{"gene":"CARD10","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2001,"finding":"CARD10/BIMP1 (CARMA3) physically binds BCL10 via its CARD domain and forms a ternary complex with BCL10 and MALT1 (with BCL10 bridging the BIMP1/MALT1 interaction). This complex activates NF-κB through IκB kinases, and a dominant-negative BIMP1 mutant inhibits NF-κB activation by anti-CD3 ligation, phorbol ester, and PKC expression, placing CARD10 upstream of IKK in the PKC-to-NF-κB signaling axis.","method":"Co-immunoprecipitation, dominant-negative mutant expression, NF-κB reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying ternary complex, dominant-negative functional validation, replicated by independent lab (PMID:11259443)","pmids":["11387339"],"is_preprint":false},{"year":2001,"finding":"CARD10 is a MAGUK/CARD family scaffold protein that binds BCL10 through its N-terminal CARD domain and activates NF-κB when expressed in cells, proposed to organize a BCL10 signaling complex at plasma membranes.","method":"Co-immunoprecipitation, NF-κB reporter assay, domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding confirmed by Co-IP with functional NF-κB activation, independently replicated (PMID:11387339)","pmids":["11259443"],"is_preprint":false},{"year":2004,"finding":"CARMA3 physically associates with IKKγ/NEMO in non-lymphoid cells. CARMA3 participates in a large inducible complex containing IKKγ/NEMO, BCL10, and IKKα/β kinases. Expression of the NEMO-binding region of CARMA3 acts as a dominant negative, suppressing BCL10-mediated NF-κB activation, establishing direct physical and functional linkage between CARMA3 and the IKK complex.","method":"Co-immunoprecipitation, dominant-negative expression, NF-κB reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating CARMA3-NEMO interaction plus dominant-negative functional validation in multiple cell types","pmids":["15184390"],"is_preprint":false},{"year":2006,"finding":"CARMA3 is required for angiotensin II (Ang II) receptor (type 1 GPCR)-induced NF-κB activation in hepatocytes. CARMA3, BCL10, and MALT1 form the CBM complex downstream of Ang II receptor; blocking any component via dominant-negative mutants, RNAi, or gene targeting abolishes Ang II-dependent NF-κB activation. The pathway activates NF-κB through ubiquitination of IKKγ/NEMO.","method":"Dominant-negative mutants, RNAi, gene targeting (Bcl10−/− mice), NF-κB activation assays, in vivo cytokine production assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic and biochemical approaches including knockout mice, confirmed in vivo","pmids":["17101977"],"is_preprint":false},{"year":2007,"finding":"CARMA3 is required for GPCR-induced IKK activation and NF-κB signaling. CARMA3-deficient mice generated by gene targeting show abrogated GPCR-induced NF-κB activation; CARMA3 physically associates with NEMO/IKKγ and induces polyubiquitination of NEMO-associated protein(s), likely by linking NEMO to TRAF6. CARMA3 deficiency impairs IKK kinase activity despite normal IKKα/β phosphorylation.","method":"CARMA3 knockout mice (gene targeting), Co-immunoprecipitation, ubiquitination assay, IKK kinase assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mice with multiple biochemical readouts, NEMO association confirmed by Co-IP","pmids":["17438001"],"is_preprint":false},{"year":2007,"finding":"PKCα links LPA receptor (GPCR) to CARMA3 for NF-κB activation and uPA upregulation in ovarian cancer cells. LPA stimulation activates PKCα and induces Ras-PKCα interaction; dominant-negative PKCα, but not PKCθ or PKCζ DN mutants, blocks LPA-induced NF-κB activation. Dominant-negative CARMA3 or siRNA silencing of CARMA3/BCL10/MALT1 abolishes LPA-induced NF-κB activation and invasion.","method":"Dominant-negative mutants, siRNA knockdown, NF-κB reporter assay, Co-immunoprecipitation, invasion assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genetic perturbations (DN mutants + siRNA) with consistent functional readouts in same lab","pmids":["17724468"],"is_preprint":false},{"year":2008,"finding":"CXCL8/IL8 acting on CXCR2 activates NF-κB and upregulates VEGF mRNA and protein in endothelial cells through the CBM complex (CARMA3/BCL10/MALT1); this is independent of HIF1α. Knockdown of CBM components blocks CXCL8-induced VEGF upregulation and autocrine VEGFR2 activation.","method":"siRNA knockdown, Western blot, NF-κB reporter assay, VEGF mRNA quantification","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA knockdown with pathway readouts, single lab, mechanistic placement within GPCR-CBM-NF-κB-VEGF axis","pmids":["19112107"],"is_preprint":false},{"year":2008,"finding":"A20 negatively regulates CARMA3/BCL10/IKKγ(NEMO)-mediated NF-κB activation via its deubiquitylation activity. A20 perturbs assembly of the CARMA3-BCL10-IKKγ/NEMO complex, thereby suppressing NF-κB activation in non-lymphoid cells.","method":"Co-immunoprecipitation, deubiquitylation assay, NF-κB reporter assay, complex assembly analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP complex assembly plus biochemical deubiquitylation activity, single lab","pmids":["18349075"],"is_preprint":false},{"year":2008,"finding":"CARMA3 is specifically expressed in human airway bronchial epithelial cells and mediates LPA-stimulated NF-κB activation and cytokine production (TSLP, CCL20) in these cells. Inhibition of CARMA3 activity reduces LPA-mediated NF-κB activity and TSLP/CCL20 production.","method":"Dominant-negative expression, NF-κB reporter assay, cytokine ELISA, expression analysis","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional inhibition with specific phenotypic readout in primary-like cells, single lab","pmids":["18757306"],"is_preprint":false},{"year":2009,"finding":"The CXCR4/SDF-1α GPCR activates NF-κB and promotes OSCC invasion through the CBM complex (CARMA3/BCL10/MALT1). Knockdown of CBM components inhibits SDF-1α-induced IκBα phosphorylation and degradation (but not TNFα-induced IKK activation). Novel and atypical (but not classical) PKCs activate IKK through CXCR4.","method":"Lentiviral shRNA knockdown, Western blot (IκBα phosphorylation), EMSA, invasion assay","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — shRNA knockdown with multiple pathway readouts, single lab","pmids":["20695076"],"is_preprint":false},{"year":2010,"finding":"Thrombin acting on PAR-1 (a GPCR) on endothelial cells uses the CARMA3·BCL10·MALT1 signalosome to link PKC activation to IKK stimulation and NF-κB-dependent ICAM-1/VCAM-1 expression, driving monocyte adhesion to endothelium. Unlike the lymphocyte CARMA1 signalosome, the CARMA3 endothelial signalosome does not require PDK1 but instead depends on β-arrestin 2 for assembly.","method":"siRNA knockdown, Co-immunoprecipitation, NF-κB reporter assay, monocyte adhesion assay, PDK1 inhibitor and β-arrestin 2 knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (siRNA, Co-IP, functional adhesion assay), mechanistic distinction from CARMA1 complex established","pmids":["21041303"],"is_preprint":false},{"year":2010,"finding":"The CARMA3-BCL10-MALT1 signalosome mediates angiotensin II type 1 receptor-induced NF-κB activation in endothelial and vascular smooth muscle cells, promoting pro-inflammatory vascular signaling and atherogenesis. Bcl10-deficient mice are protected from Ang II-dependent atherosclerosis and aortic aneurysms.","method":"siRNA knockdown, Bcl10−/− mice (in vivo atherosclerosis model), NF-κB activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in vivo model combined with in vitro knockdown, replicated Ang II/CARMA3 pathway in vascular