{"gene":"CARD14","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2001,"finding":"CARD14 is a CARD/MAGUK family scaffold protein whose CARD domain specifically associates with the CARD domain of BCL10, leading to NF-κB activation and BCL10 phosphorylation when expressed in cells.","method":"Co-immunoprecipitation, NF-κB reporter assay, domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding demonstrated, functional NF-κB activation confirmed, foundational paper replicated widely","pmids":["11278692"],"is_preprint":false},{"year":2011,"finding":"Alternative splicing of CARD14/CARMA2 generates two isoforms: CARMA2short (CARMA2sh, containing CARD, coiled-coil, and PDZ domains) and CARMA2cardless (lacking CARD domain). CARMA2sh localizes to the cytosol, interacts with TRAF2, activates NF-κB in a TRAF2-dependent manner, and protects cells from apoptosis.","method":"RT-PCR, fluorescence microscopy, co-immunoprecipitation, NF-κB reporter assay, apoptosis assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in single study; binding and functional data both provided","pmids":["21302310"],"is_preprint":false},{"year":2012,"finding":"Gain-of-function mutations in CARD14 (p.Gly117Ser, p.Glu138Ala) lead to enhanced NF-κB activation and upregulation of psoriasis-associated genes (CCL20, IL8) in keratinocytes compared to wild-type CARD14. CARD14 localizes mainly to basal and suprabasal layers of epidermis.","method":"NF-κB reporter assay, transfection in keratinocytes, transcriptome profiling, immunohistochemistry","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — functional gain-of-function assays with multiple mutations, replicated across two publications from same dataset","pmids":["22521418","22521419"],"is_preprint":false},{"year":2012,"finding":"CARD14 mutations causing familial pityriasis rubra pilaris increase CARD14 levels and activate NF-κB (p65) in affected skin, demonstrating CARD14's role as an activator of NF-κB signaling in epithelial inflammatory disease.","method":"Immunohistochemistry, NF-κB activation assay, linkage analysis and exome sequencing","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional validation in patient tissue and cells, single lab","pmids":["22703878"],"is_preprint":false},{"year":2014,"finding":"CARD14 is expressed in dermal CD31+ endothelial cells in addition to epidermal keratinocytes. Transfection of dermal endothelial cells with psoriasis-associated CARD14 mutations results in increased expression of chemokines CXCL10, IL-8, and CCL2, with phosphorylated NF-κB detected in psoriatic CARD14+ CD31+ endothelial cells.","method":"Two-color immunofluorescence co-localization, transfection with mutant CARD14, chemokine quantification","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct co-localization and functional transfection data, single lab","pmids":["25369198"],"is_preprint":false},{"year":2014,"finding":"DEPDC7 (DEP domain-containing protein) binds to CARMA2 (CARD14) and CARMA3 proteins. DEPDC7 displays cytosolic distribution, activates NF-κB when expressed, and shRNA-mediated knockdown impairs NF-κB activation downstream of G protein-coupled receptor stimulation that requires CARMA2.","method":"Yeast two-hybrid screening, co-immunoprecipitation, shRNA knockdown, NF-κB reporter assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — binding confirmed by Y2H and co-IP; functional role confirmed by shRNA; single lab","pmids":["25541973"],"is_preprint":false},{"year":2016,"finding":"Psoriasis-associated CARD14 mutations (E138A and G117S) disrupt autoinhibition by the CARD14 linker region, causing constitutive interaction with BCL10 and MALT1, BCL10- and MALT1-dependent NF-κB activation in keratinocytes, MALT1 paracaspase activity stimulation, and ERK1/2 and p38α MAP kinase activation. MALT1 inhibition with mepazine reduces mutant CARD14-induced psoriasis-associated transcripts.","method":"Co-immunoprecipitation, NF-κB reporter assay, MALT1 activity assay, kinase phosphorylation assays, pharmacological inhibition, mutagenesis of linker region","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical methods including mutagenesis and enzymatic activity assay; mechanistic model validated by inhibitor","pmids":["27071417"],"is_preprint":false},{"year":2016,"finding":"CARD14 physically interacts with the paracaspase MALT1 and activates MALT1 proteolytic activity. CARD14 also activates p38 and JNK MAP kinase pathways in addition to NF-κB, all dependent on MALT1. Psoriasis-associated CARD14 mutations enhance MALT1 proteolytic activity and inflammatory gene expression. MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits mutant CARD14-induced cytokine/chemokine expression in primary human keratinocytes.","method":"Co-immunoprecipitation, MALT1 protease activity assay, genetic knockdown (MALT1 deficiency), pharmacological inhibition, gene expression analysis in primary keratinocytes","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 — reconstituted MALT1 proteolytic activity, genetic and pharmacological validation, orthogonal methods","pmids":["27113748"],"is_preprint":false},{"year":2017,"finding":"E3 ubiquitin ligase RNF7 interacts with CARMA2 (CARD14) and negatively regulates CARMA2's NF-κB-activating capacity by regulating the ubiquitination state of MALT1 and NEMO. Psoriasis-associated CARMA2sh mutants escape RNF7-mediated negative regulation.","method":"Yeast two-hybrid screening, co-immunoprecipitation, ubiquitination assay, NF-κB reporter assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — binding and functional data with mechanistic follow-up on ubiquitination; single lab","pmids":["29194363"],"is_preprint":false},{"year":2018,"finding":"Card14 gain-of-function mutations (E138A and ΔQ136) in mice cause spontaneous psoriasis-like skin inflammation through constitutively activated CARMA2 self-aggregation, leading to enhanced IL-23–IL-17A cytokine axis activation. CARMA2 associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-κB and MAPK signaling in keratinocytes, driving pro-inflammatory gene expression. Card14-/- mice show attenuated imiquimod-induced skin inflammation due to impaired IL-17A signaling.","method":"Knock-in mouse models, Card14 knockout, co-immunoprecipitation (CARMA2 with ACT1-TRAF6), NF-κB and MAPK signaling assays, cytokine analysis, imiquimod psoriasis model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo KO and KI models combined with biochemical complex identification and signaling pathway characterization","pmids":["29980436"],"is_preprint":false},{"year":2018,"finding":"Heterozygous Card14ΔE138 gain-of-function mutation in mice is sufficient to spontaneously drive psoriatic skin disease via the IL-23/IL-17 axis. Neutralization of IL-23p19 significantly reduces skin lesions and proinflammatory cytokine expression, establishing IL-23 as a key downstream mediator of CARD14-driven