{"gene":"CARD14","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2001,"finding":"CARD14 (CARMA2) is a CARD-containing MAGUK family protein whose CARD domain specifically associates with the CARD domain of BCL10, and when expressed in cells, activates NF-κB and induces phosphorylation of BCL10.","method":"Co-immunoprecipitation, cell-based NF-κB reporter assay, transfection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal domain-mapping pulldowns and functional NF-κB reporter assay, foundational paper replicated by subsequent studies","pmids":["11278692"],"is_preprint":false},{"year":2011,"finding":"Alternative splicing of CARD14/CARMA2 produces a short isoform (CARMA2sh) containing CARD, coiled-coil, and PDZ domains, and a cardless isoform (CARMA2cl); CARMA2sh localizes to the cytosol, interacts with TRAF2, and activates NF-κB in a TRAF2-dependent manner, and also protects cells from apoptosis.","method":"RT-PCR/isoform identification, fluorescence microscopy (localization), co-immunoprecipitation (TRAF2 interaction), NF-κB reporter assay, apoptosis assay","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (localization, Co-IP, functional reporter) in single study","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; CARD14 is localized mainly to the basal and suprabasal layers of the epidermis.","method":"Genomic sequencing, NF-κB luciferase reporter assay, gene expression profiling in keratinocytes, immunohistochemistry (localization)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional reporter assay plus transcriptome profiling plus localization, replicated across multiple subsequent studies","pmids":["22521418","22521419"],"is_preprint":false},{"year":2014,"finding":"DEPDC7 (a DEP domain-containing protein) binds to CARMA2 (CARD14) and CARMA3 in the cytosol and is required for NF-κB activation downstream of G protein-coupled receptor stimulation; shRNA-mediated knockdown of DEPDC7 impairs CARMA2/CARMA3-dependent but not CARMA1-dependent NF-κB activation.","method":"Yeast two-hybrid screening, co-immunoprecipitation, shRNA knockdown, NF-κB reporter assay, subcellular localization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus functional knockdown assay, single lab","pmids":["25541973"],"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, and phosphorylated NF-κB is detected in psoriatic CARD14+ endothelial cells.","method":"Two-color immunofluorescence co-localization, transfection with mutant CARD14 constructs, gene expression assays, immunohistochemistry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (chemokine upregulation), single lab, multiple methods","pmids":["25369198"],"is_preprint":false},{"year":2016,"finding":"CARD14 physically interacts with the paracaspase MALT1, and activates NF-κB, p38, and JNK MAP kinase pathways in keratinocytes; all three pathways are dependent on MALT1. Psoriasis-associated CARD14 mutations enhance CARD14-MALT1 interaction and MALT1 proteolytic activity, and MALT1 deficiency or pharmacological inhibition reduces mutant CARD14-induced cytokine/chemokine expression in human primary keratinocytes.","method":"Co-immunoprecipitation (CARD14-MALT1 interaction), MALT1 protease activity assay, MALT1 knockdown/inhibitor experiments, NF-κB and MAPK signaling assays, cytokine expression in primary keratinocytes","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct protein interaction shown by Co-IP, enzymatic activity assay, loss-of-function with specific phenotypic readout, replicated across multiple papers","pmids":["27113748"],"is_preprint":false},{"year":2016,"finding":"Psoriasis mutants CARD14(E138A) and CARD14(G117S) constitutively interact with BCL10 and MALT1; the CARD14 linker region (LR) normally exerts an autoinhibitory effect on NF-κB activation by preventing BCL10 binding, and mutations disrupt this autoinhibition. CARD14(E138A) also stimulates MALT1 paracaspase activity and activates ERK1/2 and p38α MAP kinases.","method":"Co-immunoprecipitation (constitutive BCL10/MALT1 binding), linker region deletion mutagenesis, NF-κB reporter assay, MALT1 paracaspase activity assay, MAPK phosphorylation assay, keratinocyte gene expression","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis, reconstituted interactions, enzymatic activity assay, multiple orthogonal methods in single study","pmids":["27071417"],"is_preprint":false},{"year":2016,"finding":"CARD14-mediated activation of MALT1 protease activity in keratinocytes drives psoriasis-associated inflammatory gene expression; CARD14 forms a CBM (CARD14-BCL10-MALT1) signaling complex whose assembly and MALT1 activation are enhanced by psoriasis-associated mutations.","method":"MALT1 protease assay, co-immunoprecipitation, gene expression analysis, pharmacological inhibition of MALT1","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic assay and Co-IP evidence, review/summary paper but citing experimental data from same group","pmids":["27939769"],"is_preprint":false},{"year":2017,"finding":"The E3 ubiquitin ligase RNF7 interacts with CARMA2 (CARD14) and negatively regulates its NF-κB-activating capacity by modulating ubiquitination of MALT1 and NEMO; psoriasis-associated CARMA2sh mutants escape this negative regulation by RNF7.","method":"Yeast two-hybrid screening (RNF7 as CARMA2 interactor), co-immunoprecipitation, ubiquitination assays, NF-κB reporter assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus ubiquitination assay, single lab","pmids":["29194363"],"is_preprint":false},{"year":2018,"finding":"Card14 gain-of-function (E138A/+, ΔQ136/+) mice develop spontaneous psoriasis-like skin inflammation through constitutive CARMA2 self-aggregation, which leads to enhanced activation of the IL-23–IL-17A cytokine axis; CARMA2 associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-κB and MAPK signaling in keratinocytes. Card14-/- mice show attenuated IMQ-induced skin inflammation due to impaired IL-17A signaling.","method":"Knock-in mouse models (spontaneous disease), Card14 knockout mice (loss-of-function), co-immunoprecipitation (ACT1-TRAF6 complex), NF-κB and MAPK signaling assays, cytokine measurements","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo gain- and loss-of-function models plus biochemical complex identification, multiple orthogonal methods","pmids":["29980436"],"is_preprint":false},{"year":2018,"finding":"Heterozygous Card14ΔE138 gain-of-function mutation in mice is sufficient to drive chronic psoriatic skin disease with IL-23/IL-17 axis-dependent pathogenesis; neutralization of IL-23p19 significantly reduced skin lesions and proinflammatory gene expression.","method":"Knock-in mouse model (Card14ΔE138 heterozygous), IL-23p19 neutralizing antibody treatment, histology, cytokine/chemokine expression