context","pmids":["20605784"],"is_preprint":false},{"year":2011,"finding":"CARMA3 is required for EGF receptor (RTK)-induced IKK activation and NF-κB signaling. CARMA3 deficiency impairs EGF-induced IκBα phosphorylation and NF-κB activation. CARMA3 and BCL10 contribute to EGFR-associated proliferation, survival, migration, invasion, and tumor growth in vivo.","method":"CARMA3-deficient MEFs, siRNA knockdown, IKK assay, NF-κB reporter assay, xenograft tumor model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deficiency plus siRNA, in vitro and in vivo tumor models, multiple functional readouts","pmids":["21406399"],"is_preprint":false},{"year":2014,"finding":"DEPDC7 (DEP domain-containing protein) binds to CARMA3 as a cellular binding partner. shRNA-mediated abrogation of DEPDC7 impairs NF-κB activation following GPCR stimulation or stimuli requiring CARMA3, but not CARMA1, establishing DEPDC7 as a CARMA3-specific upstream component of the CBM complex.","method":"Co-immunoprecipitation, shRNA knockdown, NF-κB reporter assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus functional shRNA with receptor-specificity controls, single lab","pmids":["25541973"],"is_preprint":false},{"year":2015,"finding":"CARMA3 promotes lung cancer cell motility by reducing NME2 expression through the NF-κB/miR-182 pathway. Mechanistically, CARMA3 activates NF-κB, which drives miR-182 transcription (confirmed by ChIP and luciferase reporter assay), and miR-182 then suppresses NME2, a metastasis suppressor, thereby increasing cancer stemness and metastasis.","method":"ChIP assay, luciferase reporter assay, siRNA/shRNA knockdown, in vitro and in vivo metastasis assays","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirming NF-κB-driven miR-182 transcription, multiple downstream functional validations, single lab","pmids":["25906011"],"is_preprint":false},{"year":2015,"finding":"CARMA3 is required for GPCR ligand (LPA, ATP, Alternaria, house dust mite)-induced NF-κB activation and proasthmatic mediator production in airway epithelial cells (AECs). CARMA3-deficient AECs have reduced allergic inflammation. Mice with CARMA3-deficient AECs have reduced airway eosinophilia, cytokine production, and impaired dendritic cell maturation in a murine model of allergic airway inflammation.","method":"CARMA3 conditional KO mice (AEC-specific), NF-κB reporter assay, cytokine ELISA, flow cytometry, antigen processing assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional KO mice with in vivo allergic inflammation model plus multiple cellular readouts","pmids":["26041536"],"is_preprint":false},{"year":2016,"finding":"CARMA3 positively regulates MAVS-induced NF-κB activation during RNA virus infection. Conversely, CARMA3 sequesters MAVS from forming high-molecular-weight aggregates, suppressing TBK1/IRF3 activation. After NF-κB activation, CARMA3 is degraded in a proteasome-dependent manner, releasing MAVS to activate IRF3. CARMA3-deficient mice show reduced inflammation and stronger viral clearance.","method":"CARMA3-deficient mice, Co-immunoprecipitation, native PAGE (MAVS aggregate detection), proteasome inhibitor assay, NF-κB/IRF3 reporter assays, in vivo viral infection model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mice plus multiple biochemical methods demonstrating MAVS sequestration and proteasomal regulation, in vivo confirmation","pmids":["26947079"],"is_preprint":false},{"year":2017,"finding":"AGTR1 (angiotensin II receptor) overexpression in breast cancer drives NF-κB activation via the CARMA3-BCL10-MALT1 (CBM) signalosome, promoting proliferation, migration, invasion, and tumor angiogenesis. Both ligand-dependent and ligand-independent AGTR1-mediated NF-κB activation requires the CBM triad.","method":"siRNA knockdown of CBM components, NF-κB reporter assay, proliferation/migration/invasion assays, endothelial angiogenesis assay, AGTR1 overexpression models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple CBM component knockdowns with consistent functional readouts in cancer context, single lab","pmids":["29259013"],"is_preprint":false},{"year":2018,"finding":"CARD10 is a direct transcriptional target of the myeloid transcription factor CEBPE. CEBPE binds to regulatory elements upstream of the murine Card10 locus (confirmed by ChIP), and CARD10 expression is significantly reduced in Cebpe knockout mice. Silencing Card10 impairs granulopoiesis, affecting expression of genes involved in myeloid cell development and function.","method":"ChIP assay, Cebpe knockout mice, siRNA knockdown in human cell line and murine primary cells, gene expression analysis","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct CEBPE binding plus genetic KO mouse validation, single lab","pmids":["29773596"],"is_preprint":false},{"year":2018,"finding":"CARMA3 mediates Alternaria alternata-induced allergic airway inflammation in AECs. CARMA3 interacts with inositol 1,4,5-trisphosphate receptors (IP3Rs) in AECs, and inhibition of CARMA3 signaling reduces A. alternata-induced intracellular calcium release, reducing IL-33, IL-25, and type 2 immune responses.","method":"Co-immunoprecipitation (CARMA3-IP3R interaction), CARMA3-deficient AEC mice, intracellular calcium measurement, cytokine ELISA, in vivo allergic inflammation model","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel IP3R binding by Co-IP plus KO mice with functional calcium release and cytokine readouts, 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, and this cleavage dampens CARD10's capacity to activate NF-κB. Preventing CARD10 cleavage increases basal IL-6 and extracellular matrix components in vitro and leads to increased tumor growth in a mouse xenograft model, indicating that MALT1-mediated CARD10 cleavage is a built-in negative regulatory mechanism.","method":"In vitro MALT1 cleavage assay, site-directed mutagenesis (R587 cleavage site), NF-κB reporter assay, cytokine ELISA, mouse xenograft tumor model","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro cleavage assay with mutagenesis identifying precise cleavage site, plus functional in vivo xenograft validation, single lab","pmids":["33824280"],"is_preprint":false},{"year":2022,"finding":"CARMA3 localizes at mitochondria in liver sinusoidal endothelial cells (LSECs). In CARMA3-deficient mice, Con A-induced liver injury is exacerbated, with more LSEC damage, mitochondrial damage, and coagulation. In vitro, CARMA3-deficient LSECs show increased mitochondrial damage and cell death upon Con A treatment, revealing a mitochondria-protective role of CARMA3 in LSECs distinct from its NF-κB scaffolding function.","method":"CARMA3 knockout mice, subcellular fractionation/localization of CARMA3 to mitochondria, Con A hepatitis model, cell death assay, coagulation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mice plus subcellular localization to mitochondria with functional consequence, single lab","pmids":["35831018"],"is_preprint":false},{"year":2023,"finding":"CARMA3 deficiency exacerbates Ang II-induced abdominal aortic aneurysm (AAA) formation, increased inflammatory cytokines, MMP expression, and VSMC death. Mechanistically, CARMA3 deficiency activates the p38MAPK pathway, enhancing the interaction between ER stress and mitochondrial damage, ultimately promoting VSMC pyroptosis.","method":"CARMA3 knockout mice, Ang II osmotic pump model, p38MAPK pathway analysis, ER stress markers, mitochondrial damage assays, pyroptosis assays","journal":"The Canadian journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic KO in vivo model with mechanistic pathway analysis, single