inflammation.","method":"Knock-in mouse model, cytokine neutralization (anti-IL-23p19), histology, gene expression analysis","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with pathway epistasis established by cytokine blockade; replicated by independent lab","pmids":["29689250"],"is_preprint":false},{"year":2018,"finding":"Loss-of-function mutations in CARD14 exert a dominant negative effect on NF-κB signaling in keratinocytes, demonstrated by dual luciferase reporter assay, and are associated with severe atopic dermatitis, with decreased CARD14 expression and decreased activated p65 levels in patient skin.","method":"Dual luciferase reporter assay, immunohistochemistry for p65, functional assays in keratinocytes, exome sequencing","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay with patient tissue validation; single lab","pmids":["30248356"],"is_preprint":false},{"year":2019,"finding":"CARMA2sh forms a complex with TANK and MALT1 in keratinocytes. Both CARMA2sh and TANK are individually required for NF-κB activation following TLR3 stimulation (poly I:C). TANK is essential for TBK1/IRF3 pathway activation after poly I:C stimulation, whereas CARMA2sh functions as a repressor of this pathway. Psoriasis-associated CARMA2sh mutants bind TANK less efficiently and are less effective at suppressing the TBK1/IRF3 pathway.","method":"Co-immunoprecipitation, siRNA knockdown, NF-κB reporter assay, IRF3 phosphorylation assay in human keratinocyte cell line","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays with mechanistic dissection; single lab","pmids":["31486084"],"is_preprint":false},{"year":2020,"finding":"CARD14E138A-induced skin inflammation and systemic disease in knock-in mice are independent of adaptive immune cells, ameliorated by blocking TNF, and induced specifically by CARD14E138A signaling in keratinocytes. Homozygous expression induces severe systemic disease resembling GPP acute exacerbations.","method":"Tamoxifen-inducible keratinocyte-specific knock-in mouse, adaptive immune cell depletion/absence, TNF blockade, bone marrow transplant","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific and pathway-specific genetic epistasis with rigorous controls; multiple orthogonal approaches","pmids":["32597759"],"is_preprint":false},{"year":2020,"finding":"Keratinocyte-specific inducible expression of CARD14E138A rapidly induces psoriatic skin inflammation and gene expression changes. Keratinocyte-specific MALT1 deletion and oral MALT1 protease inhibitor treatment both strongly reduce psoriatic skin disease, demonstrating a keratinocyte-intrinsic causal role for CARD14/MALT1 signaling in psoriasis.","method":"Inducible keratinocyte-specific transgenic mouse, conditional MALT1 KO, pharmacological MALT1 inhibition, histology, gene expression","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 — genetic and pharmacological convergent evidence in cell-type-specific in vivo model","pmids":["32343482"],"is_preprint":false},{"year":2020,"finding":"UBAC1 (non-catalytic subunit of E3 ubiquitin ligase KPC complex) interacts with CARMA2sh and participates in the CARMA2sh/TANK complex, promoting K63-linked ubiquitination of TANK and negatively regulating the NF-κB-activating capacity of CARMA2sh following TLR3 stimulation in human keratinocytes.","method":"Yeast two-hybrid screening, co-immunoprecipitation, ubiquitination assay (K63-linkage), NF-κB reporter assay in keratinocytes","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — binding confirmed by Y2H and co-IP, ubiquitination type characterized, functional assay performed; single lab","pmids":["33316896"],"is_preprint":false},{"year":2021,"finding":"Pathogenic CARD14 mutations increase DNA double-strand breaks under conditions of replication stress (without affecting response to exogenous DNA damage stimuli), suppress new origin firings, and promote break-induced replication (BIR) via homologous recombination, leading to revertant mosaicism in patient skin.","method":"DNA damage assays (γH2AX, comet assay), replication stress assays, sequencing of revertant skin patches, X-irradiation and etoposide treatment comparisons","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays establishing mechanistic role in replication stress; single lab","pmids":["34004138"],"is_preprint":false},{"year":2024,"finding":"CARD14E138A associates with BCL10, MALT1, M1-ubiquitin E3 ligase HOIP, and K63-ubiquitin E3 ligase TRAF6; HOIP and TRAF6 interactions promote BCL10 ubiquitination and are essential for NF-κB and MAP kinase activation. Ubiquitin-binding proteins A20 and ABIN1 negatively regulate signaling by inducing CARD14E138A turnover. CARD14E138A localizes to early endosomes via association with the AP2 adaptor complex, and AP2 function is required for CARD14E138A activation of mTORC1, which stimulates keratinocyte metabolism and proliferation. Rapamycin (mTORC1 inhibitor) reduces CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice.","method":"Affinity purification-mass spectrometry, co-immunoprecipitation, subcellular fractionation/confocal imaging, mutagenesis, NF-κB reporter assay, mTORC1 activity assay, rapamycin treatment in mice","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — AP-MS discovery validated by multiple orthogonal methods including structural localization, mutagenesis, in vivo pharmacology","pmids":["39145956"],"is_preprint":false},{"year":2024,"finding":"PLK1 (polo-like kinase 1) is a novel CARD14-binding protein identified by unbiased AP-MS. CARD14-PLK1 binding is independent of the CARD domain but involves a phospho-dependent PLK1-binding motif in the CARD14 linker region. Expression of CARD14E138A recruits PLK1 to CARD14-containing signalosomes in interphase keratinocytes. Disruption of the PLK1-binding motif in CARD14E138A increases CARD14-induced proinflammatory signaling and gene expression, indicating PLK1 is a negative regulator of CARD14 signaling.","method":"Affinity purification-mass spectrometry, co-immunoprecipitation, confocal imaging, linker region mutagenesis, gene expression analysis in keratinocytes","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — AP-MS validated by co-IP and imaging; domain mapping and functional consequence of disruption shown; single lab","pmids":["38797267"],"is_preprint":false},{"year":2025,"finding":"CARD14 expressed in intestinal epithelial cells (IEC) mediates NF-κB signaling. Mice expressing the gain-of-function CARD14E138A mutant specifically in IEC develop mild intestinal inflammation, drastically reduced intestinal motility (often with rectal prolapse), decreased Paneth cell antimicrobial peptide expression, microbial dysbiosis, and increased susceptibility to enteric bacterial infection.","method":"IEC-specific transgenic mouse model, histology, intestinal motility assay, transcriptome analysis of IEC, bacterial infection