{"gene":"PKP2","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2003,"finding":"PKP2 (plakophilin-2) is a substrate of C-TAK1 kinase; C-TAK1 phosphorylates PKP2 generating a 14-3-3-binding site, and this phosphorylation influences PKP2 subcellular localization.","method":"Mutational analysis of C-TAK1 binding motifs, in vitro kinase assay, identification of 14-3-3 binding site generation, localization studies","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay with mutagenesis plus localization consequence, single rigorous paper with multiple orthogonal methods","pmids":["12941695"],"is_preprint":false},{"year":2008,"finding":"Truncated PKP2 mutants (R79x and 179fs) fail to localize to sites of cell-cell apposition in cardiomyocytes; the R79x truncation prevents physical interaction of PKP2 with desmoplakin (DP) and connexin-43 (Cx43), and R79x expression reduces Cx43 abundance and HSP90 expression.","method":"Adenoviral expression of mutant PKP2 constructs in neonatal rat ventricular myocytes, co-immunoprecipitation, immunofluorescence localization, western blot","journal":"Heart rhythm","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal Co-IP and localization with functional consequence, single lab with multiple orthogonal methods","pmids":["19084810"],"is_preprint":false},{"year":2016,"finding":"Expression of a truncated PKP2 (PKP2-Ser329) in transgenic mice causes content-dependent reduction and remodeling of desmosomal proteins (Desmocollin-2, Plakoglobin, native PKP2, Desmin, β-Catenin) and electrical coupling proteins (Connexin-43, Nav1.5), leading to ventricular dilation, dysfunction, and arrhythmia induction.","method":"Transgenic mouse model with varying transgene content, ultrastructural analysis, western blot for protein abundance, electrocardiography, echocardiography","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — clean transgenic model with defined molecular and functional phenotype, single lab with multiple orthogonal methods","pmids":["27412010"],"is_preprint":false},{"year":2017,"finding":"PKP2 gene is a direct transcriptional target of Wnt/β-catenin signaling in fibroblasts, induced via three TCF-binding sites in the promoter and one enhancer site ~20 kb upstream; conversely, plakophilin-2 antagonizes Wnt/β-catenin transcriptional activity, suggesting a feedback inhibitory role.","method":"Transcriptomic analysis, reporter assays with TCF binding site mutagenesis, ChIP, overexpression in HEK-293T cells","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assays with mutagenesis of binding sites plus functional transcriptional antagonism assay, single lab with multiple orthogonal methods","pmids":["29044515"],"is_preprint":false},{"year":2021,"finding":"PKP2 is methylated at an arginine site by PRMT1; this methylation stabilizes β-catenin by recruiting USP7, which in turn induces LIG4 (a key DNA ligase for NHEJ repair), driving radioresistance in lung cancer.","method":"CRISPR/Cas9 library screen, mass spectrometry identification of arginine methylation, Co-IP for PRMT1-PKP2 and USP7 interactions, functional radioresistance assays, PRMT1 inhibitor experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — mass spectrometry-identified PTM, Co-IP, functional rescue/inhibition with multiple orthogonal methods in single rigorous study","pmids":["33742119"],"is_preprint":false},{"year":2021,"finding":"PKP2 transcript abundance in adult cardiac myocytes is endogenously linked to transcripts participating in inflammatory/immune response pathways; loss of PKP2 in cardiomyocytes upregulates immune/inflammatory gene transcripts intrinsically, without exogenous triggers.","method":"Cardiac-specific tamoxifen-activated PKP2-knockout mice crossed with RiboTag line to isolate ribosome-resident cardiomyocyte transcriptome; RNA-seq; correlation with human cardiac GTEx transcriptomes","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 — cardiomyocyte-specific KO with ribosome-pulldown transcriptomics and human data correlation, single lab","pmids":["33536940"],"is_preprint":false},{"year":2022,"finding":"Loss of PKP2 in cardiomyocytes causes loss of nuclear envelope integrity, which leads to DNA damage and excess oxidant production (O2•- and H2O2); PKP2-deficient cells release H2O2 into the extracellular environment causing DNA damage in neighboring myocytes in a paracrine manner; transcriptional downregulation of electron transport chain proteins is an early event.","method":"High-resolution mass spectrometry, RNA-seq, transmission electron microscopy of human ARVC biopsies; cardiac-specific Pkp2-knockout mice; iPSC-derived PKP2-deficient cardiomyocytes; multiple imaging and biochemical techniques","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (proteomic, transcriptomic, ultrastructural, biochemical) in human samples and two animal/cell models, strong evidence for nuclear envelope integrity as mechanistic link","pmids":["35959657"],"is_preprint":false},{"year":2024,"finding":"CASK (a trafficking regulator) functions as a repressor of PKP2 accumulation at intercalated discs; CASK depletion increases PKP2 localization at cell contacts and promotes desmosome-like structure formation and stress resistance in PKP2+/- cardiomyocytes.","method":"AAV-mediated CASK knockdown in rat hearts and iPSC-derived cardiomyocytes; proteomics; electron microscopy; high-resolution imaging; mechano-SICM; stress resistance tests","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in