analysis","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knock-in mouse model with genetic epistasis (IL-23 neutralization), replicated by another concurrent study","pmids":["29689250"],"is_preprint":false},{"year":2018,"finding":"Loss-of-function mutations in CARD14 (dominant negative effect) result in decreased NF-κB signaling in keratinocytes and are associated with severe atopic dermatitis; CARD14-deficient or mutant-expressing keratinocytes display abnormal secretion of innate immunity mediators.","method":"Dual luciferase reporter assay (NF-κB), immunohistochemistry (p65/CARD14), direct sequencing, keratinocyte functional assays (ELISA)","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NF-κB reporter functional assay plus immunohistochemistry in patient tissue plus keratinocyte assays, single lab","pmids":["30248356"],"is_preprint":false},{"year":2019,"finding":"CARMA2sh (CARD14 short isoform) and TANK form a complex with MALT1 in human keratinocytes; CARMA2sh and TANK are both required for NF-κB activation following TLR3 stimulation with poly(I:C), while CARMA2sh functions as a repressor of the TBK1/IRF3 pathway downstream of TLR3. Psoriasis-associated CARMA2sh mutants bind less efficiently to TANK and are less effective in suppressing the TBK1/IRF3 pathway.","method":"Co-immunoprecipitation (CARMA2sh-TANK-MALT1 complex), siRNA knockdown, NF-κB reporter assay, TBK1/IRF3 pathway assays, poly(I:C) stimulation","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional knockdown, single lab, multiple signaling readouts","pmids":["31486084"],"is_preprint":false},{"year":2020,"finding":"Keratinocyte-specific expression of CARD14E138A in mice rapidly induces psoriatic skin inflammation; keratinocyte-specific MALT1 deletion or pharmacological MALT1 protease inhibition strongly reduces CARD14E138A-induced psoriatic skin disease, demonstrating a keratinocyte-intrinsic causal role of CARD14/MALT1 signaling in psoriasis.","method":"Inducible keratinocyte-specific CARD14E138A transgenic mice, conditional MALT1 knockout in keratinocytes, MALT1 pharmacological inhibitor (oral), histology, gene expression analysis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo keratinocyte-specific genetic models (gain and loss of function) plus pharmacological validation, multiple orthogonal methods","pmids":["32343482"],"is_preprint":false},{"year":2020,"finding":"CARD14E138A-induced skin inflammation and systemic disease are independent of adaptive immune cells, ameliorated by blocking TNF, and induced specifically by CARD14E138A signaling in keratinocytes (demonstrated by knock-in allowing tamoxifen-inducible keratinocyte expression); homozygous CARD14E138A induces systemic disease resembling acute generalized pustular psoriasis exacerbations.","method":"Tamoxifen-inducible knock-in mouse model, anti-TNF treatment, immunodeficient mouse crosses, histology, gene expression","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible keratinocyte-specific knock-in model plus TNF-blocking intervention plus adaptive-immune-deficient crosses, multiple orthogonal approaches","pmids":["32597759"],"is_preprint":false},{"year":2020,"finding":"UBAC1 (non-catalytic subunit of the KPC E3 ubiquitin ligase complex) interacts with CARMA2sh and participates in the CARMA2sh/TANK complex; UBAC1 promotes K63-linked ubiquitination of TANK and negatively regulates the NF-κB-activating capacity of CARMA2sh following TLR3 stimulation in human keratinocytes.","method":"Yeast two-hybrid screening, co-immunoprecipitation, K63-ubiquitination assay, siRNA knockdown, NF-κB reporter assay, poly(I:C) stimulation of keratinocytes","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus ubiquitination assay plus functional knockdown, single lab","pmids":["33316896"],"is_preprint":false},{"year":2021,"finding":"Pathogenic CARD14 mutations increase DNA double-strand breaks under replication stress conditions and suppress new origin firings without promoting crossover events, preferentially driving break-induced replication (BIR); this altered replication stress response underlies recombination-induced revertant mosaicism in CARD14-mutant patients.","method":"DNA damage assays (DSB quantification), replication stress assays, origin firing analysis, crossover analysis, patient tissue analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in patient-derived cells, single lab, novel mechanistic finding","pmids":["34004138"],"is_preprint":false},{"year":2024,"finding":"CARD14E138A associates with HOIP (M1-specific ubiquitin E3 ligase) and TRAF6 (K63-specific ubiquitin E3 ligase), which promote BCL10 ubiquitination and are essential for NF-κB and MAP kinase activation. A20 and ABIN1 negatively regulate signaling by inducing CARD14E138A turnover. CARD14E138A localizes to early endosomes via association with the AP2 adaptor complex; AP2 function is required for CARD14E138A activation of mTORC1 (but not NF-κB or MAP kinase), which stimulates keratinocyte metabolism and proliferation. Rapamycin (mTORC1 inhibitor) ameliorates CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice.","method":"Affinity purification–mass spectrometry (AP-MS), co-immunoprecipitation, ubiquitination assays, subcellular fractionation/early endosome localization, AP2 inhibition, mTORC1 signaling assays, rapamycin treatment in vivo, mouse model","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — AP-MS interactome plus Co-IP plus ubiquitination assay plus localization plus in vivo pharmacological validation, multiple orthogonal methods in single study","pmids":["39145956"],"is_preprint":false},{"year":2024,"finding":"PLK1 (polo-like kinase 1) is a novel CARD14-binding protein; the interaction is mediated by a consensus phospho-dependent PLK1-binding motif in the CARD14 linker region (LR), independent of the CARD domain. CARD14E138A expression 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 negatively regulates CARD14 signaling.","method":"Affinity purification–mass spectrometry (AP-MS), co-immunoprecipitation, CARD domain deletion mutagenesis, linker region motif mutagenesis, subcellular localization (confocal imaging in interphase vs. mitotic cells), proinflammatory gene expression assays","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — AP-MS plus Co-IP plus mutagenesis plus functional gene expression readout, multiple orthogonal methods, single lab","pmids":["38797267"],"is_preprint":false},{"year":2025,"finding":"Gain-of-function CARD14(E138A) expression specifically in intestinal epithelial cells (IEC) induces mild intestinal inflammation, drastic reduction in intestinal motility, decreased Paneth cell antimicrobial peptide expression, microbial dysbiosis, and increased susceptibility to enteric bacterial infection; transcriptome