lab","pmids":["37030515"],"is_preprint":false},{"year":2024,"finding":"Sonic hedgehog (SHH) signaling promotes myocardial pyroptosis after I/R injury via PKCα-mediated CARD10-BCL10-MALT1 (CBM) complex formation. SHH activation increases PKCα levels; PKCα inhibition attenuates CBM complex formation. Disruption of the CBM complex prevents MALT1 from recruiting TRAF6, which is required to trigger caspase-11-dependent pyroptosis.","method":"SHH pathway inhibitors, PKCα inhibitor, Co-immunoprecipitation (CBM complex), TRAF6 recruitment assay, caspase-11 activation assay, mouse I/R model and H9c2 H/R model","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibitors plus Co-IP complex analysis with in vivo and in vitro models, single lab","pmids":["39343081"],"is_preprint":false},{"year":2025,"finding":"CARMA3 suppresses myofibroblast activation in cardiac fibroblasts by inhibiting STAT1 phosphorylation. An interaction between CARMA3 and STAT1 was detected in response to pressure overload. CARMA3-knockout mice subjected to TAC or Ang II treatment show increased cardiac fibrosis, myofibroblast differentiation, and mitochondrial damage; proteomic analysis identified elevated STAT1 in CARMA3-KO cardiac fibroblasts.","method":"CARMA3 knockout mice, TAC and Ang II models, Co-immunoprecipitation (CARMA3-STAT1), proteomic analysis, flow cytometry, STAT1 phosphorylation assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mice with in vivo pressure overload model, Co-IP identifying novel STAT1 interaction, proteomic validation, single lab","pmids":["41053092"],"is_preprint":false}],"current_model":"CARD10/CARMA3 is a MAGUK/CARD-domain scaffold protein that assembles the CBM (CARMA3–BCL10–MALT1) signalosome downstream of GPCRs (e.g., LPA receptor, Ang II type 1 receptor, PAR-1, CXCR2, CXCR4) and receptor tyrosine kinases (EGFR), linking PKCα-mediated signals through BCL10 bridging to MALT1, which in turn recruits TRAF6 and triggers K63-linked ubiquitination of IKKγ/NEMO to activate the IKK complex and canonical NF-κB; MALT1 also cleaves CARD10 itself at R587 as a built-in negative feedback; the complex additionally interfaces with MAVS to balance NF-κB vs. IRF3/antiviral responses, interacts with IP3Rs to regulate calcium signaling in airway epithelium, localizes to mitochondria in endothelial cells to maintain mitochondrial integrity, and is transcriptionally controlled by CEBPE in granulocytes, while CARMA3 also interacts with STAT1 to suppress myofibroblast activation in cardiac fibroblasts."},"narrative":{"mechanistic_narrative":"CARD10 (CARMA3) is a MAGUK/CARD-domain scaffold protein that nucleates the CARMA3–BCL10–MALT1 (CBM) signalosome to couple cell-surface receptor activation to canonical NF-κB signaling in non-lymphoid cells [PMID:11387339, PMID:11259443]. It binds BCL10 through its N-terminal CARD domain, and BCL10 in turn bridges to MALT1 to form a ternary complex that activates the IκB kinases [PMID:11387339]. CARMA3 physically associates with IKKγ/NEMO and assembles a large inducible complex containing NEMO and IKKα/β, linking NEMO to TRAF6 to drive polyubiquitination that activates IKK kinase activity [PMID:15184390, PMID:17438001]. This CBM module transduces signals from a range of G-protein-coupled receptors—including the angiotensin II type 1 receptor, LPA receptor, PAR-1, CXCR2, and CXCR4—as well as the EGF receptor, typically via PKCα activation [PMID:17101977, PMID:17724468, PMID:21041303, PMID:21406399], and the complex is negatively regulated by A20-mediated deubiquitylation and by MALT1 cleavage of CARD10 at R587, a built-in feedback that dampens NF-κB output [PMID:18349075, PMID:33824280]. Through these receptors CARMA3 drives inflammatory and tumor-promoting programs in vascular, epithelial, and cancer cells, including ICAM-1/VCAM-1-dependent monocyte adhesion, VEGF induction, proasthmatic cytokine production, and proliferation/invasion [PMID:21041303, PMID:19112107, PMID:26041536, PMID:21406399], and in vivo CARMA3/BCL10 loss protects against Ang II-driven atherosclerosis and aortic aneurysm [PMID:20605784]. CARMA3 additionally exerts NF-κB-independent roles: it sequesters MAVS to balance NF-κB versus IRF3 antiviral responses [PMID:26947079], interacts with IP3 receptors to control calcium-dependent type 2 immune signaling in airway epithelium [PMID:29958012], localizes to mitochondria to preserve mitochondrial integrity in liver sinusoidal endothelial cells [PMID:35831018], and interacts with STAT1 to suppress myofibroblast activation in cardiac fibroblasts [PMID:41053092]. CARD10 is itself a direct transcriptional target of the myeloid factor CEBPE and contributes to granulopoiesis [PMID:29773596].","teleology":[{"year":2001,"claim":"Established CARD10 as a CARD-domain scaffold that physically links BCL10 and MALT1 into a ternary complex and places it upstream of IKK in the PKC-to-NF-κB axis, defining its core molecular role.","evidence":"Co-immunoprecipitation, domain mapping, and dominant-negative mutants with NF-κB reporter assays","pmids":["11387339","11259443"],"confidence":"High","gaps":["Did not define the receptor that physiologically engages the complex","Mechanism connecting the CBM complex to IKK activation not yet resolved"]},{"year":2004,"claim":"Showed CARMA3 directly contacts IKKγ/NEMO within a large inducible IKK-containing complex, providing the physical bridge from the scaffold to the kinase machinery.","evidence":"Reciprocal Co-IP and dominant-negative NEMO-binding fragment in NF-κB reporter assays in non-lymphoid cells","pmids":["15184390"],"confidence":"High","gaps":["Did not establish the ubiquitin enzymology activating IKK","Upstream receptor input still undefined"]},{"year":2006,"claim":"Identified the angiotensin II type 1 GPCR as a physiological trigger for CBM-dependent NF-κB activation, defining CARMA3 as a GPCR effector via NEMO ubiquitination.","evidence":"Dominant-negative mutants, RNAi, Bcl10−/− mice, and in vivo cytokine assays in hepatocytes","pmids":["17101977"],"confidence":"High","gaps":["Did not detail the ubiquitin ligase machinery","Generality across other GPCRs not yet tested"]},{"year":2007,"claim":"Genetic knockout established CARMA3 as broadly required for GPCR-induced IKK activation and implicated TRAF6 in linking NEMO to its polyubiquitination.","evidence":"CARMA3 knockout mice, Co-IP, ubiquitination and IKK kinase assays","pmids":["17438001"],"confidence":"High","gaps":["Direct demonstration of TRAF6 as the operative ligase incomplete","Did not address receptor-specific assembly differences"]},{"year":2007,"claim":"Defined PKCα as the specific upstream kinase coupling the LPA GPCR to CARMA3, distinguishing it from PKCθ/ζ and linking the pathway to tumor invasion.","evidence":"Isoform-specific dominant-negative PKC mutants, siRNA of CBM components, NF-κB and invasion assays in ovarian cancer cells","pmids":["17724468"],"confidence":"High","gaps":["Direct PKCα phosphorylation target on the CBM complex not identified"]},{"year":2008,"claim":"Extended CARMA3-CBM signaling to multiple GPCRs (CXCR2) and tissues, coupling NF-κB to VEGF induction and airway epithelial cytokine production.","evidence":"siRNA/dominant-negative perturbation with VEGF and cytokine readouts in endothelial and airway epithelial cells","pmids":["19112107","18757306"],"confidence":"Medium","gaps":["Single-lab pathway placements","Direct receptor-to-CARMA3 biochemical bridge not mapped"]},{"year":2008,"claim":"Identified A20 as a negative regulator that disassembles the CARMA3-BCL10-NEMO complex via deubiquitylation, adding a brake to the pathway.","evidence":"Co-IP complex assembly analysis, deubiquitylation