multiple models, preprint but mechanistically specific with functional consequence","pmids":["bio_10.1101_2024.10.14.618172"],"is_preprint":true},{"year":2025,"finding":"PKP2 orchestrates oxidative phosphorylation (OXPHOS) gene expression in cardiomyocytes via a PGC1α (PPARGC1A)-dependent mechanism; PKP2 mutant cardiomyocytes have lower PPARGC1A expression leading to decreased mitochondrial spare capacity, and induction of PPARGC1A partially restores OXPHOS component expression and contractility.","method":"RNA-seq in iPSC-CMs and explanted human PKP2 mutant hearts; PPARGC1A overexpression rescue experiments; mitochondrial functional assays; contractility measurements","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptomic and functional rescue experiments in human cells and tissues, preprint with multiple orthogonal approaches","pmids":["bio_10.1101_2025.06.02.656790"],"is_preprint":true},{"year":2025,"finding":"PKP2 deficiency in cardiomyocytes impairs lipid homeostasis, glycolysis, and glucose oxidation; these metabolic defects directly associate with poor contractility; AAV9:PKP2 restoration rescued contractility, electrophysiological properties, and Ca2+ transients, while metabolic enhancers improved contractility but not electrophysiology, indicating differential sensitivity of structure-mediated functions.","method":"Steady-state metabolite profiling in PKP2-deficient mouse hearts and iPSC-CMs; AAV9:PKP2 gene restoration; pharmacological metabolic enhancement; Ca2+ transient and electrophysiology measurements; contractility assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (metabolomics, gene therapy rescue, pharmacological rescue) in mouse and human cell models, preprint","pmids":["bio_10.1101_2025.01.17.633239"],"is_preprint":true},{"year":2025,"finding":"PKP2 is a membrane tension-dependent dynamic protein at the intercalated disc; in cardiomyocytes, PKP2 and plakoglobin (JUP) are the most abundant shared proteins between the DSG2 and CDH2 interactomes, placing PKP2 at the nexus of desmosomal and adherens junction complexes.","method":"Proximity labeling (BioID) combined with quantitative mass spectrometry to define DSG2 interactome in neonatal cardiomyocytes; comparison with CDH2 interactome","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — proximity labeling MS interactome with quantitative comparison, preprint with rigorous proteomic approach","pmids":["bio_10.1101_2025.06.09.658637"],"is_preprint":true},{"year":2025,"finding":"Loss of PKP2 expression only in cardiomyocytes is sufficient to induce pro-inflammatory senescence (SASP) in non-myocyte cardiac resident cells and premature cardiac aging, as evidenced by senescence-associated heterochromatin foci, p21 staining, and SASP cytokines in non-myocytes.","method":"Cardiomyocyte-specific tamoxifen-activated PKP2-knockout mice; multiplex imaging; cytokine arrays; epigenetic clocks; spatial transcriptomics; expansion and structured illumination microscopy","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — cardiomyocyte-specific KO with multiple orthogonal methods demonstrating non-cell-autonomous senescence induction, preprint","pmids":["bio_10.1101_2025.10.22.682160"],"is_preprint":true},{"year":2025,"finding":"PKP2 deficiency in epicardium-derived cells (EPDCs) drives emergence of a pro-inflammatory fibroblast population with senescence-associated secretory phenotype (SASP) and exaggerated inflammatory response progressing from right to biventricular predominance; B cell accumulation contributes to early inflammatory/fibrosis response.","method":"Transgenic mice lacking PKP2 in cardiomyocytes only (Pkp2-cKO) or in both cardiomyocytes and EPDCs (Pkp2-ceKO); single-cell RNA-seq of non-myocyte populations; immunohistochemistry; flow cytometry; B cell depletion experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type-specific KO comparison with scRNA-seq and functional B-cell depletion, preprint with multiple orthogonal methods","pmids":["41279609"],"is_preprint":true},{"year":2025,"finding":"PKP2-deficient iPSC-derived epicardial cells exhibit enhanced epithelial-to-mesenchymal transition, increased lipid accumulation, and fibrotic phenotype; RNA-seq reveals dysregulation of Wnt, interferon, and Rho GTPase signaling including upregulation of IGF2 and CEBPA; recombinant IGF2 enhances CEBPA expression in epicardial cells, implicating IGF signaling in ACM fatty-fibro remodeling.","method":"iPSC lines from PKP2 mutant patients and CRISPR-corrected isogenic controls; iPSC-derived epicardial cell differentiation; RNA-seq; lipid accumulation assays; IGF2 treatment experiments","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — isogenic patient-derived iPSC model with transcriptomic and functional rescue experiment, single lab with multiple orthogonal methods","pmids":["41145823"],"is_preprint":false},{"year":2025,"finding":"Exercise in PKP2-deficient cardiomyocytes leads to reduced pool of functional β1-adrenergic receptors (β1-ARs) at the sarcolemma but preservation of intracellular (dyad-associated) receptors; OCT3 knockdown reduced norepinephrine but not isoproterenol response in trained PKP2cKO myocytes; exercise also reduces abundance and causes heterogeneous distribution of sympathetic nerve terminals in PKP2-deficient hearts.","method":"Expansion microscopy and structured illumination to quantify β1-AR in sarcolemma; shRNA-mediated OCT3 knockdown; Ca2+ transient dynamics with isoproterenol vs