challenge","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type-specific in vivo model with multiple phenotypic readouts; single lab, novel finding","pmids":["41131424"],"is_preprint":false},{"year":2017,"finding":"CARD14 is essential for murine experimental psoriasis (imiquimod and IL-23 models): Card14-/- mice show abrogated psoriasiform skin inflammation. Bone marrow chimera studies indicate CARD14 in radio-sensitive hematopoietic cells is required for IMQ-induced disease, controlling Vγ4+ T cells producing IL-17/IL-22 in the dermis/epidermis. CARD14 acts downstream of IL-23, not TLR7/TLR9.","method":"Card14 knockout mouse, imiquimod and IL-23 injection psoriasis models, bone marrow chimera, cell-type specific gene signature comparison","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis established by KO and chimera experiments with defined cellular and pathway-level phenotype","pmids":["29150564"],"is_preprint":false},{"year":2026,"finding":"CARD14 interacts with MYC and promotes osteoclast (OC) differentiation via a MYC-dependent pathway while simultaneously activating NF-κB and MAPK signaling. Adenoviral CARD14 overexpression in BM-derived macrophages increases OC differentiation/activity; BM-specific Card14 KO mice show reduced OC activity, improved trabecular bone microarchitecture, and increased bone mineral density.","method":"Co-immunoprecipitation (CARD14-MYC interaction), adenoviral overexpression, BM-specific conditional KO mouse, TRAP staining, micro-CT, histology, serum bone biomarkers","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 — protein interaction and KO/OE functional data with in vivo phenotype; single lab, novel context","pmids":["40971787"],"is_preprint":false}],"current_model":"CARD14 is a CARD/MAGUK scaffold protein expressed predominantly in keratinocytes that forms a CBM (CARD14-BCL10-MALT1) signaling complex to activate NF-κB, MAPK (p38, JNK, ERK), and mTORC1 pathways; gain-of-function mutations in its coiled-coil/linker region disrupt autoinhibition, promote constitutive BCL10-MALT1 recruitment and MALT1 protease activation, drive IL-23/IL-17A-dependent psoriatic skin inflammation in vivo, and are negatively regulated by PLK1, RNF7, A20, ABIN1, and UBAC1, while also mediating IL-17A signaling via the ACT1-TRAF6 complex and TLR3 signaling via a TANK-containing complex."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing that CARD14 is a CARD/MAGUK scaffold that directly engages BCL10 via CARD–CARD interaction to activate NF-κB answered the fundamental question of how this protein initiates signaling.","evidence":"Co-immunoprecipitation and NF-κB reporter assays with domain-mapping in transfected cells","pmids":["11278692"],"confidence":"High","gaps":["Endogenous upstream stimuli unknown","No in vivo validation","Role of other MAGUK domains (PDZ, SH3, GUK) in signaling uncharacterized"]},{"year":2011,"claim":"Discovery of alternative splice isoforms (CARMA2sh and CARMA2cardless) with distinct domain compositions revealed that CARD14 can signal through TRAF2 in addition to BCL10, broadening its signaling repertoire.","evidence":"RT-PCR, co-immunoprecipitation, fluorescence microscopy, and apoptosis assays","pmids":["21302310"],"confidence":"Medium","gaps":["TRAF2-dependent pathway not validated in primary cells","Relative isoform abundance in tissues unknown","Anti-apoptotic mechanism not delineated"]},{"year":2012,"claim":"Identification of gain-of-function CARD14 mutations (G117S, E138A) as causes of familial psoriasis and pityriasis rubra pilaris established CARD14 as a disease gene and linked NF-κB hyperactivation in keratinocytes to psoriatic pathology.","evidence":"Linkage analysis, exome sequencing, NF-κB reporter assays, transcriptome profiling, and immunohistochemistry in patient skin","pmids":["22521418","22521419","22703878"],"confidence":"High","gaps":["Mechanism of autoinhibition disruption not yet defined","In vivo animal models not available","Downstream effector cytokine axis unknown"]},{"year":2016,"claim":"Demonstrating that psoriasis-associated mutations disrupt linker-mediated autoinhibition, constitutively recruit BCL10 and MALT1, and activate MALT1 paracaspase activity answered how gain-of-function mutations mechanistically drive inflammation and identified MALT1 as a druggable node.","evidence":"Co-immunoprecipitation, MALT1 enzymatic activity assays, MAPK phosphorylation, linker mutagenesis, and pharmacological MALT1 inhibition (mepazine) in primary keratinocytes","pmids":["27071417","27113748"],"confidence":"High","gaps":["Structural basis of autoinhibition not resolved at atomic level","Relative contribution of MALT1 protease vs. scaffold function unclear","No in vivo validation yet"]},{"year":2017,"claim":"Card14 knockout mice revealed that CARD14 is essential for experimental psoriasis and acts downstream of IL-23 in hematopoietic cells controlling dermal γδ T cell IL-17 production, resolving the question of whether CARD14 functions cell-autonomously only in keratinocytes.","evidence":"Card14-/- mice, imiquimod and IL-23 injection models, bone marrow chimeras","pmids":["29150564"],"confidence":"High","gaps":["Molecular mechanism in hematopoietic cells not defined","Relationship between keratinocyte-intrinsic and hematopoietic CARD14 functions unresolved"]},{"year":2018,"claim":"Card14 gain-of-function knock-in mice developed spontaneous IL-23/IL-17A–dependent psoriasis, and CARD14 was shown to mediate IL-17A signaling through association with the ACT1–TRAF6 complex, integrating CARD14 into the IL-17 receptor signaling pathway.","evidence":"Card14 knock-in and knockout mice, co-immunoprecipitation of CARD14 with ACT1–TRAF6, NF-κB/MAPK assays, cytokine neutralization (anti-IL-23p19)","pmids":["29980436","29689250"],"confidence":"High","gaps":["How CARD14 is recruited to the IL-17R complex unclear","Whether CARD14 functions in IL-17 signaling in non-skin tissues not tested"]},{"year":2018,"claim":"Loss-of-function CARD14 mutations acting as dominant negatives on NF-κB in keratinocytes were linked to severe atopic dermatitis, revealing that CARD14 signaling dosage bidirectionally determines skin inflammatory phenotype.","evidence":"Dual luciferase reporter assay, immunohistochemistry in patient skin, exome sequencing","pmids":["30248356"],"confidence":"Medium","gaps":["Animal model of loss-of-function alleles not generated","Mechanism of dominant-negative effect not molecularly defined"]},{"year":2019,"claim":"Identifying a CARMA2sh–TANK–MALT1 complex that mediates TLR3-induced NF-κB activation while CARMA2sh simultaneously represses TBK1/IRF3 revealed a dual signaling role downstream of innate immune receptors.","evidence":"Co-immunoprecipitation, siRNA knockdown, NF-κB reporter and IRF3 phosphorylation assays in keratinocyte cell line","pmids":["31486084"],"confidence":"Medium","gaps":["In vivo relevance of TLR3–CARD14 axis not