assay, NF-κB reporter","pmids":["18349075"],"confidence":"Medium","gaps":["Single lab","Specific ubiquitin chains targeted on the complex not fully defined"]},{"year":2010,"claim":"Revealed cell-type-specific assembly logic—the endothelial CARMA3 signalosome requires β-arrestin 2 rather than PDK1—distinguishing it from the lymphocyte CARMA1 complex downstream of PAR-1.","evidence":"siRNA, Co-IP, PDK1 inhibitor, β-arrestin 2 knockdown, monocyte adhesion assay","pmids":["21041303"],"confidence":"High","gaps":["Structural basis of β-arrestin 2-dependent assembly unresolved"]},{"year":2010,"claim":"Demonstrated the CBM signalosome's pathophysiological role in vascular inflammation, with genetic loss protecting against Ang II-driven atherosclerosis and aneurysm.","evidence":"siRNA in endothelial/VSMCs and Bcl10−/− mice in atherosclerosis models","pmids":["20605784"],"confidence":"High","gaps":["Used Bcl10 rather than CARMA3 genetic ablation for the in vivo arm"]},{"year":2011,"claim":"Showed CARMA3 also transduces receptor tyrosine kinase (EGFR) signals to IKK/NF-κB, broadening its receptor repertoire beyond GPCRs and linking it to tumor growth.","evidence":"CARMA3-deficient MEFs, siRNA, IKK and NF-κB assays, xenograft tumor model","pmids":["21406399"],"confidence":"High","gaps":["Mechanism coupling EGFR to PKC and CARMA3 not fully defined"]},{"year":2014,"claim":"Identified DEPDC7 as a CARMA3-specific upstream binding partner required for CBM-dependent but not CARMA1-dependent NF-κB activation.","evidence":"Co-IP and shRNA with receptor-specificity controls","pmids":["25541973"],"confidence":"Medium","gaps":["Single lab","How DEPDC7 modulates complex assembly mechanistically unknown"]},{"year":2015,"claim":"Connected CARMA3-driven NF-κB to a transcriptional metastasis program (NF-κB/miR-182/NME2) and to allergic airway inflammation in vivo.","evidence":"ChIP, luciferase, knockdown, metastasis assays; AEC-specific conditional knockout mice in allergic airway model","pmids":["25906011","26041536"],"confidence":"High","gaps":["Single-lab mechanistic chains","Generality of the miR-182 axis across tumor types untested"]},{"year":2016,"claim":"Uncovered an NF-κB-independent function: CARMA3 sequesters MAVS to restrain TBK1/IRF3 antiviral signaling, and is proteasomally degraded to release MAVS, positioning it as a switch balancing inflammation versus antiviral response.","evidence":"CARMA3-deficient mice, Co-IP, native PAGE MAVS aggregation, proteasome inhibitor, NF-κB/IRF3 reporters, viral infection model","pmids":["26947079"],"confidence":"High","gaps":["E3 ligase mediating CARMA3 degradation not identified","Structural basis of MAVS sequestration unresolved"]},{"year":2017,"claim":"Confirmed AGTR1-CBM signaling drives breast cancer progression through both ligand-dependent and ligand-independent NF-κB activation.","evidence":"siRNA of CBM components with proliferation/invasion/angiogenesis assays and AGTR1 overexpression models","pmids":["29259013"],"confidence":"Medium","gaps":["Single lab","Mechanism of ligand-independent activation not defined"]},{"year":2018,"claim":"Placed CARD10 within myeloid development as a direct CEBPE transcriptional target required for normal granulopoiesis, defining an upstream transcriptional control point.","evidence":"ChIP, Cebpe knockout mice, siRNA, gene expression analysis","pmids":["29773596"],"confidence":"Medium","gaps":["Single lab","Whether CARD10's scaffold function or another activity drives granulopoiesis unclear"]},{"year":2018,"claim":"Identified a physical CARMA3-IP3R interaction controlling calcium release and type 2 immune mediators, an NF-κB-independent role in airway epithelium.","evidence":"Co-IP, CARMA3-deficient AEC mice, intracellular calcium measurement, cytokine ELISA, allergic inflammation model","pmids":["29958012"],"confidence":"Medium","gaps":["Single lab without reciprocal structural validation","Domain mediating IP3R binding unmapped"]},{"year":2021,"claim":"Established CARD10 as the first MALT1 substrate in non-hematopoietic cells, with cleavage at R587 forming a built-in negative feedback that limits NF-κB, cytokine, and tumor output.","evidence":"In vitro MALT1 cleavage assay, R587 site-directed mutagenesis, NF-κB reporter, cytokine ELISA, xenograft model","pmids":["33824280"],"confidence":"High","gaps":["Single lab","Fate and function of the cleavage fragments not defined"]},{"year":2022,"claim":"Revealed a mitochondria-localized, scaffold-independent protective role of CARMA3 in liver sinusoidal endothelial cells against immune-mediated injury.","evidence":"CARMA3 knockout mice, subcellular fractionation, Con A hepatitis, cell death and coagulation assays","pmids":["35831018"],"confidence":"Medium","gaps":["Single lab","Molecular mechanism of mitochondrial protection not defined"]},{"year":2023,"claim":"Linked CARMA3 loss to enhanced VSMC pyroptosis via p38MAPK-coupled ER stress/mitochondrial damage, indicating a protective vascular role distinct from its pro-inflammatory NF-κB function.","evidence":"CARMA3 knockout mice, Ang II osmotic pump model, p38MAPK, ER stress, mitochondrial and pyroptosis assays","pmids":["37030515"],"confidence":"Medium","gaps":["Single lab","Reconciliation with the pro-atherogenic CBM role unaddressed"]},{"year":2024,"claim":"Showed SHH-PKCα-driven CBM complex formation recruits TRAF6 to trigger caspase-11-dependent myocardial pyroptosis, connecting the scaffold to a programmed cell death pathway.","evidence":"SHH and PKCα inhibitors, Co-IP, TRAF6 recruitment, caspase-11 assays, mouse I/R and H9c2 H/R models","pmids":["39343081"],"confidence":"Medium","gaps":["Single lab","Direct CBM-to-caspase-11 molecular link not fully mapped"]},{"year":2025,"claim":"Identified a CARMA3-STAT1 interaction that suppresses STAT1 phosphorylation and myofibroblast activation, defining an anti-fibrotic, NF-κB-independent role in cardiac fibroblasts.","evidence":"CARMA3 knockout mice, TAC and Ang II models, Co-IP, proteomics, STAT1 phosphorylation assays","pmids":["41053092"],"confidence":"Medium","gaps":["Single lab without reciprocal validation","Mechanism by which CARMA3 inhibits STAT1 phosphorylation unknown"]},{"year":null,"claim":"How CARMA3 partitions between its canonical CBM/NF-κB scaffolding role and its growing set of NF-κB-independent activities (MAVS sequestration, IP3R-calcium control, mitochondrial protection, STAT1 inhibition) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the assembled CBM signalosome","Domains and post-translational modifications governing the switch between scaffold and non-scaffold functions undefined","No human disease mutation linkage established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[21]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,10,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,16,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[22,23]}],"complexes":["CBM (CARMA3-BCL10-MALT1) signalosome","IKK 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binds BCL10 via its CARD domain and forms a ternary complex with BCL10 and MALT1 (with BCL10 bridging the BIMP1/MALT1 interaction). This complex activates NF-κB through IκB kinases, and a dominant-negative BIMP1 mutant inhibits NF-κB activation by anti-CD3 ligation, phorbol ester, and PKC expression, placing CARD10 upstream of IKK in the PKC-to-NF-κB signaling axis.