norepinephrine; sympathetic terminal distribution imaging","journal":"Heart rhythm","confidence":"Medium","confidence_rationale":"Tier 2 — multiple imaging and pharmacological methods in cardiomyocyte-specific KO model with defined mechanistic outcome, single lab","pmids":["40383179"],"is_preprint":false},{"year":2024,"finding":"In PKP2-deficient arrhythmogenic cardiomyopathy, enrichment of pro-fibrotic cardiac fibroblast populations is observed; AAV9-PKP2 restoration induces phenotypic conversion of activated cardiac fibroblasts into quiescent antifibrotic states via a mechanism involving Ptprc (protein tyrosine phosphatase receptor type C) as a pivotal regulator.","method":"Single-cell RNA sequencing of Pkp2-knockout rat hearts; AAV9-PKP2 gene therapy; integrated bioinformatics to identify Ptprc; cardiac organoid HF model from hiPSCs","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 — scRNA-seq in KO rat model with gene therapy rescue identifying specific fibroblast mechanism, single lab","pmids":["40979216"],"is_preprint":false},{"year":2024,"finding":"MYZAP stabilizes PKP2 and Nav1.5 levels in atrial tissue; overexpression of MYZAP in post-MI hearts reverses decreased PKP2 and Nav1.5 levels and reduces atrial fibrillation incidence, placing PKP2 downstream of the CCRR/MYZAP signaling axis.","method":"Cardiac-specific transgenic CCRR overexpression mice; AAV9-CCRR delivery; MYZAP overexpression experiments; western blot for PKP2 and Nav1.5 levels; AF incidence measurements","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2-3 — transgenic and AAV overexpression models with protein level measurements placing PKP2 in pathway, single lab","pmids":["39507261"],"is_preprint":false}],"current_model":"Plakophilin-2 (PKP2) is a desmosomal scaffolding protein that serves as a substrate for C-TAK1 kinase (generating a 14-3-3 binding site that controls localization) and PRMT1 arginine methyltransferase (stabilizing β-catenin via USP7 recruitment), physically interacts with desmoplakin and connexin-43 at intercalated discs to support both mechanical coupling and gap junction function, regulates OXPHOS gene expression via PGC1α, controls nuclear envelope integrity (loss causing DNA damage and paracrine oxidative stress), and transcriptionally suppresses Wnt/β-catenin signaling as part of a feedback loop, with deficiency additionally driving metabolic impairment, pro-inflammatory senescence of non-myocytes, and remodeling of the adrenergic response in cardiomyocytes."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that PKP2 is post-translationally regulated by phosphorylation revealed how its subcellular distribution is controlled: C-TAK1 phosphorylation generates a 14-3-3 docking site that governs PKP2 localization.","evidence":"In vitro kinase assay with mutagenesis of C-TAK1 binding motifs and localization studies","pmids":["12941695"],"confidence":"High","gaps":["Upstream signals that regulate C-TAK1-PKP2 phosphorylation remain undefined","Functional consequence of 14-3-3 binding on desmosome assembly not tested"]},{"year":2008,"claim":"Demonstrating that disease-associated PKP2 truncations disrupt interactions with desmoplakin and connexin-43 established PKP2 as a nexus linking desmosomal adhesion to gap junction and ion channel function in cardiomyocytes.","evidence":"Adenoviral expression of R79x and 179fs PKP2 mutants in neonatal rat ventricular myocytes with co-immunoprecipitation and immunofluorescence","pmids":["19084810"],"confidence":"Medium","gaps":["Studies used overexpression of truncated constructs rather than endogenous mutation knock-in","Whether Cx43 loss is due to direct binding loss or secondary remodeling was not resolved"]},{"year":2016,"claim":"An in vivo transgenic model demonstrated that truncated PKP2 causes dose-dependent remodeling of desmosomal, gap junction, and sodium channel proteins with progressive ventricular dysfunction and arrhythmia, confirming PKP2 as a master organizer of intercalated disc integrity.","evidence":"Transgenic mice expressing PKP2-Ser329 at varying content levels with ultrastructural, protein-level, and electrophysiological characterization","pmids":["27412010"],"confidence":"Medium","gaps":["Mechanism by which truncated PKP2 dominantly destabilizes native full-length PKP2 not defined","Contribution of individual downstream targets (Cx43 vs Nav1.5 vs desmosomal proteins) to arrhythmogenesis not dissected"]},{"year":2017,"claim":"Identification of PKP2 as both a direct transcriptional target of Wnt/β-catenin signaling and an antagonist of Wnt/β-catenin transcriptional activity revealed a negative feedback loop through which PKP2 constrains Wnt pathway output.","evidence":"Reporter assays with TCF binding site mutagenesis, ChIP, and overexpression in HEK-293T cells","pmids":["29044515"],"confidence":"Medium","gaps":["Feedback loop not validated in cardiomyocytes","Molecular mechanism by which PKP2 protein antagonizes β-catenin transcriptional activity not identified"]},{"year":2021,"claim":"Discovery that PRMT1-mediated arginine methylation of PKP2 recruits USP7 to stabilize β-catenin, thereby inducing LIG4 and radioresistance, expanded PKP2's role beyond structural scaffolding to signaling-dependent regulation of DNA repair.","evidence":"CRISPR screen, mass spectrometry identification of arginine methylation, Co-IP for PRMT1-PKP2 and USP7, functional radioresistance assays in lung cancer cells","pmids":["33742119"],"confidence":"High","gaps":["Relevance