1 phosphorylation, exacerbated myofibroblast differentiation, collagen production, and cardiac fibrosis.\",\n      \"method\": \"Co-immunoprecipitation (CARMA3-STAT1 interaction), CARMA3 knockout mice (TAC and Ang II models), proteomic analysis, flow cytometry\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of novel binding partner plus genetic KO with in vivo phenotype, single lab\",\n      \"pmids\": [\"41053092\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CARD10 (CARMA3) is a CARD-MAGUK scaffold protein that assembles the CARMA3-BCL10-MALT1 (CBM) signalosome downstream of GPCRs, RTKs (EGFR), and innate immune sensors (RIG-I/MAVS), recruits NEMO/IKKγ and TRAF6 to drive canonical NF-κB activation via IKK complex polyubiquitination, and is itself feedback-regulated by MALT1-mediated cleavage at R587 and by proteasomal degradation following viral activation, with additional non-NF-κB roles including mitochondrial integrity maintenance in endothelial cells, STAT1 phosphorylation suppression in cardiac fibroblasts, and IP3R-mediated calcium signaling in airway epithelium.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CARD10 (CARMA3) is a CARD-domain-containing MAGUK scaffold protein that assembles the CARMA3–BCL10–MALT1 (CBM) signalosome to activate canonical NF-κB signaling downstream of G protein-coupled receptors, receptor tyrosine kinases (EGFR), and innate immune sensors (RIG-I/MAVS). CARD10 binds BCL10 via its CARD domain and recruits NEMO/IKKγ and TRAF6 to drive IKK complex polyubiquitination and NF-κB nuclear translocation; in the GPCR context, β-arrestin 2 is required for signalosome assembly, distinguishing it mechanistically from the lymphocyte CARMA1 complex [PMID:11387339, PMID:17438001, PMID:21041303]. The pathway is negatively regulated by MALT1-mediated cleavage of CARD10 at R587, by A20 deubiquitylase activity disrupting the CBM–NEMO complex, and by proteasomal degradation of CARD10 following viral infection [PMID:33824280, PMID:18349075, PMID:26947079]. Beyond NF-κB scaffolding, CARD10 maintains mitochondrial integrity in endothelial cells, interacts with IP3 receptors to regulate calcium signaling in airway epithelium, and suppresses STAT1 phosphorylation in cardiac fibroblasts [PMID:35831018, PMID:29958012, PMID:41053092].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of CARD10 as a MAGUK-family scaffold that binds BCL10 and MALT1 to activate NF-κB established the existence of a non-lymphocyte CBM signalosome and its core molecular architecture.\",\n      \"evidence\": \"Co-immunoprecipitation, domain deletion mapping, dominant-negative expression, and NF-κB reporter assays in multiple cell types\",\n      \"pmids\": [\"11387339\", \"11259443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream receptor inputs not yet defined\", \"Endogenous stoichiometry and oligomerization state unknown\", \"No structural model of the CARD10–BCL10 interface\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that CARD10 physically associates with NEMO/IKKγ in an inducible complex with BCL10 and IKKα/β revealed how the CBM signalosome engages the IKK complex to transmit NF-κB activation signals.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation in lymphoid and non-lymphoid cells, dominant-negative NEMO-binding region expression\",\n      \"pmids\": [\"15184390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain type mediating IKK activation not specified\", \"Direct vs. bridged interaction between CARD10 and NEMO not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic knockout studies established that CARD10 is essential for GPCR-induced NF-κB activation and showed that TRAF6 is recruited to NEMO via CARD10 to catalyze polyubiquitination, defining the pathway from receptor to IKK activation.\",\n      \"evidence\": \"CARMA3 knockout mice, IKK kinase assays, ubiquitination assays, co-immunoprecipitation, and PKCα epistasis with dominant-negatives in ovarian cancer cells\",\n      \"pmids\": [\"17438001\", \"17101977\", \"17724468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PKC phosphorylation site on CARD10 not mapped\", \"Relationship to alternative ubiquitin ligases (e.g., cIAP1/2) not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that β-arrestin 2 (not PDK1) mediates CBM signalosome assembly downstream of GPCRs distinguished the CARD10 pathway from the CARMA1-dependent lymphocyte signalosome and linked it to vascular inflammation and atherosclerosis.\",\n      \"evidence\": \"siRNA knockdown and co-IP in endothelial cells for β-arrestin 2 dependence; Bcl10 knockout mice protected from Ang II-induced atherosclerosis and aortic aneurysms\",\n      \"pmids\": [\"21041303\", \"20605784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"β-arrestin 2 binding site on CARD10 not mapped\", \"Whether β-arrestin 2 acts as adaptor or conformational activator is unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extension of CARD10 function to RTK signaling showed that EGFR activates NF-κB through the CBM signalosome, broadening CARD10's role beyond GPCRs to receptor tyrosine kinase-driven oncogenesis.