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative mutant expression, NF-κB reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying ternary complex, dominant-negative functional validation, replicated by independent lab (PMID:11259443)\",\n      \"pmids\": [\"11387339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CARD10 is a MAGUK/CARD family scaffold protein that binds BCL10 through its N-terminal CARD domain and activates NF-κB when expressed in cells, proposed to organize a BCL10 signaling complex at plasma membranes.\",\n      \"method\": \"Co-immunoprecipitation, NF-κB reporter assay, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding confirmed by Co-IP with functional NF-κB activation, independently replicated (PMID:11387339)\",\n      \"pmids\": [\"11259443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CARMA3 physically associates with IKKγ/NEMO in non-lymphoid cells. CARMA3 participates in a large inducible complex containing IKKγ/NEMO, BCL10, and IKKα/β kinases. Expression of the NEMO-binding region of CARMA3 acts as a dominant negative, suppressing BCL10-mediated NF-κB activation, establishing direct physical and functional linkage between CARMA3 and the IKK complex.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative expression, NF-κB reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating CARMA3-NEMO interaction plus dominant-negative functional validation in multiple cell types\",\n      \"pmids\": [\"15184390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CARMA3 is required for angiotensin II (Ang II) receptor (type 1 GPCR)-induced NF-κB activation in hepatocytes. CARMA3, BCL10, and MALT1 form the CBM complex downstream of Ang II receptor; blocking any component via dominant-negative mutants, RNAi, or gene targeting abolishes Ang II-dependent NF-κB activation. The pathway activates NF-κB through ubiquitination of IKKγ/NEMO.\",\n      \"method\": \"Dominant-negative mutants, RNAi, gene targeting (Bcl10−/− mice), NF-κB activation assays, in vivo cytokine production assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic and biochemical approaches including knockout mice, confirmed in vivo\",\n      \"pmids\": [\"17101977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CARMA3 is required for GPCR-induced IKK activation and NF-κB signaling. CARMA3-deficient mice generated by gene targeting show abrogated GPCR-induced NF-κB activation; CARMA3 physically associates with NEMO/IKKγ and induces polyubiquitination of NEMO-associated protein(s), likely by linking NEMO to TRAF6. CARMA3 deficiency impairs IKK kinase activity despite normal IKKα/β phosphorylation.\",\n      \"method\": \"CARMA3 knockout mice (gene targeting), Co-immunoprecipitation, ubiquitination assay, IKK kinase assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mice with multiple biochemical readouts, NEMO association confirmed by Co-IP\",\n      \"pmids\": [\"17438001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PKCα links LPA receptor (GPCR) to CARMA3 for NF-κB activation and uPA upregulation in ovarian cancer cells. LPA stimulation activates PKCα and induces Ras-PKCα interaction; dominant-negative PKCα, but not PKCθ or PKCζ DN mutants, blocks LPA-induced NF-κB activation. Dominant-negative CARMA3 or siRNA silencing of CARMA3/BCL10/MALT1 abolishes LPA-induced NF-κB activation and invasion.\",\n      \"method\": \"Dominant-negative mutants, siRNA knockdown, NF-κB reporter assay, Co-immunoprecipitation, invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genetic perturbations (DN mutants + siRNA) with consistent functional readouts in same lab\",\n      \"pmids\": [\"17724468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CXCL8/IL8 acting on CXCR2 activates NF-κB and upregulates VEGF mRNA and protein in endothelial cells through the CBM complex (CARMA3/BCL10/MALT1); this is independent of HIF1α. Knockdown of CBM components blocks CXCL8-induced VEGF upregulation and autocrine VEGFR2 activation.\",\n      \"method\": \"siRNA knockdown, Western blot, NF-κB reporter assay, VEGF mRNA quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA knockdown with pathway readouts, single lab, mechanistic placement within GPCR-CBM-NF-κB-VEGF axis\",\n      \"pmids\": [\"19112107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A20 negatively regulates CARMA3/BCL10/IKKγ(NEMO)-mediated NF-κB activation via its deubiquitylation activity. A20 perturbs assembly of the CARMA3-BCL10-IKKγ/NEMO complex, thereby suppressing NF-κB activation in non-lymphoid cells.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitylation assay, NF-κB reporter assay, complex assembly analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP complex assembly plus biochemical deubiquitylation activity, single lab\",\n      \"pmids\": [\"18349075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CARMA3 is specifically expressed in human airway bronchial epithelial cells and mediates LPA-stimulated NF-κB activation and cytokine production (TSLP, CCL20) in these cells. Inhibition of CARMA3 activity reduces LPA-mediated NF-κB activity and TSLP/CCL20 production.\",\n      \"method\": \"Dominant-negative expression, NF-κB reporter assay, cytokine ELISA, expression analysis\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional inhibition with specific phenotypic readout in primary-like cells, single lab\",\n      \"pmids\": [\"18757306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The CXCR4/SDF-1α GPCR activates NF-κB and promotes OSCC invasion through the CBM complex (CARMA3/BCL10/MALT1). Knockdown of CBM components inhibits SDF-1α-induced IκBα phosphorylation and degradation (but not TNFα-induced IKK activation). Novel and atypical (but not classical) PKCs activate IKK through CXCR4.\",\n      \"method\": \"Lentiviral shRNA knockdown, Western blot (IκBα phosphorylation), EMSA, invasion assay\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — shRNA knockdown with multiple pathway readouts, single lab\",\n      \"pmids\": [\"20695076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Thrombin acting on PAR-1 (a GPCR) on endothelial cells uses the CARMA3·BCL10·MALT1 signalosome to link PKC activation to IKK stimulation and NF-κB-dependent ICAM-1/VCAM-1 expression, driving monocyte adhesion to endothelium. Unlike the lymphocyte CARMA1 signalosome, the CARMA3 endothelial signalosome does not require PDK1 but instead depends on β-arrestin 2 for assembly.\",\n      \"method\": \"siRNA knockdown, Co-immunoprecipitation, NF-κB reporter assay, monocyte adhesion assay, PDK1 inhibitor and β-arrestin 2 knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (siRNA, Co-IP, functional adhesion assay), mechanistic distinction from CARMA1 complex established\",\n      \"pmids\": [\"21041303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The CARMA3-BCL10-MALT1 signalosome mediates angiotensin II type 1 receptor-induced NF-κB activation in endothelial and vascular smooth muscle cells, promoting pro-inflammatory vascular signaling and atherogenesis. Bcl10-deficient mice are protected from Ang II-dependent atherosclerosis and aortic aneurysms.\",\n      \"method\": \"siRNA knockdown, Bcl10−/− mice (in vivo atherosclerosis model), NF-κB activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in vivo model combined with in vitro knockdown, replicated Ang II/CARMA3 pathway in vascular context\",\n      \"pmids\": [\"20605784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CARMA3 is required for EGF receptor (RTK)-induced IKK activation and NF-κB signaling. CARMA3 deficiency impairs EGF-induced 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-deficient MEFs, siRNA knockdown, IKK assay, NF-κB reporter assay, xenograft tumor model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deficiency plus siRNA, in vitro and in vivo tumor models, multiple functional readouts\",\n      \"pmids\": [\"21406399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DEPDC7 (DEP domain-containing protein) binds to CARMA3 as a cellular binding partner. shRNA-mediated abrogation of DEPDC7 impairs NF-κB activation following GPCR stimulation or stimuli requiring CARMA3, but not CARMA1, establishing DEPDC7 as a CARMA3-specific upstream component of the CBM complex.