of PRMT1-PKP2-USP7 axis in cardiomyocytes not tested","Whether other armadillo proteins are similarly methylated by PRMT1 is unknown"]},{"year":2021,"claim":"Cardiomyocyte-specific PKP2 knockout revealed that PKP2 loss cell-autonomously upregulates inflammatory/immune transcripts in cardiomyocytes, establishing an intrinsic inflammatory program independent of immune cell infiltration.","evidence":"Cardiac-specific tamoxifen-activated Pkp2-KO mice with RiboTag ribosome-resident transcriptomics; correlation with human GTEx data","pmids":["33536940"],"confidence":"Medium","gaps":["Transcription factor(s) driving cardiomyocyte-intrinsic inflammatory gene induction not identified","Causal relationship between inflammatory gene expression and disease phenotype not established"]},{"year":2022,"claim":"Demonstrating that PKP2 deficiency compromises nuclear envelope integrity, causing DNA damage and extracellular H₂O₂ release that damages neighboring cells, revealed a non-cell-autonomous paracrine injury mechanism and identified nuclear envelope disruption as an early mechanistic node.","evidence":"High-resolution mass spectrometry, RNA-seq, TEM of human ARVC biopsies, cardiac-specific Pkp2-KO mice, and iPSC-derived PKP2-deficient cardiomyocytes","pmids":["35959657"],"confidence":"High","gaps":["Molecular link between desmosomal PKP2 loss and nuclear envelope destabilization not fully defined","Whether antioxidant intervention can prevent disease progression in vivo not tested"]},{"year":2024,"claim":"Identification of MYZAP as a stabilizer of PKP2 and Nav1.5 levels, and CASK as a repressor of PKP2 accumulation at intercalated discs, defined upstream regulators that control PKP2 protein abundance and localization at cell contacts.","evidence":"AAV-mediated CASK knockdown in rat hearts and iPSC-CMs with proteomics and electron microscopy (preprint); cardiac-specific CCRR/MYZAP transgenic and AAV models with protein level measurements","pmids":["39507261","bio_10.1101_2024.10.14.618172"],"confidence":"Medium","gaps":["CASK mechanism is from a preprint awaiting peer review","Direct physical interaction between MYZAP and PKP2 not demonstrated","Whether CASK and MYZAP pathways converge or act independently is unknown"]},{"year":2025,"claim":"Multiple studies converged to show that PKP2 deficiency causes broad metabolic dysfunction — reduced OXPHOS gene expression via PGC1α, impaired lipid homeostasis and glycolysis — and that metabolic restoration partially rescues contractility but not electrophysiological defects, separating metabolic from structural functions of PKP2.","evidence":"RNA-seq and PGC1α rescue in iPSC-CMs and human PKP2 mutant hearts (preprint); metabolite profiling and AAV9:PKP2 vs metabolic enhancer rescue in mouse and iPSC-CM models (preprint)","pmids":["bio_10.1101_2025.06.02.656790","bio_10.1101_2025.01.17.633239"],"confidence":"Medium","gaps":["Both metabolic studies are preprints awaiting peer review","Mechanism linking PKP2 protein to PGC1α transcriptional regulation is unknown","Whether metabolic impairment is downstream of nuclear envelope disruption or independent is unresolved"]},{"year":2025,"claim":"PKP2 deficiency in cardiomyocytes was shown to non-cell-autonomously induce pro-inflammatory senescence (SASP) in neighboring non-myocyte populations including fibroblasts and epicardium-derived cells, with B cell infiltration contributing to early fibrosis, and AAV9-PKP2 gene therapy reversing fibroblast activation via Ptprc.","evidence":"Cardiomyocyte-specific Pkp2-KO mice with multiplex imaging, scRNA-seq, cytokine arrays, epigenetic clocks (preprints); scRNA-seq of Pkp2-KO rat hearts with AAV9-PKP2 rescue and B cell depletion; iPSC-derived epicardial cells with isogenic controls","pmids":["bio_10.1101_2025.10.22.682160","41279609","40979216","41145823"],"confidence":"Medium","gaps":["Most senescence studies are preprints","Whether paracrine H₂O₂ from cardiomyocytes is the direct trigger for non-myocyte senescence is not confirmed","Ptprc mechanism of fibroblast phenotypic conversion is correlative"]},{"year":2025,"claim":"Exercise-induced remodeling of β1-adrenergic receptor distribution and sympathetic innervation in PKP2-deficient hearts revealed a previously unknown link between desmosomal integrity and adrenergic signaling that may explain exercise-triggered arrhythmias.","evidence":"Expansion and structured illumination microscopy of β1-AR localization; OCT3 knockdown and pharmacological dissection of catecholamine response in cardiomyocyte-specific Pkp2-KO mice","pmids":["40383179"],"confidence":"Medium","gaps":["Mechanism by which PKP2 loss causes β1-AR redistribution not defined","OCT3 role is based on shRNA knockdown without genetic confirmation","Whether β1-AR remodeling is a direct structural consequence or secondary to metabolic/inflammatory changes is unknown"]},{"year":null,"claim":"The molecular link between desmosomal PKP2 loss and nuclear envelope disruption — the central early node connecting structural, metabolic, oxidative, and inflammatory pathologies — remains uncharacterized, and whether distinct PKP2 functions (scaffolding, signaling, metabolic regulation) are mediated by separate protein domains or interaction surfaces is unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PKP2 in complex with nuclear envelope components exists","Domain-function mapping for PKP2's non-desmosomal roles (metabolic, signaling) has not been performed","Therapeutic thresholds for