tested","Whether TBK1 repression is direct or indirect unknown","Psoriasis mutant TANK-binding defect not validated in primary cells"]},{"year":2020,"claim":"Keratinocyte-specific inducible CARD14E138A expression and conditional MALT1 deletion proved that keratinocyte-intrinsic CARD14–MALT1 signaling is sufficient and necessary for psoriatic inflammation, and that this axis is independent of adaptive immunity but dependent on TNF.","evidence":"Tamoxifen-inducible keratinocyte-specific transgenic mice, conditional MALT1 KO, MALT1 protease inhibitor, adaptive immune cell depletion, TNF blockade","pmids":["32597759","32343482"],"confidence":"High","gaps":["Identity of TNF-producing cell type not established","Whether innate lymphoid cells contribute not tested"]},{"year":2020,"claim":"Identification of negative regulators RNF7, UBAC1/KPC, A20, and ABIN1 that modulate CARD14 signaling through ubiquitination of MALT1, NEMO, and TANK defined a regulatory layer controlling CARD14 signalosome output.","evidence":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assays (K63-linkage), NF-κB reporters","pmids":["29194363","33316896"],"confidence":"Medium","gaps":["In vivo confirmation of negative regulator roles lacking","Whether these regulators are relevant in psoriasis patient tissue unknown","Relationship among multiple E3 ligases not tested"]},{"year":2021,"claim":"Finding that pathogenic CARD14 mutations increase replication stress–associated DNA double-strand breaks and promote break-induced replication revealed an unexpected role linking CARD14 signaling to genome maintenance and revertant mosaicism.","evidence":"γH2AX and comet assays, replication stress assays, sequencing of revertant patient skin patches","pmids":["34004138"],"confidence":"Medium","gaps":["Mechanism connecting CARD14 NF-κB signaling to replication fork stress not defined","Whether effect is NF-κB-dependent or MALT1-dependent not tested","Generalizability beyond CARD14 mutations unknown"]},{"year":2024,"claim":"AP-MS–based interactome mapping revealed CARD14E138A associates with HOIP, TRAF6, AP2 adaptor complex, and PLK1, establishing that the active signalosome localizes to early endosomes via AP2, activates mTORC1 to drive keratinocyte proliferation, and is negatively regulated by PLK1.","evidence":"Affinity purification-mass spectrometry, co-immunoprecipitation, confocal/subcellular fractionation, mTORC1 activity assays, rapamycin treatment in mice, linker mutagenesis","pmids":["39145956","38797267"],"confidence":"High","gaps":["Structural basis of endosomal targeting unknown","Whether mTORC1 activation occurs in WT CARD14 signaling not addressed","PLK1 regulatory mechanism (direct phosphorylation of CARD14?) not resolved"]},{"year":2025,"claim":"Intestinal epithelial CARD14E138A expression caused intestinal inflammation, reduced motility, Paneth cell dysfunction, and infection susceptibility, extending CARD14's physiological role beyond skin.","evidence":"IEC-specific transgenic mouse, histology, motility assay, transcriptomics, bacterial infection challenge","pmids":["41131424"],"confidence":"Medium","gaps":["Whether endogenous intestinal CARD14 participates in homeostatic signaling unknown","Upstream stimuli activating CARD14 in IEC not defined","Relevance to human IBD not established"]},{"year":null,"claim":"The physiological upstream signals that activate wild-type CARD14, the atomic-resolution structure of the autoinhibited and active signalosome, and the full extent of CARD14's roles beyond skin (gut, bone, vasculature) remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No ligand or receptor that activates WT CARD14 identified","No crystal or cryo-EM structure of CARD14 or its signalosome","Relative contributions of keratinocyte-intrinsic vs. hematopoietic CARD14 in human psoriasis not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6,9,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,7,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[17]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,6,7,9,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,10,12,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,10,14]}],"complexes":["CBM signalosome (CARD14-BCL10-MALT1)","CARD14-TANK-MALT1 complex","ACT1-TRAF6 complex"],"partners":["BCL10","MALT1","TANK","TRAF6","TRAF2","PLK1","HOIP","ACT1"],"other_free_text":[]},"mechanistic_narrative":"CARD14 is a CARD/MAGUK scaffold protein that nucleates a CBM (CARD14–BCL10–MALT1) signalosome in keratinocytes and other epithelial cells to activate NF-κB, MAPK (p38, JNK, ERK), and mTORC1 pathways, thereby controlling inflammatory gene expression, cell proliferation, and tissue homeostasis [PMID:11278692, PMID:27071417, PMID:39145956]. The coiled-coil/linker region maintains autoinhibition; gain-of-function mutations that disrupt this region cause constitutive BCL10–MALT1 recruitment, MALT1 paracaspase activation, and upregulation of psoriasis-associated chemokines (CCL20, IL-8), while loss-of-function mutations dominantly suppress NF-κB and are linked to severe atopic dermatitis [PMID:22521418, PMID:27071417, PMID:30248356]. In vivo, keratinocyte-intrinsic gain-of-function CARD14 signaling through MALT1 drives IL-23/IL-17A–dependent psoriatic inflammation that is ameliorated by MALT1 inhibition, TNF blockade, or IL-23 neutralization, and CARD14 also mediates IL-17A signaling via the ACT1–TRAF6 complex and TLR3 signaling via a TANK-containing complex [PMID:29980436, PMID:32343482, PMID:29689250, PMID:31486084]. Gain-of-function CARD14 mutations cause familial psoriasis and pityriasis rubra pilaris [PMID:22521418, PMID:22703878]."},"prefetch_data":{"uniprot":{"accession":"Q9BXL6","full_name":"Caspase recruitment domain-containing protein 14","aliases":["CARD-containing MAGUK protein 2","Carma 2"],"length_aa":1004,"mass_kda":113.3,"function":"Acts as a scaffolding protein that can activate the inflammatory transcription factor NF-kappa-B and p38/JNK MAP kinase signaling pathways. Forms a signaling complex with BCL10 and MALT1, and activates MALT1 proteolytic activity and inflammatory gene expression. MALT1 is indispensable for CARD14-induced activation of NF-kappa-B and p38/JNK MAP kinases (PubMed:11278692, PubMed:21302310, PubMed:27071417, PubMed:27113748). May play a role in signaling mediated by TRAF2, TRAF3 and TRAF6 and protects cells against apoptosis Not able to activate the inflammatory transcription factor NF-kappa-B and may function as a dominant negative regulator (PubMed:21302310, PubMed:26358359)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9BXL6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CARD14","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CARD14","total_profiled":1310},"omim":[{"mim_id":"616106","title":"PSORIASIS 15, PUSTULAR, SUSCEPTIBILITY TO; PSORS15","url":"https://www.omim.org/entry/616106"},{"mim_id":"614204","title":"PSORIASIS 14, PUSTULAR; 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specifically associates with the CARD domain of BCL10, leading to NF-κB activation and BCL10 phosphorylation when expressed in cells.