analysis confirms cell-autonomous IEC signaling.","method":"IEC-specific CARD14(E138A) transgenic mouse model, intestinal motility assays, enteric neuron analysis, RNA-seq of IEC, antimicrobial peptide assays, bacterial infection challenge","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo cell-type-specific transgenic model with multiple functional readouts, single study","pmids":["41131424"],"is_preprint":false},{"year":2026,"finding":"CARD14 interacts with MYC and regulates osteoclast differentiation through a MYC-dependent pathway while simultaneously activating NF-κB and MAPK signaling; adenoviral CARD14 overexpression in bone marrow-derived macrophages markedly increases osteoclast differentiation and activity, and bone marrow-specific Card14 knockout mice show reduced osteoclast activity, improved trabecular bone microarchitecture, and increased BMD.","method":"Co-immunoprecipitation (CARD14-MYC interaction), adenoviral CARD14 overexpression in bone marrow macrophages, BM-specific Card14 knockout mice, micro-CT, TRAP staining, resorption pit assay, serum bone metabolism markers","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro overexpression plus conditional KO in vivo, single lab, novel context","pmids":["40971787"],"is_preprint":false}],"current_model":"CARD14 (CARMA2) is a CARD-MAGUK scaffold protein predominantly expressed in keratinocytes that, upon activation or gain-of-function mutation, forms a CBM (CARD14–BCL10–MALT1) signaling complex whose assembly is normally autoinhibited by the linker region; pathogenic mutations disrupt this autoinhibition, leading to constitutive BCL10/MALT1 recruitment, MALT1 protease activation, BCL10 ubiquitination (via HOIP/TRAF6), and downstream NF-κB and MAPK (p38, JNK, ERK) pathway activation that drives proinflammatory gene expression—and additionally activates mTORC1 from early endosomes to stimulate keratinocyte proliferation—while multiple negative regulators (RNF7/ubiquitination of MALT1/NEMO, A20/ABIN1-mediated turnover, PLK1 via the linker region, UBAC1/TANK complex) fine-tune signaling, and CARD14 also mediates IL-17A signaling in keratinocytes by associating with the ACT1–TRAF6 complex, collectively driving the IL-23–IL-17A inflammatory axis that underlies psoriasis pathogenesis."},"narrative":{"mechanistic_narrative":"CARD14 (CARMA2) is a CARD-MAGUK scaffold protein, predominantly expressed in the basal and suprabasal epidermis, that nucleates inflammatory signaling in keratinocytes by assembling a CARD14–BCL10–MALT1 (CBM) complex [PMID:11278692, PMID:22521418, PMID:22521419, PMID:27939769]. Its CARD domain engages BCL10, recruiting and activating the paracaspase MALT1 to drive NF-κB and p38/JNK/ERK MAPK signaling and proinflammatory cytokine/chemokine expression [PMID:11278692, PMID:27113748, PMID:27071417]. Complex assembly is normally restrained by the linker region, which autoinhibits BCL10 binding; psoriasis-associated gain-of-function mutations (e.g., G117S, E138A) disrupt this autoinhibition, producing constitutive BCL10/MALT1 recruitment, enhanced MALT1 protease activity, and elevated expression of psoriasis genes such as CCL20 and IL8 [PMID:22521418, PMID:22521419, PMID:27113748, PMID:27071417]. Active CARD14 signalosomes recruit the ubiquitin ligases HOIP and TRAF6 to ubiquitinate BCL10—an event essential for NF-κB and MAPK activation—while CARD14 additionally localizes to early endosomes via the AP2 adaptor complex to activate mTORC1 and stimulate keratinocyte metabolism and proliferation [PMID:39145956]. Multiple negative regulators tune this output, including RNF7 (ubiquitination of MALT1/NEMO), A20/ABIN1 (CARD14 turnover), UBAC1/TANK, and PLK1 binding the linker region [PMID:29194363, PMID:33316896, PMID:39145956, PMID:38797267]. In vivo, keratinocyte-intrinsic CARD14 gain-of-function drives IL-23–IL-17A axis-dependent psoriatic skin disease that is reversed by MALT1, TNF, or IL-23 blockade [PMID:29980436, PMID:29689250, PMID:32343482, PMID:32597759], and CARD14 mediates IL-17A signaling itself by associating with the ACT1–TRAF6 complex [PMID:29980436]. Dominant-negative loss-of-function CARD14 mutations reduce keratinocyte NF-κB signaling and are associated with severe atopic dermatitis [PMID:30248356]. Beyond skin, CARD14 gain-of-function disrupts intestinal epithelial homeostasis [PMID:41131424] and promotes osteoclast differentiation through a MYC-dependent pathway [PMID:40971787].","teleology":[{"year":2001,"claim":"Established CARD14's founding molecular activity—how it could trigger inflammatory signaling—by showing its CARD domain binds BCL10 and activates NF-κB.","evidence":"Reciprocal domain-mapping Co-IP and NF-κB reporter assays in transfected cells","pmids":["11278692"],"confidence":"High","gaps":["Did not identify downstream effectors beyond BCL10","No endogenous/physiological trigger defined","No disease link yet"]},{"year":2011,"claim":"Resolved isoform-specific function by showing a short CARMA2 isoform localizes to cytosol, binds TRAF2, activates NF-κB and is anti-apoptotic, indicating splicing diversifies CARD14 signaling.","evidence":"Isoform RT-PCR, fluorescence localization, Co-IP, NF-κB reporter and apoptosis assays","pmids":["21302310"],"confidence":"High","gaps":["Physiological role of cardless isoform unclear","TRAF2 dependence not tied to keratinocyte biology"]},{"year":2012,"claim":"Connected CARD14 to human disease by demonstrating gain-of-function mutations enhance NF-κB and induce psoriasis-associated genes in keratinocytes where CARD14 is expressed.","evidence":"Genomic sequencing, NF-κB reporter, keratinocyte expression profiling, immunohistochemistry","pmids":["22521418","22521419"],"confidence":"High","gaps":["Did not define the effector complex downstream of mutant CARD14","Mechanism of mutational hyperactivation unresolved"]},{"year":2014,"claim":"Expanded the interactome and cellular context by identifying DEPDC7 as a required cofactor for CARMA2-dependent NF-κB and showing CARD14 acts in dermal endothelial cells as well as keratinocytes.","evidence":"Yeast two-hybrid, Co-IP, shRNA knockdown; immunofluorescence co-localization and mutant transfection in endothelial cells","pmids":["25541973","25369198"],"confidence":"Medium","gaps":["DEPDC7 mechanism single-lab","Endothelial contribution to psoriasis in vivo untested"]},{"year":2016,"claim":"Defined the core effector mechanism and its autoinhibition: CARD14 recruits MALT1 via BCL10 to drive NF-κB/MAPK, the linker region autoinhibits assembly, and psoriasis mutations relieve this to boost MALT1 protease activity.","evidence":"Co-IP, MALT1 protease assays, linker-region deletion mutagenesis, MAPK and reporter assays in primary keratinocytes","pmids":["27113748","27071417","27939769"],"confidence":"High","gaps":["Structural