PKP2 restoration (how much protein is sufficient) are not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,7,10,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,2,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,11,12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,8,9]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4,6]}],"complexes":["desmosome","intercalated disc complex"],"partners":["DSP","GJA1","JUP","PRMT1","USP7","CTNNB1","CASK","MYZAP"],"other_free_text":[]},"mechanistic_narrative":"Plakophilin-2 (PKP2) is a desmosomal armadillo-repeat protein that serves as a multifunctional scaffold at cardiac intercalated discs, integrating mechanical coupling, electrical communication, metabolic regulation, and signaling homeostasis in cardiomyocytes. PKP2 physically bridges desmosomal and adherens junction complexes by interacting with desmoplakin and connexin-43, and its loss disrupts both mechanical integrity and gap junction/sodium channel function, causing arrhythmia and ventricular dysfunction [PMID:19084810, PMID:27412010]. PKP2 subcellular localization is regulated by C-TAK1-mediated phosphorylation that creates a 14-3-3 binding site [PMID:12941695], and PRMT1-catalyzed arginine methylation stabilizes β-catenin through USP7 recruitment, linking PKP2 to DNA repair and Wnt pathway modulation [PMID:33742119, PMID:29044515]. In cardiomyocytes, PKP2 deficiency compromises nuclear envelope integrity causing DNA damage and paracrine oxidative stress, downregulates oxidative phosphorylation via reduced PGC1α expression, and non-cell-autonomously induces pro-inflammatory senescence in neighboring non-myocyte populations [PMID:35959657, PMID:33536940]."},"prefetch_data":{"uniprot":{"accession":"Q99959","full_name":"Plakophilin-2","aliases":[],"length_aa":881,"mass_kda":97.4,"function":"A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion (PubMed:25208567). Regulates focal adhesion turnover resulting in changes in focal adhesion size, cell adhesion and cell spreading, potentially via transcriptional modulation of beta-integrins (PubMed:23884246). Required to maintain gingival epithelial barrier function (PubMed:34368962). Important component of the desmosome that is also required for localization of desmosome component proteins such as DSC2, DSG2 and JUP to the desmosome cell-cell junction (PubMed:22781308, PubMed:25208567). Required for the formation of desmosome cell junctions in cardiomyocytes, thereby required for the correct formation of the heart, specifically trabeculation and formation of the atria walls (By similarity). Loss of desmosome cell junctions leads to mis-localization of DSP and DSG2 resulting in disruption of cell-cell adhesion and disordered intermediate filaments (By similarity). Modulates profibrotic gene expression in cardiomyocytes via regulation of DSP expression and subsequent activation of downstream TGFB1 and MAPK14/p38 MAPK signaling (By similarity). Required for cardiac sodium current propagation and electrical synchrony in cardiac myocytes, via ANK3 stabilization and modulation of SCN5A/Nav1.5 localization to cell-cell junctions (By similarity). Required for mitochondrial function, nuclear envelope integrity and positive regulation of SIRT3 transcription via maintaining DES localization at its nuclear envelope and cell tip anchoring points, and thereby preserving regulation of the transcriptional program (PubMed:35959657). Maintenance of nuclear envelope integrity protects against DNA damage and transcriptional dysregulation of genes, especially those involved in the electron transport chain, thereby preserving mitochondrial function and protecting against superoxide radical anion generation (PubMed:35959657). Binds single-stranded DNA (ssDNA) (PubMed:20613778). May regulate the localization of GJA1 to gap junctions in intercalated disks of the heart (PubMed:18662195). Involved in the inhibition of viral infection by influenza A viruses (IAV) (PubMed:28169297). Acts as a host restriction factor for IAV viral propagation, potentially via disrupting the interaction of IAV polymerase complex proteins (PubMed:28169297)","subcellular_location":"Nucleus; Cell junction, desmosome; Cell junction; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q99959/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PKP2","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PKP2","total_profiled":1310},"omim":[{"mim_id":"620734","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 30, ATRIAL; CMH30","url":"https://www.omim.org/entry/620734"},{"mim_id":"619747","title":"CARDIOMYOPATHY, DILATED, 2F; CMD2F","url":"https://www.omim.org/entry/619747"},{"mim_id":"615821","title":"CARDIOMYOPATHY, DILATED, WITH WOOLLY HAIR, KERATODERMA, AND TOOTH AGENESIS; DCWHKTA","url":"https://www.omim.org/entry/615821"},{"mim_id":"614071","title":"MYOCARDIAL ZONULA ADHERENS PROTEIN; MYZAP","url":"https://www.omim.org/entry/614071"},{"mim_id":"612048","title":"TRANSMEMBRANE PROTEIN 43; TMEM43","url":"https://www.omim.org/entry/612048"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cell Junctions","reliability":"Enhanced"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":185.4}],"url":"https://www.proteinatlas.org/search/PKP2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q99959","domains":[{"cath_id":"1.25.10.10","chopping":"353-447","consensus_level":"medium","plddt":91.9682,"start":353,"end":447},{"cath_id":"1.20.930","chopping":"760-881","consensus_level":"medium","plddt":92.645,"start":760,"end":881}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99959","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99959-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99959-F1-predicted_aligned_error_v6.png","plddt_mean":64.