\",\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 — reciprocal binding demonstrated, functional NF-κB activation confirmed, foundational paper replicated widely\",\n      \"pmids\": [\"11278692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Alternative splicing of CARD14/CARMA2 generates two isoforms: CARMA2short (CARMA2sh, containing CARD, coiled-coil, and PDZ domains) and CARMA2cardless (lacking CARD domain). CARMA2sh localizes to the cytosol, interacts with TRAF2, activates NF-κB in a TRAF2-dependent manner, and protects cells from apoptosis.\",\n      \"method\": \"RT-PCR, fluorescence microscopy, co-immunoprecipitation, NF-κB reporter assay, apoptosis assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in single study; binding and functional data both provided\",\n      \"pmids\": [\"21302310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Gain-of-function mutations in CARD14 (p.Gly117Ser, p.Glu138Ala) lead to enhanced NF-κB activation and upregulation of psoriasis-associated genes (CCL20, IL8) in keratinocytes compared to wild-type CARD14. CARD14 localizes mainly to basal and suprabasal layers of epidermis.\",\n      \"method\": \"NF-κB reporter assay, transfection in keratinocytes, transcriptome profiling, immunohistochemistry\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional gain-of-function assays with multiple mutations, replicated across two publications from same dataset\",\n      \"pmids\": [\"22521418\", \"22521419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CARD14 mutations causing familial pityriasis rubra pilaris increase CARD14 levels and activate NF-κB (p65) in affected skin, demonstrating CARD14's role as an activator of NF-κB signaling in epithelial inflammatory disease.\",\n      \"method\": \"Immunohistochemistry, NF-κB activation assay, linkage analysis and exome sequencing\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional validation in patient tissue and cells, single lab\",\n      \"pmids\": [\"22703878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CARD14 is expressed in dermal CD31+ endothelial cells in addition to epidermal keratinocytes. Transfection of dermal endothelial cells with psoriasis-associated CARD14 mutations results in increased expression of chemokines CXCL10, IL-8, and CCL2, with phosphorylated NF-κB detected in psoriatic CARD14+ CD31+ endothelial cells.\",\n      \"method\": \"Two-color immunofluorescence co-localization, transfection with mutant CARD14, chemokine quantification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct co-localization and functional transfection data, single lab\",\n      \"pmids\": [\"25369198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DEPDC7 (DEP domain-containing protein) binds to CARMA2 (CARD14) and CARMA3 proteins. DEPDC7 displays cytosolic distribution, activates NF-κB when expressed, and shRNA-mediated knockdown impairs NF-κB activation downstream of G protein-coupled receptor stimulation that requires CARMA2.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, shRNA knockdown, NF-κB reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding confirmed by Y2H and co-IP; functional role confirmed by shRNA; single lab\",\n      \"pmids\": [\"25541973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Psoriasis-associated CARD14 mutations (E138A and G117S) disrupt autoinhibition by the CARD14 linker region, causing constitutive interaction with BCL10 and MALT1, BCL10- and MALT1-dependent NF-κB activation in keratinocytes, MALT1 paracaspase activity stimulation, and ERK1/2 and p38α MAP kinase activation. MALT1 inhibition with mepazine reduces mutant CARD14-induced psoriasis-associated transcripts.\",\n      \"method\": \"Co-immunoprecipitation, NF-κB reporter assay, MALT1 activity assay, kinase phosphorylation assays, pharmacological inhibition, mutagenesis of linker region\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biochemical methods including mutagenesis and enzymatic activity assay; mechanistic model validated by inhibitor\",\n      \"pmids\": [\"27071417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CARD14 physically interacts with the paracaspase MALT1 and activates MALT1 proteolytic activity. CARD14 also activates p38 and JNK MAP kinase pathways in addition to NF-κB, all dependent on MALT1. Psoriasis-associated CARD14 mutations enhance MALT1 proteolytic activity and inflammatory gene expression. MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits mutant CARD14-induced cytokine/chemokine expression in primary human keratinocytes.\",\n      \"method\": \"Co-immunoprecipitation, MALT1 protease activity assay, genetic knockdown (MALT1 deficiency), pharmacological inhibition, gene expression analysis in primary keratinocytes\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted MALT1 proteolytic activity, genetic and pharmacological validation, orthogonal methods\",\n      \"pmids\": [\"27113748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"E3 ubiquitin ligase RNF7 interacts with CARMA2 (CARD14) and negatively regulates CARMA2's NF-κB-activating capacity by regulating the ubiquitination state of MALT1 and NEMO. Psoriasis-associated CARMA2sh mutants escape RNF7-mediated negative regulation.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, ubiquitination assay, NF-κB reporter assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding and functional data with mechanistic follow-up on ubiquitination; single lab\",\n      \"pmids\": [\"29194363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Card14 gain-of-function mutations (E138A and ΔQ136) in mice cause spontaneous psoriasis-like skin inflammation through constitutively activated CARMA2 self-aggregation, leading to enhanced IL-23–IL-17A cytokine axis activation. CARMA2 associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-κB and MAPK signaling in keratinocytes, driving pro-inflammatory gene expression. Card14-/- mice show attenuated imiquimod-induced skin inflammation due to impaired IL-17A signaling.\",\n      \"method\": \"Knock-in mouse models, Card14 knockout, co-immunoprecipitation (CARMA2 with ACT1-TRAF6), NF-κB and MAPK signaling assays, cytokine analysis, imiquimod psoriasis model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo KO and KI models combined with biochemical complex identification and signaling pathway characterization\",\n      \"pmids\": [\"29980436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Heterozygous Card14ΔE138 gain-of-function mutation in mice is sufficient to spontaneously drive psoriatic skin disease via the IL-23/IL-17 axis. Neutralization of IL-23p19 significantly reduces skin lesions and proinflammatory cytokine expression, establishing IL-23 as a key downstream mediator of CARD14-driven inflammation.