basis of linker autoinhibition not solved","MALT1 substrates in keratinocytes not enumerated"]},{"year":2017,"claim":"Identified a negative regulator, showing RNF7 dampens CARMA2 NF-κB output via MALT1/NEMO ubiquitination and that mutants escape this control.","evidence":"Yeast two-hybrid, Co-IP, ubiquitination assays, NF-κB reporter","pmids":["29194363"],"confidence":"Medium","gaps":["Single-lab interaction","In vivo relevance of RNF7 regulation untested"]},{"year":2018,"claim":"Provided definitive in vivo causation, linking CARD14 self-aggregation to IL-23/IL-17A-axis-driven psoriasis and to IL-17A signaling via the ACT1-TRAF6 complex, with concurrent demonstration of IL-23 dependence.","evidence":"Card14 gain-of-function knock-in and knockout mice, IL-23p19 neutralization, Co-IP of ACT1-TRAF6, cytokine measurements","pmids":["29980436","29689250"],"confidence":"High","gaps":["Cell type initiating disease not yet isolated","Mechanism coupling aggregation to ACT1-TRAF6 unclear"]},{"year":2018,"claim":"Showed the bidirectional disease spectrum—dominant-negative CARD14 mutations reduce keratinocyte NF-κB and cause severe atopic dermatitis—establishing signaling dosage as the determinant.","evidence":"NF-κB reporter, immunohistochemistry of patient tissue, keratinocyte ELISA, sequencing","pmids":["30248356"],"confidence":"Medium","gaps":["No animal model of loss-of-function allele","Innate mediator dysregulation mechanism incomplete"]},{"year":2019,"claim":"Linked CARD14 to TLR3 antiviral signaling by showing CARMA2sh/TANK/MALT1 complexes are required for poly(I:C)-induced NF-κB while repressing the TBK1/IRF3 arm.","evidence":"Co-IP, siRNA knockdown, NF-κB and TBK1/IRF3 pathway assays in keratinocytes","pmids":["31486084"],"confidence":"Medium","gaps":["Physiological role of IRF3 repression untested","Single-lab"]},{"year":2020,"claim":"Pinpointed keratinocyte-intrinsic CARD14/MALT1 signaling as causal and druggable, showing MALT1 deletion/inhibition, TNF blockade, and adaptive-immune-independence all shape disease.","evidence":"Keratinocyte-specific and inducible CARD14E138A mice, conditional MALT1 KO, MALT1 inhibitor, anti-TNF, immunodeficient crosses, histology","pmids":["32343482","32597759"],"confidence":"High","gaps":["Innate effector circuit downstream of keratinocytes not fully mapped","Systemic pustular phenotype mechanism partial"]},{"year":2020,"claim":"Added a further negative regulator, UBAC1, which K63-ubiquitinates TANK within the CARMA2sh/TANK complex to restrain TLR3-induced NF-κB.","evidence":"Yeast two-hybrid, Co-IP, K63-ubiquitination assay, siRNA, reporter in keratinocytes","pmids":["33316896"],"confidence":"Medium","gaps":["Single-lab","In vivo significance untested"]},{"year":2021,"claim":"Revealed an unexpected genome-stability consequence: pathogenic CARD14 mutations increase DSBs under replication stress and favor break-induced replication, explaining revertant mosaicism.","evidence":"DSB quantification, replication stress and origin-firing assays, patient tissue analysis","pmids":["34004138"],"confidence":"Medium","gaps":["Mechanistic link between CARD14 signaling and replication stress unclear","Single-lab"]},{"year":2024,"claim":"Defined the ubiquitin-driven activation circuit and a proliferative arm: HOIP/TRAF6 ubiquitinate BCL10 for NF-κB/MAPK, A20/ABIN1 drive CARD14 turnover, and AP2-mediated endosomal localization activates mTORC1 to promote keratinocyte proliferation.","evidence":"AP-MS, Co-IP, ubiquitination assays, endosome fractionation, AP2 inhibition, mTORC1 assays, in vivo rapamycin","pmids":["39145956"],"confidence":"High","gaps":["How AP2 selectively routes mTORC1 but not NF-κB activation unresolved","Structural basis of endosomal signalosome unknown"]},{"year":2024,"claim":"Identified PLK1 as a phospho-dependent linker-region binder that negatively regulates CARD14 inflammatory signaling, coupling the scaffold to cell-cycle kinase control.","evidence":"AP-MS, Co-IP, linker-motif and CARD-domain mutagenesis, confocal localization, proinflammatory gene expression","pmids":["38797267"],"confidence":"High","gaps":["Whether PLK1 phosphorylates CARD14 directly unestablished","Physiological/in vivo role of PLK1 regulation untested"]},{"year":2025,"claim":"Extended CARD14 function beyond skin by showing intestinal epithelial gain-of-function causes inflammation, reduced motility, Paneth cell/antimicrobial defects, and dysbiosis.","evidence":"IEC-specific CARD14E138A transgenic mice, motility and antimicrobial assays, IEC RNA-seq, bacterial challenge","pmids":["41131424"],"confidence":"Medium","gaps":["Effector pathway in IECs not dissected","Single study"]},{"year":2026,"claim":"Implicated CARD14 in bone biology by showing it interacts with MYC and promotes osteoclast differentiation alongside NF-κB/MAPK activation.","evidence":"Co-IP, adenoviral overexpression in BM macrophages, BM-specific Card14 KO mice, micro-CT, TRAP and resorption assays","pmids":["40971787"],"confidence":"Medium","gaps":["Mechanism coupling CARD14 to MYC in osteoclasts unclear","Single lab, novel context"]},{"year":null,"claim":"How distinct CARD14 outputs (NF-κB/MAPK inflammation, endosomal mTORC1 proliferation, replication-stress, MYC-dependent osteoclastogenesis) are selectively wired from a single scaffold, and the structural basis of linker autoinhibition, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of autoinhibited vs. active CARD14 signalosome","Determinants of output selectivity (NF-κB vs mTORC1 vs MYC) unknown","Cross-tissue regulatory differences uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,6,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,17,18]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,10,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,11,16]}],"complexes":["CBM complex (CARD14-BCL10-MALT1)","CARMA2sh-TANK-MALT1 complex","ACT1-TRAF6 complex"],"partners":["BCL10","MALT1","TRAF2","DEPDC7","TANK","HOIP","TRAF6","PLK1"],"other_free_text":[]}},"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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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42180729","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34621,"output_tokens":5885,"usd":0.096069,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14528,"output_tokens":5224,"usd":0.10162,"stage2_stop_reason":"end_turn"},"total_usd":0.197689,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"CARD14 (CARMA2) is a CARD-containing MAGUK family protein whose CARD domain specifically associates with the CARD domain of BCL10, and when expressed in cells, activates NF-κB and induces phosphorylation of BCL10.