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PKP2","jax_strain_url":"https://www.jax.org/strain/search?query=PKP2"},"sequence":{"accession":"Q99959","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99959.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99959/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99959"}},"corpus_meta":[{"pmid":"17041889","id":"PMC_17041889","title":"Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2.","date":"2006","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/17041889","citation_count":67,"is_preprint":false},{"pmid":"12827610","id":"PMC_12827610","title":"Immunohistochemical localization of plakophilins (PKP1, PKP2, PKP3, and p0071) in primary oropharyngeal tumors: correlation with clinical parameters.","date":"2003","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12827610","citation_count":62,"is_preprint":false},{"pmid":"12941695","id":"PMC_12941695","title":"Functional analysis of C-TAK1 substrate binding and identification of PKP2 as a new C-TAK1 substrate.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12941695","citation_count":59,"is_preprint":false},{"pmid":"35959657","id":"PMC_35959657","title":"Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2: A Molecular Substrate of ARVC.","date":"2022","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/35959657","citation_count":55,"is_preprint":false},{"pmid":"38665939","id":"PMC_38665939","title":"Therapeutic efficacy of AAV-mediated restoration of PKP2 in arrhythmogenic cardiomyopathy.","date":"2023","source":"Nature cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/38665939","citation_count":54,"is_preprint":false},{"pmid":"19084810","id":"PMC_19084810","title":"Characterization of the molecular phenotype of two arrhythmogenic right ventricular cardiomyopathy (ARVC)-related plakophilin-2 (PKP2) mutations.","date":"2008","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/19084810","citation_count":45,"is_preprint":false},{"pmid":"38499690","id":"PMC_38499690","title":"AAV9:PKP2 improves heart function and survival in a Pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy.","date":"2024","source":"Communications medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38499690","citation_count":40,"is_preprint":false},{"pmid":"21194493","id":"PMC_21194493","title":"Expression of plakophilins (PKP1, PKP2, and PKP3) in gastric cancers.","date":"2011","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21194493","citation_count":40,"is_preprint":false},{"pmid":"33742119","id":"PMC_33742119","title":"CRISPR/Cas9 library screening uncovered methylated PKP2 as a critical driver of lung cancer radioresistance by stabilizing β-catenin.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33742119","citation_count":40,"is_preprint":false},{"pmid":"23486541","id":"PMC_23486541","title":"Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy.","date":"2013","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/23486541","citation_count":35,"is_preprint":false},{"pmid":"21947748","id":"PMC_21947748","title":"Expression of Plakophilins (PKP1, PKP2, and PKP3) in breast cancers.","date":"2011","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21947748","citation_count":34,"is_preprint":false},{"pmid":"22889254","id":"PMC_22889254","title":"Detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy.","date":"2012","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22889254","citation_count":32,"is_preprint":false},{"pmid":"29044515","id":"PMC_29044515","title":"The human PKP2/plakophilin-2 gene is induced by Wnt/β-catenin in normal and colon cancer-associated fibroblasts.","date":"2017","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29044515","citation_count":31,"is_preprint":false},{"pmid":"22019812","id":"PMC_22019812","title":"PKP2 mutations in sudden death from arrhythmogenic right ventricular cardiomyopathy (ARVC) and sudden unexpected death with negative autopsy (SUDNA).","date":"2011","source":"Circulation journal : official journal of the Japanese Circulation Society","url":"https://pubmed.ncbi.nlm.nih.gov/22019812","citation_count":31,"is_preprint":false},{"pmid":"30619891","id":"PMC_30619891","title":"Pleiotropic Phenotypes Associated With PKP2 Variants.","date":"2018","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30619891","citation_count":27,"is_preprint":false},{"pmid":"27412010","id":"PMC_27412010","title":"Molecular disturbance underlies to arrhythmogenic cardiomyopathy induced by transgene content, age and exercise in a truncated PKP2 mouse model.","date":"2016","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27412010","citation_count":27,"is_preprint":false},{"pmid":"33536940","id":"PMC_33536940","title":"Transcriptomic Coupling of PKP2 With Inflammatory and Immune Pathways Endogenous to Adult Cardiac Myocytes.","date":"2021","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33536940","citation_count":25,"is_preprint":false},{"pmid":"37051130","id":"PMC_37051130","title":"Structural characterization and anti-inflammatory activity of a novel polysaccharide PKP2-1 from Polygonatum