\",\n      \"method\": \"Knock-in mouse model, cytokine neutralization (anti-IL-23p19), histology, gene expression analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with pathway epistasis established by cytokine blockade; replicated by independent lab\",\n      \"pmids\": [\"29689250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss-of-function mutations in CARD14 exert a dominant negative effect on NF-κB signaling in keratinocytes, demonstrated by dual luciferase reporter assay, and are associated with severe atopic dermatitis, with decreased CARD14 expression and decreased activated p65 levels in patient skin.\",\n      \"method\": \"Dual luciferase reporter assay, immunohistochemistry for p65, functional assays in keratinocytes, exome sequencing\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay with patient tissue validation; single lab\",\n      \"pmids\": [\"30248356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CARMA2sh forms a complex with TANK and MALT1 in keratinocytes. Both CARMA2sh and TANK are individually required for NF-κB activation following TLR3 stimulation (poly I:C). TANK is essential for TBK1/IRF3 pathway activation after poly I:C stimulation, whereas CARMA2sh functions as a repressor of this pathway. Psoriasis-associated CARMA2sh mutants bind TANK less efficiently and are less effective at suppressing the TBK1/IRF3 pathway.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, NF-κB reporter assay, IRF3 phosphorylation assay in human keratinocyte cell line\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with mechanistic dissection; single lab\",\n      \"pmids\": [\"31486084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CARD14E138A-induced skin inflammation and systemic disease in knock-in mice are independent of adaptive immune cells, ameliorated by blocking TNF, and induced specifically by CARD14E138A signaling in keratinocytes. Homozygous expression induces severe systemic disease resembling GPP acute exacerbations.\",\n      \"method\": \"Tamoxifen-inducible keratinocyte-specific knock-in mouse, adaptive immune cell depletion/absence, TNF blockade, bone marrow transplant\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific and pathway-specific genetic epistasis with rigorous controls; multiple orthogonal approaches\",\n      \"pmids\": [\"32597759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Keratinocyte-specific inducible expression of CARD14E138A rapidly induces psoriatic skin inflammation and gene expression changes. Keratinocyte-specific MALT1 deletion and oral MALT1 protease inhibitor treatment both strongly reduce psoriatic skin disease, demonstrating a keratinocyte-intrinsic causal role for CARD14/MALT1 signaling in psoriasis.\",\n      \"method\": \"Inducible keratinocyte-specific transgenic mouse, conditional MALT1 KO, pharmacological MALT1 inhibition, histology, gene expression\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic and pharmacological convergent evidence in cell-type-specific in vivo model\",\n      \"pmids\": [\"32343482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBAC1 (non-catalytic subunit of E3 ubiquitin ligase KPC complex) interacts with CARMA2sh and participates in the CARMA2sh/TANK complex, promoting K63-linked ubiquitination of TANK and negatively regulating the NF-κB-activating capacity of CARMA2sh following TLR3 stimulation in human keratinocytes.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, ubiquitination assay (K63-linkage), NF-κB reporter assay in keratinocytes\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding confirmed by Y2H and co-IP, ubiquitination type characterized, functional assay performed; single lab\",\n      \"pmids\": [\"33316896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pathogenic CARD14 mutations increase DNA double-strand breaks under conditions of replication stress (without affecting response to exogenous DNA damage stimuli), suppress new origin firings, and promote break-induced replication (BIR) via homologous recombination, leading to revertant mosaicism in patient skin.\",\n      \"method\": \"DNA damage assays (γH2AX, comet assay), replication stress assays, sequencing of revertant skin patches, X-irradiation and etoposide treatment comparisons\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays establishing mechanistic role in replication stress; single lab\",\n      \"pmids\": [\"34004138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CARD14E138A associates with BCL10, MALT1, M1-ubiquitin E3 ligase HOIP, and K63-ubiquitin E3 ligase TRAF6; HOIP and TRAF6 interactions promote BCL10 ubiquitination and are essential for NF-κB and MAP kinase activation. Ubiquitin-binding proteins A20 and ABIN1 negatively regulate signaling by inducing CARD14E138A turnover. CARD14E138A localizes to early endosomes via association with the AP2 adaptor complex, and AP2 function is required for CARD14E138A activation of mTORC1, which stimulates keratinocyte metabolism and proliferation. Rapamycin (mTORC1 inhibitor) reduces CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice.\",\n      \"method\": \"Affinity purification-mass spectrometry, co-immunoprecipitation, subcellular fractionation/confocal imaging, mutagenesis, NF-κB reporter assay, mTORC1 activity assay, rapamycin treatment in mice\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — AP-MS discovery validated by multiple orthogonal methods including structural localization, mutagenesis, in vivo pharmacology\",\n      \"pmids\": [\"39145956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLK1 (polo-like kinase 1) is a novel CARD14-binding protein identified by unbiased AP-MS. CARD14-PLK1 binding is independent of the CARD domain but involves a phospho-dependent PLK1-binding motif in the CARD14 linker region. Expression of CARD14E138A recruits PLK1 to CARD14-containing signalosomes in interphase keratinocytes. Disruption of the PLK1-binding motif in CARD14E138A increases CARD14-induced proinflammatory signaling and gene expression, indicating PLK1 is a negative regulator of CARD14 signaling.\",\n      \"method\": \"Affinity purification-mass spectrometry, co-immunoprecipitation, confocal imaging, linker region mutagenesis, gene expression analysis in keratinocytes\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — AP-MS validated by co-IP and imaging; domain mapping and functional consequence of disruption shown; single lab\",\n      \"pmids\": [\"38797267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CARD14 expressed in intestinal epithelial cells (IEC) mediates NF-κB signaling. Mice expressing the gain-of-function CARD14E138A mutant specifically in IEC develop mild intestinal inflammation, drastically reduced intestinal motility (often with rectal prolapse), decreased Paneth cell antimicrobial peptide expression, microbial dysbiosis, and increased susceptibility to enteric bacterial infection.