\",\n      \"method\": \"Co-immunoprecipitation, cell-based NF-κB reporter assay, transfection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal domain-mapping pulldowns and functional NF-κB reporter assay, foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"11278692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Alternative splicing of CARD14/CARMA2 produces a short isoform (CARMA2sh) containing CARD, coiled-coil, and PDZ domains, and a cardless isoform (CARMA2cl); CARMA2sh localizes to the cytosol, interacts with TRAF2, and activates NF-κB in a TRAF2-dependent manner, and also protects cells from apoptosis.\",\n      \"method\": \"RT-PCR/isoform identification, fluorescence microscopy (localization), co-immunoprecipitation (TRAF2 interaction), NF-κB reporter assay, apoptosis assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (localization, Co-IP, functional reporter) in single study\",\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; CARD14 is localized mainly to the basal and suprabasal layers of the epidermis.\",\n      \"method\": \"Genomic sequencing, NF-κB luciferase reporter assay, gene expression profiling in keratinocytes, immunohistochemistry (localization)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional reporter assay plus transcriptome profiling plus localization, replicated across multiple subsequent studies\",\n      \"pmids\": [\"22521418\", \"22521419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DEPDC7 (a DEP domain-containing protein) binds to CARMA2 (CARD14) and CARMA3 in the cytosol and is required for NF-κB activation downstream of G protein-coupled receptor stimulation; shRNA-mediated knockdown of DEPDC7 impairs CARMA2/CARMA3-dependent but not CARMA1-dependent NF-κB activation.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, shRNA knockdown, NF-κB reporter assay, subcellular localization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus functional knockdown assay, single lab\",\n      \"pmids\": [\"25541973\"],\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, and phosphorylated NF-κB is detected in psoriatic CARD14+ endothelial cells.\",\n      \"method\": \"Two-color immunofluorescence co-localization, transfection with mutant CARD14 constructs, gene expression assays, immunohistochemistry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (chemokine upregulation), single lab, multiple methods\",\n      \"pmids\": [\"25369198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CARD14 physically interacts with the paracaspase MALT1, and activates NF-κB, p38, and JNK MAP kinase pathways in keratinocytes; all three pathways are dependent on MALT1. Psoriasis-associated CARD14 mutations enhance CARD14-MALT1 interaction and MALT1 proteolytic activity, and MALT1 deficiency or pharmacological inhibition reduces mutant CARD14-induced cytokine/chemokine expression in human primary keratinocytes.\",\n      \"method\": \"Co-immunoprecipitation (CARD14-MALT1 interaction), MALT1 protease activity assay, MALT1 knockdown/inhibitor experiments, NF-κB and MAPK signaling assays, cytokine expression in primary keratinocytes\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct protein interaction shown by Co-IP, enzymatic activity assay, loss-of-function with specific phenotypic readout, replicated across multiple papers\",\n      \"pmids\": [\"27113748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Psoriasis mutants CARD14(E138A) and CARD14(G117S) constitutively interact with BCL10 and MALT1; the CARD14 linker region (LR) normally exerts an autoinhibitory effect on NF-κB activation by preventing BCL10 binding, and mutations disrupt this autoinhibition. CARD14(E138A) also stimulates MALT1 paracaspase activity and activates ERK1/2 and p38α MAP kinases.\",\n      \"method\": \"Co-immunoprecipitation (constitutive BCL10/MALT1 binding), linker region deletion mutagenesis, NF-κB reporter assay, MALT1 paracaspase activity assay, MAPK phosphorylation assay, keratinocyte gene expression\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis, reconstituted interactions, enzymatic activity assay, multiple orthogonal methods in single study\",\n      \"pmids\": [\"27071417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CARD14-mediated activation of MALT1 protease activity in keratinocytes drives psoriasis-associated inflammatory gene expression; CARD14 forms a CBM (CARD14-BCL10-MALT1) signaling complex whose assembly and MALT1 activation are enhanced by psoriasis-associated mutations.\",\n      \"method\": \"MALT1 protease assay, co-immunoprecipitation, gene expression analysis, pharmacological inhibition of MALT1\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic assay and Co-IP evidence, review/summary paper but citing experimental data from same group\",\n      \"pmids\": [\"27939769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The E3 ubiquitin ligase RNF7 interacts with CARMA2 (CARD14) and negatively regulates its NF-κB-activating capacity by modulating ubiquitination of MALT1 and NEMO; psoriasis-associated CARMA2sh mutants escape this negative regulation by RNF7.\",\n      \"method\": \"Yeast two-hybrid screening (RNF7 as CARMA2 interactor), co-immunoprecipitation, ubiquitination assays, NF-κB reporter assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus ubiquitination assay, single lab\",\n      \"pmids\": [\"29194363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Card14 gain-of-function (E138A/+, ΔQ136/+) mice develop spontaneous psoriasis-like skin inflammation through constitutive CARMA2 self-aggregation, which leads to enhanced activation of the IL-23–IL-17A cytokine axis; CARMA2 associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-κB and MAPK signaling in keratinocytes. Card14-/- mice show attenuated IMQ-induced skin inflammation due to impaired IL-17A signaling.\",\n      \"method\": \"Knock-in mouse models (spontaneous disease), Card14 knockout mice (loss-of-function), co-immunoprecipitation (ACT1-TRAF6 complex), NF-κB and MAPK signaling assays, cytokine measurements\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo gain- and loss-of-function models plus biochemical complex identification, multiple orthogonal methods\",\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 drive chronic psoriatic skin disease with IL-23/IL-17 axis-dependent pathogenesis; neutralization of IL-23p19 significantly reduced skin lesions and proinflammatory gene expression.\",\n      \"method\": \"Knock-in mouse model (Card14ΔE138 heterozygous), IL-23p19 neutralizing antibody treatment, histology, cytokine/chemokine expression analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knock-in mouse model with genetic epistasis (IL-23 neutralization), replicated by another concurrent study\",\n      \"pmids\": [\"29689250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss-of-function mutations in CARD14 (dominant negative effect) result in decreased NF-κB signaling in keratinocytes and are associated with severe atopic dermatitis; CARD14-deficient or mutant-expressing keratinocytes display abnormal secretion of innate immunity mediators.