kingianum.","date":"2023","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/37051130","citation_count":23,"is_preprint":false},{"pmid":"24967631","id":"PMC_24967631","title":"Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24967631","citation_count":21,"is_preprint":false},{"pmid":"27085656","id":"PMC_27085656","title":"Brugada Syndrome and PKP2: Evidences and uncertainties.","date":"2016","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/27085656","citation_count":17,"is_preprint":false},{"pmid":"34191271","id":"PMC_34191271","title":"Pathogenic variants in plakophilin-2 gene (PKP2) are associated with better survival in arrhythmogenic right ventricular cardiomyopathy.","date":"2021","source":"Journal of applied genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34191271","citation_count":11,"is_preprint":false},{"pmid":"28431057","id":"PMC_28431057","title":"Quantitative analysis of PKP2 and neighbouring genes in a patient with arrhythmogenic right ventricular cardiomyopathy caused by heterozygous PKP2 deletion.","date":"2017","source":"Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/28431057","citation_count":10,"is_preprint":false},{"pmid":"29977873","id":"PMC_29977873","title":"A novel PKP2 mutation and intrafamilial phenotypic variability in ARVC/D.","date":"2018","source":"Medical journal of the Islamic Republic of Iran","url":"https://pubmed.ncbi.nlm.nih.gov/29977873","citation_count":9,"is_preprint":false},{"pmid":"33506895","id":"PMC_33506895","title":"PPM1D accelerates proliferation and metastasis of osteosarcoma by activating PKP2.","date":"2021","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33506895","citation_count":9,"is_preprint":false},{"pmid":"29034900","id":"PMC_29034900","title":"Generation of iPSC line from patient with arrhythmogenic right ventricular cardiomyopathy carrying mutations in PKP2 gene.","date":"2017","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29034900","citation_count":9,"is_preprint":false},{"pmid":"32485643","id":"PMC_32485643","title":"Generation of human induced pluripotent stem cell line LUMCi027-A and its isogenic gene-corrected line from a patient affected by arrhythmogenic cardiomyopathy and carrying the c.2013delC PKP2 mutation.","date":"2020","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32485643","citation_count":8,"is_preprint":false},{"pmid":"27357287","id":"PMC_27357287","title":"Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs.","date":"2016","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27357287","citation_count":7,"is_preprint":false},{"pmid":"27335691","id":"PMC_27335691","title":"Arrhythmogenic Right Ventricular Cardiomyopathy - 4 Swedish families with an associated PKP2 c.2146-1G>C variant.","date":"2016","source":"American journal of cardiovascular disease","url":"https://pubmed.ncbi.nlm.nih.gov/27335691","citation_count":7,"is_preprint":false},{"pmid":"34095246","id":"PMC_34095246","title":"Phenotypic Variability of a Pathogenic PKP2 Mutation in an Italian Family Affected by Arrhythmogenic Cardiomyopathy and Juvenile Sudden Death: Considerations From Molecular Autopsy to Sport Restriction.","date":"2021","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34095246","citation_count":5,"is_preprint":false},{"pmid":"34034221","id":"PMC_34034221","title":"Establishment of an arrhythmogenic right ventricular cardiomyopathy derived iPSC cell line (USFi004-A) carrying a heterozygous mutation in PKP2 (c.1799delA).","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34034221","citation_count":5,"is_preprint":false},{"pmid":"32916635","id":"PMC_32916635","title":"Generation of an induced pluripotent stem cell line from the dermal fibroblasts of a patient with arrhythmogenic right ventricular cardiomyopathy carrying a PKP2/c.2489 + 1G > A mutation.","date":"2020","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32916635","citation_count":4,"is_preprint":false},{"pmid":"33743362","id":"PMC_33743362","title":"Generation of three induced pluripotent stem cell lines, SCVIi003-A, SCVIi004-A, SCVIi005-A, from patients with ARVD/C caused by heterozygous mutations in the PKP2 gene.","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33743362","citation_count":4,"is_preprint":false},{"pmid":"35059364","id":"PMC_35059364","title":"A Novel Homozygous PKP2 Variant in Severe Neonatal Non-compaction and Concomitant Ventricular Septal Defect: A Case Report.","date":"2022","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/35059364","citation_count":4,"is_preprint":false},{"pmid":"30219716","id":"PMC_30219716","title":"Derivation of human induced pluripotent stem cell line EURACi004-A from skin fibroblasts of a patient with Arrhythmogenic Cardiomyopathy carrying the heterozygous PKP2 mutation c.2569_3018del50.","date":"2018","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30219716","citation_count":4,"is_preprint":false},{"pmid":"38804704","id":"PMC_38804704","title":"PKP2 induced by YAP/TEAD4 promotes malignant progression of gastric cancer.","date":"2024","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/38804704","citation_count":4,"is_preprint":false},{"pmid":"26701096","id":"PMC_26701096","title":"Novel frame-shift mutation in PKP2 associated with arrhythmogenic right ventricular cardiomyopathy: a case report.","date":"2015","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26701096","citation_count":4,"is_preprint":false},{"pmid":"37505369","id":"PMC_37505369","title":"The arrhythmogenic cardiomyopathy phenotype associated with PKP2 c.1211dup variant.","date":"2023","source":"Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation","url":"https://pubmed.ncbi.nlm.nih.gov/37505369","citation_count":3,"is_preprint":false},{"pmid":"32443836","id":"PMC_32443836","title":"Clinical and Molecular Data Define a Diagnosis of Arrhythmogenic Cardiomyopathy in a Carrier of a Brugada-Syndrome-Associated PKP2 Mutation.