\",\n      \"evidence\": \"CARMA3 knockout cells, siRNA, NF-κB reporter, and in vivo tumor xenograft\",\n      \"pmids\": [\"21406399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EGFR signals to CARD10 (direct phosphorylation vs. intermediate PKC) not determined\", \"Generality to other RTKs untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Conditional knockout of CARD10 in airway epithelial cells demonstrated its non-redundant requirement for allergic airway inflammation, establishing the CBM signalosome as a critical innate epithelial signaling node for proasthmatic mediator production.\",\n      \"evidence\": \"CARMA3 conditional knockout mice, primary human bronchial epithelial cell siRNA, in vivo allergen challenge models with multiple stimuli\",\n      \"pmids\": [\"26041536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of NF-κB versus calcium signaling arms in airway inflammation not dissected\", \"Therapeutic window for CARD10 inhibition in asthma not assessed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealing that CARD10 sequesters MAVS from forming high-molecular-weight aggregates to suppress TBK1/IRF3 activation while simultaneously promoting MAVS-dependent NF-κB uncovered a dual regulatory role and a proteasome-dependent degradation switch during antiviral signaling.\",\n      \"evidence\": \"CARMA3 knockout mice, sucrose gradient sedimentation for MAVS aggregation, proteasome inhibitor experiments, in vivo viral infection\",\n      \"pmids\": [\"26947079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase responsible for CARD10 proteasomal targeting not identified\", \"Whether CARD10–MAVS interaction is direct or BCL10-bridged not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of CARD10 interaction with IP3 receptors in airway epithelial cells revealed a non-NF-κB function in calcium signaling, expanding the mechanistic repertoire of the scaffold beyond inflammatory transcription.\",\n      \"evidence\": \"Co-immunoprecipitation of CARMA3–IP3R, intracellular calcium measurement, CARMA3-deficient AEC mice\",\n      \"pmids\": [\"29958012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface between CARD10 and IP3R not mapped\", \"Whether calcium regulation requires BCL10/MALT1 or is independent unknown\", \"Single-lab finding awaits independent replication\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that MALT1 cleaves CARD10 at R587 to dampen NF-κB signaling identified the first non-hematopoietic MALT1 substrate and revealed a built-in negative feedback mechanism controlling tumor-promoting inflammation.\",\n      \"evidence\": \"In vitro MALT1 cleavage assay, R587A mutagenesis, NF-κB reporter, cytokine ELISA, mouse xenograft tumor growth\",\n      \"pmids\": [\"33824280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cleavage generates a dominant-negative fragment or simply inactivates CARD10 not fully resolved\", \"Kinetics of cleavage relative to signalosome disassembly unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Localization of CARD10 to mitochondria in liver sinusoidal endothelial cells and its requirement for mitochondrial integrity independent of NF-κB revealed a previously unsuspected organelle-level function.\",\n      \"evidence\": \"Subcellular fractionation and co-localization in LSECs, CARMA3 knockout mice, Con A hepatitis model\",\n      \"pmids\": [\"35831018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial binding partners and targeting signal not identified\", \"Mechanism by which CARD10 preserves mitochondrial integrity unknown\", \"Single-lab observation in one cell type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that CARD10 physically interacts with STAT1 to suppress its phosphorylation in cardiac fibroblasts uncovered an NF-κB-independent anti-fibrotic mechanism, expanding CARD10's functional scope to JAK-STAT regulation.\",\n      \"evidence\": \"Co-immunoprecipitation of CARD10–STAT1, CARMA3 knockout mice subjected to TAC and Ang II pressure overload, proteomics\",\n      \"pmids\": [\"41053092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain on CARD10 mediating STAT1 interaction not mapped\", \"Whether STAT1 suppression is direct (sequestration) or involves a phosphatase intermediary unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of CARD10 signalosome assembly, the identity of the E3 ubiquitin ligase targeting CARD10 for proteasomal degradation during antiviral signaling, whether the mitochondrial and calcium-signaling functions operate through BCL10/MALT1 or represent independent scaffolding modes, and the direct PKC phosphorylation site(s) on CARD10 that activate the signalosome.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of CARD10 or the CBM signalosome\", \"PKC phosphorylation site on CARD10 not mapped in any system\", \"Relative physiological importance of NF-κB-dependent vs. -independent functions not compared in a single genetic model\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 10, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [20, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 10, 11, 12, 20, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 19, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 16, 21, 24, 25]}\n    ],\n    \"complexes\": [\n      \"CARMA3-BCL10-MALT1 (CBM) signalosome\"\n    ],\n    \"partners\": [\n      \"BCL10\",\n      \"MALT1\",\n      \"NEMO\",\n      \"TRAF6\",\n      \"MAVS\",\n      \"STAT1\",\n      \"ITPR1\",\n      \"DEPDC7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}