\",\n      \"method\": \"Dual luciferase reporter assay (NF-κB), immunohistochemistry (p65/CARD14), direct sequencing, keratinocyte functional assays (ELISA)\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NF-κB reporter functional assay plus immunohistochemistry in patient tissue plus keratinocyte assays, single lab\",\n      \"pmids\": [\"30248356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CARMA2sh (CARD14 short isoform) and TANK form a complex with MALT1 in human keratinocytes; CARMA2sh and TANK are both required for NF-κB activation following TLR3 stimulation with poly(I:C), while CARMA2sh functions as a repressor of the TBK1/IRF3 pathway downstream of TLR3. Psoriasis-associated CARMA2sh mutants bind less efficiently to TANK and are less effective in suppressing the TBK1/IRF3 pathway.\",\n      \"method\": \"Co-immunoprecipitation (CARMA2sh-TANK-MALT1 complex), siRNA knockdown, NF-κB reporter assay, TBK1/IRF3 pathway assays, poly(I:C) stimulation\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional knockdown, single lab, multiple signaling readouts\",\n      \"pmids\": [\"31486084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Keratinocyte-specific expression of CARD14E138A in mice rapidly induces psoriatic skin inflammation; keratinocyte-specific MALT1 deletion or pharmacological MALT1 protease inhibition strongly reduces CARD14E138A-induced psoriatic skin disease, demonstrating a keratinocyte-intrinsic causal role of CARD14/MALT1 signaling in psoriasis.\",\n      \"method\": \"Inducible keratinocyte-specific CARD14E138A transgenic mice, conditional MALT1 knockout in keratinocytes, MALT1 pharmacological inhibitor (oral), histology, gene expression analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo keratinocyte-specific genetic models (gain and loss of function) plus pharmacological validation, multiple orthogonal methods\",\n      \"pmids\": [\"32343482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CARD14E138A-induced skin inflammation and systemic disease are independent of adaptive immune cells, ameliorated by blocking TNF, and induced specifically by CARD14E138A signaling in keratinocytes (demonstrated by knock-in allowing tamoxifen-inducible keratinocyte expression); homozygous CARD14E138A induces systemic disease resembling acute generalized pustular psoriasis exacerbations.\",\n      \"method\": \"Tamoxifen-inducible knock-in mouse model, anti-TNF treatment, immunodeficient mouse crosses, histology, gene expression\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible keratinocyte-specific knock-in model plus TNF-blocking intervention plus adaptive-immune-deficient crosses, multiple orthogonal approaches\",\n      \"pmids\": [\"32597759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBAC1 (non-catalytic subunit of the KPC E3 ubiquitin ligase complex) interacts with CARMA2sh and participates in the CARMA2sh/TANK complex; UBAC1 promotes K63-linked ubiquitination of TANK and negatively regulates the NF-κB-activating capacity of CARMA2sh following TLR3 stimulation in human keratinocytes.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, K63-ubiquitination assay, siRNA knockdown, NF-κB reporter assay, poly(I:C) stimulation of keratinocytes\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus ubiquitination assay plus functional knockdown, 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 replication stress conditions and suppress new origin firings without promoting crossover events, preferentially driving break-induced replication (BIR); this altered replication stress response underlies recombination-induced revertant mosaicism in CARD14-mutant patients.\",\n      \"method\": \"DNA damage assays (DSB quantification), replication stress assays, origin firing analysis, crossover analysis, patient tissue analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in patient-derived cells, single lab, novel mechanistic finding\",\n      \"pmids\": [\"34004138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CARD14E138A associates with HOIP (M1-specific ubiquitin E3 ligase) and TRAF6 (K63-specific ubiquitin E3 ligase), which promote BCL10 ubiquitination and are essential for NF-κB and MAP kinase activation. A20 and ABIN1 negatively regulate signaling by inducing CARD14E138A turnover. CARD14E138A localizes to early endosomes via association with the AP2 adaptor complex; AP2 function is required for CARD14E138A activation of mTORC1 (but not NF-κB or MAP kinase), which stimulates keratinocyte metabolism and proliferation. Rapamycin (mTORC1 inhibitor) ameliorates CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice.\",\n      \"method\": \"Affinity purification–mass spectrometry (AP-MS), co-immunoprecipitation, ubiquitination assays, subcellular fractionation/early endosome localization, AP2 inhibition, mTORC1 signaling assays, rapamycin treatment in vivo, mouse model\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — AP-MS interactome plus Co-IP plus ubiquitination assay plus localization plus in vivo pharmacological validation, multiple orthogonal methods in single study\",\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; the interaction is mediated by a consensus phospho-dependent PLK1-binding motif in the CARD14 linker region (LR), independent of the CARD domain. CARD14E138A expression 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 negatively regulates CARD14 signaling.\",\n      \"method\": \"Affinity purification–mass spectrometry (AP-MS), co-immunoprecipitation, CARD domain deletion mutagenesis, linker region motif mutagenesis, subcellular localization (confocal imaging in interphase vs. mitotic cells), proinflammatory gene expression assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — AP-MS plus Co-IP plus mutagenesis plus functional gene expression readout, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38797267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Gain-of-function CARD14(E138A) expression specifically in intestinal epithelial cells (IEC) induces mild intestinal inflammation, drastic reduction in intestinal motility, decreased Paneth cell antimicrobial peptide expression, microbial dysbiosis, and increased susceptibility to enteric bacterial infection; transcriptome analysis confirms cell-autonomous IEC signaling.