\",\n      \"method\": \"IEC-specific transgenic mouse model, histology, intestinal motility assay, transcriptome analysis of IEC, bacterial infection challenge\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific in vivo model with multiple phenotypic readouts; single lab, novel finding\",\n      \"pmids\": [\"41131424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CARD14 is essential for murine experimental psoriasis (imiquimod and IL-23 models): Card14-/- mice show abrogated psoriasiform skin inflammation. Bone marrow chimera studies indicate CARD14 in radio-sensitive hematopoietic cells is required for IMQ-induced disease, controlling Vγ4+ T cells producing IL-17/IL-22 in the dermis/epidermis. CARD14 acts downstream of IL-23, not TLR7/TLR9.\",\n      \"method\": \"Card14 knockout mouse, imiquimod and IL-23 injection psoriasis models, bone marrow chimera, cell-type specific gene signature comparison\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis established by KO and chimera experiments with defined cellular and pathway-level phenotype\",\n      \"pmids\": [\"29150564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CARD14 interacts with MYC and promotes osteoclast (OC) differentiation via a MYC-dependent pathway while simultaneously activating NF-κB and MAPK signaling. Adenoviral CARD14 overexpression in BM-derived macrophages increases OC differentiation/activity; BM-specific Card14 KO mice show reduced OC activity, improved trabecular bone microarchitecture, and increased bone mineral density.\",\n      \"method\": \"Co-immunoprecipitation (CARD14-MYC interaction), adenoviral overexpression, BM-specific conditional KO mouse, TRAP staining, micro-CT, histology, serum bone biomarkers\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein interaction and KO/OE functional data with in vivo phenotype; single lab, novel context\",\n      \"pmids\": [\"40971787\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CARD14 is a CARD/MAGUK scaffold protein expressed predominantly in keratinocytes that forms a CBM (CARD14-BCL10-MALT1) signaling complex to activate NF-κB, MAPK (p38, JNK, ERK), and mTORC1 pathways; gain-of-function mutations in its coiled-coil/linker region disrupt autoinhibition, promote constitutive BCL10-MALT1 recruitment and MALT1 protease activation, drive IL-23/IL-17A-dependent psoriatic skin inflammation in vivo, and are negatively regulated by PLK1, RNF7, A20, ABIN1, and UBAC1, while also mediating IL-17A signaling via the ACT1-TRAF6 complex and TLR3 signaling via a TANK-containing complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CARD14 is a CARD/MAGUK scaffold protein that nucleates a CBM (CARD14–BCL10–MALT1) signalosome in keratinocytes and other epithelial cells to activate NF-κB, MAPK (p38, JNK, ERK), and mTORC1 pathways, thereby controlling inflammatory gene expression, cell proliferation, and tissue homeostasis [PMID:11278692, PMID:27071417, PMID:39145956]. The coiled-coil/linker region maintains autoinhibition; gain-of-function mutations that disrupt this region cause constitutive BCL10–MALT1 recruitment, MALT1 paracaspase activation, and upregulation of psoriasis-associated chemokines (CCL20, IL-8), while loss-of-function mutations dominantly suppress NF-κB and are linked to severe atopic dermatitis [PMID:22521418, PMID:27071417, PMID:30248356]. In vivo, keratinocyte-intrinsic gain-of-function CARD14 signaling through MALT1 drives IL-23/IL-17A–dependent psoriatic inflammation that is ameliorated by MALT1 inhibition, TNF blockade, or IL-23 neutralization, and CARD14 also mediates IL-17A signaling via the ACT1–TRAF6 complex and TLR3 signaling via a TANK-containing complex [PMID:29980436, PMID:32343482, PMID:29689250, PMID:31486084]. Gain-of-function CARD14 mutations cause familial psoriasis and pityriasis rubra pilaris [PMID:22521418, PMID:22703878].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that CARD14 is a CARD/MAGUK scaffold that directly engages BCL10 via CARD–CARD interaction to activate NF-κB answered the fundamental question of how this protein initiates signaling.\",\n      \"evidence\": \"Co-immunoprecipitation and NF-κB reporter assays with domain-mapping in transfected cells\",\n      \"pmids\": [\"11278692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous upstream stimuli unknown\", \"No in vivo validation\", \"Role of other MAGUK domains (PDZ, SH3, GUK) in signaling uncharacterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery of alternative splice isoforms (CARMA2sh and CARMA2cardless) with distinct domain compositions revealed that CARD14 can signal through TRAF2 in addition to BCL10, broadening its signaling repertoire.\",\n      \"evidence\": \"RT-PCR, co-immunoprecipitation, fluorescence microscopy, and apoptosis assays\",\n      \"pmids\": [\"21302310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRAF2-dependent pathway not validated in primary cells\", \"Relative isoform abundance in tissues unknown\", \"Anti-apoptotic mechanism not delineated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of gain-of-function CARD14 mutations (G117S, E138A) as causes of familial psoriasis and pityriasis rubra pilaris established CARD14 as a disease gene and linked NF-κB hyperactivation in keratinocytes to psoriatic pathology.\",\n      \"evidence\": \"Linkage analysis, exome sequencing, NF-κB reporter assays, transcriptome profiling, and immunohistochemistry in patient skin\",\n      \"pmids\": [\"22521418\", \"22521419\", \"22703878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of autoinhibition disruption not yet defined\", \"In vivo animal models not available\", \"Downstream effector cytokine axis unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that psoriasis-associated mutations disrupt linker-mediated autoinhibition, constitutively recruit BCL10 and MALT1, and activate MALT1 paracaspase activity answered how gain-of-function mutations mechanistically drive inflammation and identified MALT1 as a druggable node.\",\n      \"evidence\": \"Co-immunoprecipitation, MALT1 enzymatic activity assays, MAPK phosphorylation, linker mutagenesis, and pharmacological MALT1 inhibition (mepazine) in primary keratinocytes\",\n      \"pmids\": [\"27071417\", \"27113748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of autoinhibition not resolved at atomic level\", \"Relative contribution of MALT1 protease vs. scaffold function unclear\", \"No in vivo validation yet\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Card14 knockout mice revealed that CARD14 is essential for experimental psoriasis and acts downstream of IL-23 in hematopoietic cells controlling dermal γδ T cell IL-17 production, resolving the question of whether CARD14 functions cell-autonomously only in keratinocytes.