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, NF-κB reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus functional shRNA with receptor-specificity controls, single lab\",\n      \"pmids\": [\"25541973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CARMA3 promotes lung cancer cell motility by reducing NME2 expression through the NF-κB/miR-182 pathway. Mechanistically, CARMA3 activates NF-κB, which drives miR-182 transcription (confirmed by ChIP and luciferase reporter assay), and miR-182 then suppresses NME2, a metastasis suppressor, thereby increasing cancer stemness and metastasis.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, siRNA/shRNA 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 / Moderate — ChIP and luciferase confirming NF-κB-driven miR-182 transcription, multiple downstream functional validations, single lab\",\n      \"pmids\": [\"25906011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CARMA3 is required for GPCR ligand (LPA, ATP, Alternaria, house dust mite)-induced NF-κB activation and proasthmatic mediator production in airway epithelial cells (AECs). CARMA3-deficient AECs have reduced allergic inflammation. Mice with CARMA3-deficient AECs have reduced airway eosinophilia, cytokine production, and impaired dendritic cell maturation in a murine model of allergic airway inflammation.\",\n      \"method\": \"CARMA3 conditional KO mice (AEC-specific), NF-κB reporter assay, cytokine ELISA, flow cytometry, antigen processing assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional KO mice with in vivo allergic inflammation model plus multiple cellular readouts\",\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. Conversely, CARMA3 sequesters MAVS from forming high-molecular-weight aggregates, suppressing TBK1/IRF3 activation. After NF-κB activation, CARMA3 is degraded in a proteasome-dependent manner, releasing MAVS to activate IRF3. CARMA3-deficient mice show reduced inflammation and stronger viral clearance.\",\n      \"method\": \"CARMA3-deficient mice, Co-immunoprecipitation, native PAGE (MAVS aggregate detection), proteasome inhibitor assay, NF-κB/IRF3 reporter assays, in vivo viral infection model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mice plus multiple biochemical methods demonstrating MAVS sequestration and proteasomal regulation, in vivo confirmation\",\n      \"pmids\": [\"26947079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AGTR1 (angiotensin II receptor) overexpression in breast cancer drives NF-κB activation via the CARMA3-BCL10-MALT1 (CBM) signalosome, promoting proliferation, migration, invasion, and tumor angiogenesis. Both ligand-dependent and ligand-independent AGTR1-mediated NF-κB activation requires the CBM triad.\",\n      \"method\": \"siRNA knockdown of CBM components, NF-κB reporter assay, proliferation/migration/invasion assays, endothelial angiogenesis assay, AGTR1 overexpression models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple CBM component knockdowns with consistent functional readouts in cancer context, single lab\",\n      \"pmids\": [\"29259013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARD10 is a direct transcriptional target of the myeloid transcription factor CEBPE. CEBPE binds to regulatory elements upstream of the murine Card10 locus (confirmed by ChIP), and CARD10 expression is significantly reduced in Cebpe knockout mice. Silencing Card10 impairs granulopoiesis, affecting expression of genes involved in myeloid cell development and function.\",\n      \"method\": \"ChIP assay, Cebpe knockout mice, siRNA knockdown in human cell line and murine primary cells, gene expression analysis\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct CEBPE binding plus genetic KO mouse validation, single lab\",\n      \"pmids\": [\"29773596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARMA3 mediates Alternaria alternata-induced allergic airway inflammation in AECs. CARMA3 interacts with inositol 1,4,5-trisphosphate receptors (IP3Rs) in AECs, and inhibition of CARMA3 signaling reduces A. alternata-induced intracellular calcium release, reducing IL-33, IL-25, and type 2 immune responses.\",\n      \"method\": \"Co-immunoprecipitation (CARMA3-IP3R interaction), CARMA3-deficient AEC mice, intracellular calcium measurement, cytokine ELISA, in vivo allergic inflammation model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel IP3R binding by Co-IP plus KO mice with functional calcium release and cytokine readouts, 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, and this cleavage dampens CARD10's capacity to activate NF-κB. Preventing CARD10 cleavage increases basal IL-6 and extracellular matrix components in vitro and leads to increased tumor growth in a mouse xenograft model, indicating that MALT1-mediated CARD10 cleavage is a built-in negative regulatory mechanism.\",\n      \"method\": \"In vitro MALT1 cleavage assay, site-directed mutagenesis (R587 cleavage site), NF-κB reporter assay, cytokine ELISA, mouse xenograft tumor model\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro cleavage assay with mutagenesis identifying precise cleavage site, plus functional in vivo xenograft validation, single lab\",\n      \"pmids\": [\"33824280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CARMA3 localizes at mitochondria in liver sinusoidal endothelial cells (LSECs). In CARMA3-deficient mice, Con A-induced liver injury is exacerbated, with more LSEC damage, mitochondrial damage, and coagulation. In vitro, CARMA3-deficient LSECs show increased mitochondrial damage and cell death upon Con A treatment, revealing a mitochondria-protective role of CARMA3 in LSECs distinct from its NF-κB scaffolding function.\",\n      \"method\": \"CARMA3 knockout mice, subcellular fractionation/localization of CARMA3 to mitochondria, Con A hepatitis model, cell death assay, coagulation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mice plus subcellular localization to mitochondria with functional consequence, single lab\",\n      \"pmids\": [\"35831018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CARMA3 deficiency exacerbates Ang II-induced abdominal aortic aneurysm (AAA) formation, increased inflammatory cytokines, MMP expression, and VSMC death. Mechanistically, CARMA3 deficiency activates the p38MAPK pathway, enhancing the interaction between ER stress and mitochondrial damage, ultimately promoting VSMC pyroptosis.\",\n      \"method\": \"CARMA3 knockout mice, Ang II osmotic pump model, p38MAPK pathway analysis, ER stress markers, mitochondrial damage assays, pyroptosis assays\",\n      \"journal\": \"The Canadian journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic KO in vivo model with mechanistic pathway analysis, single lab\",\n      \"pmids\": [\"37030515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sonic hedgehog (SHH) signaling promotes myocardial pyroptosis after I/R injury via PKCα-mediated CARD10-BCL10-MALT1 (CBM) complex formation. SHH activation increases PKCα levels; PKCα inhibition attenuates CBM complex formation. Disruption of the CBM complex prevents MALT1 from recruiting TRAF6, which is required to trigger caspase-11-dependent pyroptosis.