\",\n      \"method\": \"IEC-specific CARD14(E138A) transgenic mouse model, intestinal motility assays, enteric neuron analysis, RNA-seq of IEC, antimicrobial peptide assays, bacterial infection challenge\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo cell-type-specific transgenic model with multiple functional readouts, single study\",\n      \"pmids\": [\"41131424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CARD14 interacts with MYC and regulates osteoclast differentiation through a MYC-dependent pathway while simultaneously activating NF-κB and MAPK signaling; adenoviral CARD14 overexpression in bone marrow-derived macrophages markedly increases osteoclast differentiation and activity, and bone marrow-specific Card14 knockout mice show reduced osteoclast activity, improved trabecular bone microarchitecture, and increased BMD.\",\n      \"method\": \"Co-immunoprecipitation (CARD14-MYC interaction), adenoviral CARD14 overexpression in bone marrow macrophages, BM-specific Card14 knockout mice, micro-CT, TRAP staining, resorption pit assay, serum bone metabolism markers\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro overexpression plus conditional KO in vivo, single lab, novel context\",\n      \"pmids\": [\"40971787\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CARD14 (CARMA2) is a CARD-MAGUK scaffold protein predominantly expressed in keratinocytes that, upon activation or gain-of-function mutation, forms a CBM (CARD14–BCL10–MALT1) signaling complex whose assembly is normally autoinhibited by the linker region; pathogenic mutations disrupt this autoinhibition, leading to constitutive BCL10/MALT1 recruitment, MALT1 protease activation, BCL10 ubiquitination (via HOIP/TRAF6), and downstream NF-κB and MAPK (p38, JNK, ERK) pathway activation that drives proinflammatory gene expression—and additionally activates mTORC1 from early endosomes to stimulate keratinocyte proliferation—while multiple negative regulators (RNF7/ubiquitination of MALT1/NEMO, A20/ABIN1-mediated turnover, PLK1 via the linker region, UBAC1/TANK complex) fine-tune signaling, and CARD14 also mediates IL-17A signaling in keratinocytes by associating with the ACT1–TRAF6 complex, collectively driving the IL-23–IL-17A inflammatory axis that underlies psoriasis pathogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CARD14 (CARMA2) is a CARD-MAGUK scaffold protein, predominantly expressed in the basal and suprabasal epidermis, that nucleates inflammatory signaling in keratinocytes by assembling a CARD14–BCL10–MALT1 (CBM) complex [#0, #2, #7]. Its CARD domain engages BCL10, recruiting and activating the paracaspase MALT1 to drive NF-κB and p38/JNK/ERK MAPK signaling and proinflammatory cytokine/chemokine expression [#0, #5, #6]. Complex assembly is normally restrained by the linker region, which autoinhibits BCL10 binding; psoriasis-associated gain-of-function mutations (e.g., G117S, E138A) disrupt this autoinhibition, producing constitutive BCL10/MALT1 recruitment, enhanced MALT1 protease activity, and elevated expression of psoriasis genes such as CCL20 and IL8 [#2, #5, #6]. Active CARD14 signalosomes recruit the ubiquitin ligases HOIP and TRAF6 to ubiquitinate BCL10—an event essential for NF-κB and MAPK activation—while CARD14 additionally localizes to early endosomes via the AP2 adaptor complex to activate mTORC1 and stimulate keratinocyte metabolism and proliferation [#17]. Multiple negative regulators tune this output, including RNF7 (ubiquitination of MALT1/NEMO), A20/ABIN1 (CARD14 turnover), UBAC1/TANK, and PLK1 binding the linker region [#8, #15, #17, #18]. In vivo, keratinocyte-intrinsic CARD14 gain-of-function drives IL-23–IL-17A axis-dependent psoriatic skin disease that is reversed by MALT1, TNF, or IL-23 blockade [#9, #10, #13, #14], and CARD14 mediates IL-17A signaling itself by associating with the ACT1–TRAF6 complex [#9]. Dominant-negative loss-of-function CARD14 mutations reduce keratinocyte NF-κB signaling and are associated with severe atopic dermatitis [#11]. Beyond skin, CARD14 gain-of-function disrupts intestinal epithelial homeostasis [#19] and promotes osteoclast differentiation through a MYC-dependent pathway [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established CARD14's founding molecular activity—how it could trigger inflammatory signaling—by showing its CARD domain binds BCL10 and activates NF-κB.\",\n      \"evidence\": \"Reciprocal domain-mapping Co-IP and NF-κB reporter assays in transfected cells\",\n      \"pmids\": [\"11278692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify downstream effectors beyond BCL10\", \"No endogenous/physiological trigger defined\", \"No disease link yet\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved isoform-specific function by showing a short CARMA2 isoform localizes to cytosol, binds TRAF2, activates NF-κB and is anti-apoptotic, indicating splicing diversifies CARD14 signaling.\",\n      \"evidence\": \"Isoform RT-PCR, fluorescence localization, Co-IP, NF-κB reporter and apoptosis assays\",\n      \"pmids\": [\"21302310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of cardless isoform unclear\", \"TRAF2 dependence not tied to keratinocyte biology\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected CARD14 to human disease by demonstrating gain-of-function mutations enhance NF-κB and induce psoriasis-associated genes in keratinocytes where CARD14 is expressed.\",\n      \"evidence\": \"Genomic sequencing, NF-κB reporter, keratinocyte expression profiling, immunohistochemistry\",\n      \"pmids\": [\"22521418\", \"22521419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the effector complex downstream of mutant CARD14\", \"Mechanism of mutational hyperactivation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expanded the interactome and cellular context by identifying DEPDC7 as a required cofactor for CARMA2-dependent NF-κB and showing CARD14 acts in dermal endothelial cells as well as keratinocytes.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, shRNA knockdown; immunofluorescence co-localization and mutant transfection in endothelial cells\",\n      \"pmids\": [\"25541973\", \"25369198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DEPDC7 mechanism single-lab\", \"Endothelial contribution to psoriasis in vivo untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the core effector mechanism and its autoinhibition: CARD14 recruits MALT1 via BCL10 to drive NF-κB/MAPK, the linker region autoinhibits assembly, and psoriasis mutations relieve this to boost MALT1 protease activity.\",\n      \"evidence\": \"Co-IP, MALT1 protease assays, linker-region deletion mutagenesis, MAPK and reporter assays in primary keratinocytes\",\n      \"pmids\": [\"27113748\", \"27071417\", \"27939769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of linker autoinhibition not solved\", \"MALT1 substrates in keratinocytes not enumerated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a negative regulator, showing RNF7 dampens CARMA2 NF-κB output via MALT1/NEMO ubiquitination and that mutants escape this control.