\",\n      \"evidence\": \"Card14-/- mice, imiquimod and IL-23 injection models, bone marrow chimeras\",\n      \"pmids\": [\"29150564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism in hematopoietic cells not defined\", \"Relationship between keratinocyte-intrinsic and hematopoietic CARD14 functions unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Card14 gain-of-function knock-in mice developed spontaneous IL-23/IL-17A–dependent psoriasis, and CARD14 was shown to mediate IL-17A signaling through association with the ACT1–TRAF6 complex, integrating CARD14 into the IL-17 receptor signaling pathway.\",\n      \"evidence\": \"Card14 knock-in and knockout mice, co-immunoprecipitation of CARD14 with ACT1–TRAF6, NF-κB/MAPK assays, cytokine neutralization (anti-IL-23p19)\",\n      \"pmids\": [\"29980436\", \"29689250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CARD14 is recruited to the IL-17R complex unclear\", \"Whether CARD14 functions in IL-17 signaling in non-skin tissues not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Loss-of-function CARD14 mutations acting as dominant negatives on NF-κB in keratinocytes were linked to severe atopic dermatitis, revealing that CARD14 signaling dosage bidirectionally determines skin inflammatory phenotype.\",\n      \"evidence\": \"Dual luciferase reporter assay, immunohistochemistry in patient skin, exome sequencing\",\n      \"pmids\": [\"30248356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Animal model of loss-of-function alleles not generated\", \"Mechanism of dominant-negative effect not molecularly defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying a CARMA2sh–TANK–MALT1 complex that mediates TLR3-induced NF-κB activation while CARMA2sh simultaneously represses TBK1/IRF3 revealed a dual signaling role downstream of innate immune receptors.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, NF-κB reporter and IRF3 phosphorylation assays in keratinocyte cell line\",\n      \"pmids\": [\"31486084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of TLR3–CARD14 axis not tested\", \"Whether TBK1 repression is direct or indirect unknown\", \"Psoriasis mutant TANK-binding defect not validated in primary cells\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Keratinocyte-specific inducible CARD14E138A expression and conditional MALT1 deletion proved that keratinocyte-intrinsic CARD14–MALT1 signaling is sufficient and necessary for psoriatic inflammation, and that this axis is independent of adaptive immunity but dependent on TNF.\",\n      \"evidence\": \"Tamoxifen-inducible keratinocyte-specific transgenic mice, conditional MALT1 KO, MALT1 protease inhibitor, adaptive immune cell depletion, TNF blockade\",\n      \"pmids\": [\"32597759\", \"32343482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of TNF-producing cell type not established\", \"Whether innate lymphoid cells contribute not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of negative regulators RNF7, UBAC1/KPC, A20, and ABIN1 that modulate CARD14 signaling through ubiquitination of MALT1, NEMO, and TANK defined a regulatory layer controlling CARD14 signalosome output.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assays (K63-linkage), NF-κB reporters\",\n      \"pmids\": [\"29194363\", \"33316896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo confirmation of negative regulator roles lacking\", \"Whether these regulators are relevant in psoriasis patient tissue unknown\", \"Relationship among multiple E3 ligases not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Finding that pathogenic CARD14 mutations increase replication stress–associated DNA double-strand breaks and promote break-induced replication revealed an unexpected role linking CARD14 signaling to genome maintenance and revertant mosaicism.\",\n      \"evidence\": \"γH2AX and comet assays, replication stress assays, sequencing of revertant patient skin patches\",\n      \"pmids\": [\"34004138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting CARD14 NF-κB signaling to replication fork stress not defined\", \"Whether effect is NF-κB-dependent or MALT1-dependent not tested\", \"Generalizability beyond CARD14 mutations unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"AP-MS–based interactome mapping revealed CARD14E138A associates with HOIP, TRAF6, AP2 adaptor complex, and PLK1, establishing that the active signalosome localizes to early endosomes via AP2, activates mTORC1 to drive keratinocyte proliferation, and is negatively regulated by PLK1.\",\n      \"evidence\": \"Affinity purification-mass spectrometry, co-immunoprecipitation, confocal/subcellular fractionation, mTORC1 activity assays, rapamycin treatment in mice, linker mutagenesis\",\n      \"pmids\": [\"39145956\", \"38797267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of endosomal targeting unknown\", \"Whether mTORC1 activation occurs in WT CARD14 signaling not addressed\", \"PLK1 regulatory mechanism (direct phosphorylation of CARD14?) not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Intestinal epithelial CARD14E138A expression caused intestinal inflammation, reduced motility, Paneth cell dysfunction, and infection susceptibility, extending CARD14's physiological role beyond skin.\",\n      \"evidence\": \"IEC-specific transgenic mouse, histology, motility assay, transcriptomics, bacterial infection challenge\",\n      \"pmids\": [\"41131424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether endogenous intestinal CARD14 participates in homeostatic signaling unknown\", \"Upstream stimuli activating CARD14 in IEC not defined\", \"Relevance to human IBD not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological upstream signals that activate wild-type CARD14, the atomic-resolution structure of the autoinhibited and active signalosome, and the full extent of CARD14's roles beyond skin (gut, bone, vasculature) remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ligand or receptor that activates WT CARD14 identified\", \"No crystal or cryo-EM structure of CARD14 or its signalosome\", \"Relative contributions of keratinocyte-intrinsic vs. hematopoietic CARD14 in human psoriasis not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6, 9, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 7, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 6, 7, 9, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 10, 12, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 10, 14]}\n    ],\n    \"complexes\": [\n      \"CBM signalosome (CARD14-BCL10-MALT1)\",\n      \"CARD14-TANK-MALT1 complex\",\n      \"ACT1-TRAF6 complex\"\n    ],\n    \"partners\": [\n      \"BCL10\",\n      \"MALT1\",\n      \"TANK\",\n      \"TRAF6\",\n      \"TRAF2\",\n      \"PLK1\",\n      \"HOIP\",\n      \"ACT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}