\",\n      \"method\": \"SHH pathway inhibitors, PKCα inhibitor, Co-immunoprecipitation (CBM complex), TRAF6 recruitment assay, caspase-11 activation assay, mouse I/R model and H9c2 H/R model\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibitors plus Co-IP complex analysis with in vivo and in vitro models, single lab\",\n      \"pmids\": [\"39343081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CARMA3 suppresses myofibroblast activation in cardiac fibroblasts by inhibiting STAT1 phosphorylation. An interaction between CARMA3 and STAT1 was detected in response to pressure overload. CARMA3-knockout mice subjected to TAC or Ang II treatment show increased cardiac fibrosis, myofibroblast differentiation, and mitochondrial damage; proteomic analysis identified elevated STAT1 in CARMA3-KO cardiac fibroblasts.\",\n      \"method\": \"CARMA3 knockout mice, TAC and Ang II models, Co-immunoprecipitation (CARMA3-STAT1), proteomic analysis, flow cytometry, STAT1 phosphorylation assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mice with in vivo pressure overload model, Co-IP identifying novel STAT1 interaction, proteomic validation, single lab\",\n      \"pmids\": [\"41053092\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CARD10/CARMA3 is a MAGUK/CARD-domain scaffold protein that assembles the CBM (CARMA3–BCL10–MALT1) signalosome downstream of GPCRs (e.g., LPA receptor, Ang II type 1 receptor, PAR-1, CXCR2, CXCR4) and receptor tyrosine kinases (EGFR), linking PKCα-mediated signals through BCL10 bridging to MALT1, which in turn recruits TRAF6 and triggers K63-linked ubiquitination of IKKγ/NEMO to activate the IKK complex and canonical NF-κB; MALT1 also cleaves CARD10 itself at R587 as a built-in negative feedback; the complex additionally interfaces with MAVS to balance NF-κB vs. IRF3/antiviral responses, interacts with IP3Rs to regulate calcium signaling in airway epithelium, localizes to mitochondria in endothelial cells to maintain mitochondrial integrity, and is transcriptionally controlled by CEBPE in granulocytes, while CARMA3 also interacts with STAT1 to suppress myofibroblast activation in cardiac fibroblasts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CARD10 (CARMA3) is a MAGUK/CARD-domain scaffold protein that nucleates the CARMA3–BCL10–MALT1 (CBM) signalosome to couple cell-surface receptor activation to canonical NF-κB signaling in non-lymphoid cells [#0, #1]. It binds BCL10 through its N-terminal CARD domain, and BCL10 in turn bridges to MALT1 to form a ternary complex that activates the IκB kinases [#0]. CARMA3 physically associates with IKKγ/NEMO and assembles a large inducible complex containing NEMO and IKKα/β, linking NEMO to TRAF6 to drive polyubiquitination that activates IKK kinase activity [#2, #4]. This CBM module transduces signals from a range of G-protein-coupled receptors—including the angiotensin II type 1 receptor, LPA receptor, PAR-1, CXCR2, and CXCR4—as well as the EGF receptor, typically via PKCα activation [#3, #5, #10, #12], and the complex is negatively regulated by A20-mediated deubiquitylation and by MALT1 cleavage of CARD10 at R587, a built-in feedback that dampens NF-κB output [#7, #20]. Through these receptors CARMA3 drives inflammatory and tumor-promoting programs in vascular, epithelial, and cancer cells, including ICAM-1/VCAM-1-dependent monocyte adhesion, VEGF induction, proasthmatic cytokine production, and proliferation/invasion [#10, #6, #15, #12], and in vivo CARMA3/BCL10 loss protects against Ang II-driven atherosclerosis and aortic aneurysm [#11]. CARMA3 additionally exerts NF-κB-independent roles: it sequesters MAVS to balance NF-κB versus IRF3 antiviral responses [#16], interacts with IP3 receptors to control calcium-dependent type 2 immune signaling in airway epithelium [#19], localizes to mitochondria to preserve mitochondrial integrity in liver sinusoidal endothelial cells [#21], and interacts with STAT1 to suppress myofibroblast activation in cardiac fibroblasts [#24]. CARD10 is itself a direct transcriptional target of the myeloid factor CEBPE and contributes to granulopoiesis [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established CARD10 as a CARD-domain scaffold that physically links BCL10 and MALT1 into a ternary complex and places it upstream of IKK in the PKC-to-NF-κB axis, defining its core molecular role.\",\n      \"evidence\": \"Co-immunoprecipitation, domain mapping, and dominant-negative mutants with NF-κB reporter assays\",\n      \"pmids\": [\"11387339\", \"11259443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the receptor that physiologically engages the complex\", \"Mechanism connecting the CBM complex to IKK activation not yet resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed CARMA3 directly contacts IKKγ/NEMO within a large inducible IKK-containing complex, providing the physical bridge from the scaffold to the kinase machinery.\",\n      \"evidence\": \"Reciprocal Co-IP and dominant-negative NEMO-binding fragment in NF-κB reporter assays in non-lymphoid cells\",\n      \"pmids\": [\"15184390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the ubiquitin enzymology activating IKK\", \"Upstream receptor input still undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the angiotensin II type 1 GPCR as a physiological trigger for CBM-dependent NF-κB activation, defining CARMA3 as a GPCR effector via NEMO ubiquitination.\",\n      \"evidence\": \"Dominant-negative mutants, RNAi, Bcl10−/− mice, and in vivo cytokine assays in hepatocytes\",\n      \"pmids\": [\"17101977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not detail the ubiquitin ligase machinery\", \"Generality across other GPCRs not yet tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic knockout established CARMA3 as broadly required for GPCR-induced IKK activation and implicated TRAF6 in linking NEMO to its polyubiquitination.\",\n      \"evidence\": \"CARMA3 knockout mice, Co-IP, ubiquitination and IKK kinase assays\",\n      \"pmids\": [\"17438001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of TRAF6 as the operative ligase incomplete\", \"Did not address receptor-specific assembly differences\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined PKCα as the specific upstream kinase coupling the LPA GPCR to CARMA3, distinguishing it from PKCθ/ζ and linking the pathway to tumor invasion.\",\n      \"evidence\": \"Isoform-specific dominant-negative PKC mutants, siRNA of CBM components, NF-κB and invasion assays in ovarian cancer cells\",\n      \"pmids\": [\"17724468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PKCα phosphorylation target on the CBM complex not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended CARMA3-CBM signaling to multiple GPCRs (CXCR2) and tissues, coupling NF-κB to VEGF induction and airway epithelial cytokine production.\",\n      \"evidence\": \"siRNA/dominant-negative perturbation with VEGF and cytokine readouts in endothelial and airway epithelial cells\",\n      \"pmids\": [\"19112107\", \"18757306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pathway placements\", \"Direct receptor-to-CARMA3 biochemical bridge not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified A20 as a negative regulator that disassembles the CARMA3-BCL10-NEMO complex via deubiquitylation, adding a brake to the pathway.\",\n      \"evidence\": \"Co-IP complex assembly analysis, deubiquitylation assay, NF-κB reporter\",\n      \"pmids\": [\"18349075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Specific ubiquitin chains targeted on the complex not fully defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed cell-type-specific assembly logic—the endothelial CARMA3 signalosome requires β-arrestin 2 rather than PDK1—distinguishing it from the lymphocyte CARMA1 complex downstream of PAR-1.