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, ubiquitination assays, NF-κB reporter\",\n      \"pmids\": [\"29194363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction\", \"In vivo relevance of RNF7 regulation untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided definitive in vivo causation, linking CARD14 self-aggregation to IL-23/IL-17A-axis-driven psoriasis and to IL-17A signaling via the ACT1-TRAF6 complex, with concurrent demonstration of IL-23 dependence.\",\n      \"evidence\": \"Card14 gain-of-function knock-in and knockout mice, IL-23p19 neutralization, Co-IP of ACT1-TRAF6, cytokine measurements\",\n      \"pmids\": [\"29980436\", \"29689250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell type initiating disease not yet isolated\", \"Mechanism coupling aggregation to ACT1-TRAF6 unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed the bidirectional disease spectrum—dominant-negative CARD14 mutations reduce keratinocyte NF-κB and cause severe atopic dermatitis—establishing signaling dosage as the determinant.\",\n      \"evidence\": \"NF-κB reporter, immunohistochemistry of patient tissue, keratinocyte ELISA, sequencing\",\n      \"pmids\": [\"30248356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No animal model of loss-of-function allele\", \"Innate mediator dysregulation mechanism incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked CARD14 to TLR3 antiviral signaling by showing CARMA2sh/TANK/MALT1 complexes are required for poly(I:C)-induced NF-κB while repressing the TBK1/IRF3 arm.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, NF-κB and TBK1/IRF3 pathway assays in keratinocytes\",\n      \"pmids\": [\"31486084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of IRF3 repression untested\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Pinpointed keratinocyte-intrinsic CARD14/MALT1 signaling as causal and druggable, showing MALT1 deletion/inhibition, TNF blockade, and adaptive-immune-independence all shape disease.\",\n      \"evidence\": \"Keratinocyte-specific and inducible CARD14E138A mice, conditional MALT1 KO, MALT1 inhibitor, anti-TNF, immunodeficient crosses, histology\",\n      \"pmids\": [\"32343482\", \"32597759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Innate effector circuit downstream of keratinocytes not fully mapped\", \"Systemic pustular phenotype mechanism partial\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Added a further negative regulator, UBAC1, which K63-ubiquitinates TANK within the CARMA2sh/TANK complex to restrain TLR3-induced NF-κB.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, K63-ubiquitination assay, siRNA, reporter in keratinocytes\",\n      \"pmids\": [\"33316896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab\", \"In vivo significance untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed an unexpected genome-stability consequence: pathogenic CARD14 mutations increase DSBs under replication stress and favor break-induced replication, explaining revertant mosaicism.\",\n      \"evidence\": \"DSB quantification, replication stress and origin-firing assays, patient tissue analysis\",\n      \"pmids\": [\"34004138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between CARD14 signaling and replication stress unclear\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the ubiquitin-driven activation circuit and a proliferative arm: HOIP/TRAF6 ubiquitinate BCL10 for NF-κB/MAPK, A20/ABIN1 drive CARD14 turnover, and AP2-mediated endosomal localization activates mTORC1 to promote keratinocyte proliferation.\",\n      \"evidence\": \"AP-MS, Co-IP, ubiquitination assays, endosome fractionation, AP2 inhibition, mTORC1 assays, in vivo rapamycin\",\n      \"pmids\": [\"39145956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How AP2 selectively routes mTORC1 but not NF-κB activation unresolved\", \"Structural basis of endosomal signalosome unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified PLK1 as a phospho-dependent linker-region binder that negatively regulates CARD14 inflammatory signaling, coupling the scaffold to cell-cycle kinase control.\",\n      \"evidence\": \"AP-MS, Co-IP, linker-motif and CARD-domain mutagenesis, confocal localization, proinflammatory gene expression\",\n      \"pmids\": [\"38797267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PLK1 phosphorylates CARD14 directly unestablished\", \"Physiological/in vivo role of PLK1 regulation untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended CARD14 function beyond skin by showing intestinal epithelial gain-of-function causes inflammation, reduced motility, Paneth cell/antimicrobial defects, and dysbiosis.\",\n      \"evidence\": \"IEC-specific CARD14E138A transgenic mice, motility and antimicrobial assays, IEC RNA-seq, bacterial challenge\",\n      \"pmids\": [\"41131424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effector pathway in IECs not dissected\", \"Single study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated CARD14 in bone biology by showing it interacts with MYC and promotes osteoclast differentiation alongside NF-κB/MAPK activation.\",\n      \"evidence\": \"Co-IP, adenoviral overexpression in BM macrophages, BM-specific Card14 KO mice, micro-CT, TRAP and resorption assays\",\n      \"pmids\": [\"40971787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling CARD14 to MYC in osteoclasts unclear\", \"Single lab, novel context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct CARD14 outputs (NF-κB/MAPK inflammation, endosomal mTORC1 proliferation, replication-stress, MYC-dependent osteoclastogenesis) are selectively wired from a single scaffold, and the structural basis of linker autoinhibition, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of autoinhibited vs. active CARD14 signalosome\", \"Determinants of output selectivity (NF-κB vs mTORC1 vs MYC) unknown\", \"Cross-tissue regulatory differences uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 6, 7]},\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": [0, 5, 17, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 17, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 10, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 11, 16]}\n    ],\n    \"complexes\": [\n      \"CBM complex (CARD14-BCL10-MALT1)\",\n      \"CARMA2sh-TANK-MALT1 complex\",\n      \"ACT1-TRAF6 complex\"\n    ],\n    \"partners\": [\n      \"BCL10\",\n      \"MALT1\",\n      \"TRAF2\",\n      \"DEPDC7\",\n      \"TANK\",\n      \"HOIP\",\n      \"TRAF6\",\n      \"PLK1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}