\",\n      \"evidence\": \"siRNA, Co-IP, PDK1 inhibitor, β-arrestin 2 knockdown, monocyte adhesion assay\",\n      \"pmids\": [\"21041303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of β-arrestin 2-dependent assembly unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated the CBM signalosome's pathophysiological role in vascular inflammation, with genetic loss protecting against Ang II-driven atherosclerosis and aneurysm.\",\n      \"evidence\": \"siRNA in endothelial/VSMCs and Bcl10−/− mice in atherosclerosis models\",\n      \"pmids\": [\"20605784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Used Bcl10 rather than CARMA3 genetic ablation for the in vivo arm\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed CARMA3 also transduces receptor tyrosine kinase (EGFR) signals to IKK/NF-κB, broadening its receptor repertoire beyond GPCRs and linking it to tumor growth.\",\n      \"evidence\": \"CARMA3-deficient MEFs, siRNA, IKK and NF-κB assays, xenograft tumor model\",\n      \"pmids\": [\"21406399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling EGFR to PKC and CARMA3 not fully defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified DEPDC7 as a CARMA3-specific upstream binding partner required for CBM-dependent but not CARMA1-dependent NF-κB activation.\",\n      \"evidence\": \"Co-IP and shRNA with receptor-specificity controls\",\n      \"pmids\": [\"25541973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How DEPDC7 modulates complex assembly mechanistically unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected CARMA3-driven NF-κB to a transcriptional metastasis program (NF-κB/miR-182/NME2) and to allergic airway inflammation in vivo.\",\n      \"evidence\": \"ChIP, luciferase, knockdown, metastasis assays; AEC-specific conditional knockout mice in allergic airway model\",\n      \"pmids\": [\"25906011\", \"26041536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-lab mechanistic chains\", \"Generality of the miR-182 axis across tumor types untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered an NF-κB-independent function: CARMA3 sequesters MAVS to restrain TBK1/IRF3 antiviral signaling, and is proteasomally degraded to release MAVS, positioning it as a switch balancing inflammation versus antiviral response.\",\n      \"evidence\": \"CARMA3-deficient mice, Co-IP, native PAGE MAVS aggregation, proteasome inhibitor, NF-κB/IRF3 reporters, viral infection model\",\n      \"pmids\": [\"26947079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating CARMA3 degradation not identified\", \"Structural basis of MAVS sequestration unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed AGTR1-CBM signaling drives breast cancer progression through both ligand-dependent and ligand-independent NF-κB activation.\",\n      \"evidence\": \"siRNA of CBM components with proliferation/invasion/angiogenesis assays and AGTR1 overexpression models\",\n      \"pmids\": [\"29259013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of ligand-independent activation not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed CARD10 within myeloid development as a direct CEBPE transcriptional target required for normal granulopoiesis, defining an upstream transcriptional control point.\",\n      \"evidence\": \"ChIP, Cebpe knockout mice, siRNA, gene expression analysis\",\n      \"pmids\": [\"29773596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether CARD10's scaffold function or another activity drives granulopoiesis unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a physical CARMA3-IP3R interaction controlling calcium release and type 2 immune mediators, an NF-κB-independent role in airway epithelium.\",\n      \"evidence\": \"Co-IP, CARMA3-deficient AEC mice, intracellular calcium measurement, cytokine ELISA, allergic inflammation model\",\n      \"pmids\": [\"29958012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without reciprocal structural validation\", \"Domain mediating IP3R binding unmapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established CARD10 as the first MALT1 substrate in non-hematopoietic cells, with cleavage at R587 forming a built-in negative feedback that limits NF-κB, cytokine, and tumor output.\",\n      \"evidence\": \"In vitro MALT1 cleavage assay, R587 site-directed mutagenesis, NF-κB reporter, cytokine ELISA, xenograft model\",\n      \"pmids\": [\"33824280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Fate and function of the cleavage fragments not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a mitochondria-localized, scaffold-independent protective role of CARMA3 in liver sinusoidal endothelial cells against immune-mediated injury.\",\n      \"evidence\": \"CARMA3 knockout mice, subcellular fractionation, Con A hepatitis, cell death and coagulation assays\",\n      \"pmids\": [\"35831018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular mechanism of mitochondrial protection not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked CARMA3 loss to enhanced VSMC pyroptosis via p38MAPK-coupled ER stress/mitochondrial damage, indicating a protective vascular role distinct from its pro-inflammatory NF-κB function.\",\n      \"evidence\": \"CARMA3 knockout mice, Ang II osmotic pump model, p38MAPK, ER stress, mitochondrial and pyroptosis assays\",\n      \"pmids\": [\"37030515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Reconciliation with the pro-atherogenic CBM role unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed SHH-PKCα-driven CBM complex formation recruits TRAF6 to trigger caspase-11-dependent myocardial pyroptosis, connecting the scaffold to a programmed cell death pathway.\",\n      \"evidence\": \"SHH and PKCα inhibitors, Co-IP, TRAF6 recruitment, caspase-11 assays, mouse I/R and H9c2 H/R models\",\n      \"pmids\": [\"39343081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct CBM-to-caspase-11 molecular link not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a CARMA3-STAT1 interaction that suppresses STAT1 phosphorylation and myofibroblast activation, defining an anti-fibrotic, NF-κB-independent role in cardiac fibroblasts.\",\n      \"evidence\": \"CARMA3 knockout mice, TAC and Ang II models, Co-IP, proteomics, STAT1 phosphorylation assays\",\n      \"pmids\": [\"41053092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without reciprocal validation\", \"Mechanism by which CARMA3 inhibits STAT1 phosphorylation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CARMA3 partitions between its canonical CBM/NF-κB scaffolding role and its growing set of NF-κB-independent activities (MAVS sequestration, IP3R-calcium control, mitochondrial protection, STAT1 inhibition) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the assembled CBM signalosome\", \"Domains and post-translational modifications governing the switch between scaffold and non-scaffold functions undefined\", \"No human disease mutation linkage established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 10, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 16, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [22, 23]}\n    ],\n    \"complexes\": [\"CBM (CARMA3-BCL10-MALT1) signalosome\", \"IKK complex\"],\n    \"partners\": [\"BCL10\", \"MALT1\", \"IKBKG\", \"TRAF6\", \"DEPDC7\", \"MAVS\", \"ITPR1\", \"STAT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}