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/32443836","citation_count":3,"is_preprint":false},{"pmid":"30391969","id":"PMC_30391969","title":"PKP2 and DSG2 genetic variations in Latvian arrhythmogenic right ventricular dysplasia/cardiomyopathy registry patients.","date":"2018","source":"Anatolian journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/30391969","citation_count":3,"is_preprint":false},{"pmid":"40374728","id":"PMC_40374728","title":"Low expression of miR-7-5p promotes resistance to radiotherapy in lung cancer through direct upregulation of PKP2 expression.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40374728","citation_count":2,"is_preprint":false},{"pmid":"40201954","id":"PMC_40201954","title":"Computational Modeling of Effects of PKP2 Gene Therapy on Ventricular Conduction Properties in Arrhythmogenic Cardiomyopathy.","date":"2025","source":"Circulation. Arrhythmia and electrophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/40201954","citation_count":2,"is_preprint":false},{"pmid":"39507261","id":"PMC_39507261","title":"CCRR regulate MYZAP-PKP2-Nav1.5 signaling pathway in atrial fibrillation following myocardial infarction.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/39507261","citation_count":2,"is_preprint":false},{"pmid":"29288195","id":"PMC_29288195","title":"Sequencing of Linkage Region on Chromosome 12p11 Identifies PKP2 as a Candidate Gene for Left Ventricular Mass in Dominican Families.","date":"2018","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/29288195","citation_count":2,"is_preprint":false},{"pmid":"33640690","id":"PMC_33640690","title":"CRISPR/Cas9-edited PKP2 knock-out (JMUi001-A-2) and DSG2 knock-out (JMUi001-A-3) iPSC lines as an isogenic human model system for arrhythmogenic cardiomyopathy (ACM).","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33640690","citation_count":2,"is_preprint":false},{"pmid":"40383179","id":"PMC_40383179","title":"Exercise-induced dysregulation of the adrenergic response in a mouse model of PKP2-arrhythmogenic cardiomyopathy.","date":"2025","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/40383179","citation_count":1,"is_preprint":false},{"pmid":"37643967","id":"PMC_37643967","title":"[Analysis of PKP2 gene variants in a child with Arrhythmogenic right ventricular cardiomyopathy].","date":"2023","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37643967","citation_count":1,"is_preprint":false},{"pmid":"40979216","id":"PMC_40979216","title":"Gene Therapy Targeting Pkp2 Deficiency Attenuates Cardiac Fibrosis: Insights From Single-Cell Transcriptomics in Pkp2-Knockout Rats.","date":"2025","source":"MedComm","url":"https://pubmed.ncbi.nlm.nih.gov/40979216","citation_count":1,"is_preprint":false},{"pmid":"37510372","id":"PMC_37510372","title":"The Novel Variant NP_00454563.2 (p.Glu259Glyfs*77) in Gene PKP2 Associated with Arrhythmogenic Cardiomyopathy in 8 Families from Malaga, Spain.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37510372","citation_count":1,"is_preprint":false},{"pmid":"41279609","id":"PMC_41279609","title":"Epicardial contributions to fibro-inflammatory signaling in a Pkp2-deficient arrhythmogenic cardiomyopathy model.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279609","citation_count":1,"is_preprint":false},{"pmid":"39595168","id":"PMC_39595168","title":"Adipocyte-Mediated Electrophysiological Remodeling of PKP-2 Mutant Human Pluripotent Stem Cell-Derived Cardiomyocytes.","date":"2024","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/39595168","citation_count":1,"is_preprint":false},{"pmid":"37393721","id":"PMC_37393721","title":"Generation of two edited iPSCs lines by CRISPR/Cas9 with point mutations in PKP2 gene for arrhythmogenic cardiomyopathy in vitro modeling.","date":"2023","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/37393721","citation_count":1,"is_preprint":false},{"pmid":"34134068","id":"PMC_34134068","title":"Generation of human induced pluripotent stem cell line EURACi006-A and its isogenic gene-corrected line EURACi006-A-1 from an arrhythmogenic cardiomyopathy patient carrying the c.1643delG PKP2 mutation.","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34134068","citation_count":1,"is_preprint":false},{"pmid":"38382214","id":"PMC_38382214","title":"Generation of CRISPR/Cas9 edited human induced pluripotent stem cell line carrying the heterozygous p.H695VfsX5 frameshift mutation in the exon 10 of the PKP2 gene.","date":"2024","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38382214","citation_count":1,"is_preprint":false},{"pmid":"39764031","id":"PMC_39764031","title":"Computational Modeling of Effects of PKP2 Gene Therapy on Ventricular Conduction Properties in Arrhythmogenic Cardiomyopathy.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39764031","citation_count":0,"is_preprint":false},{"pmid":"41145823","id":"PMC_41145823","title":"Modelling arrhythmogenic cardiomyopathy fattyfibro pathology with PKP2-deficient epicardial cells derived from human iPSCs.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41145823","citation_count":0,"is_preprint":false},{"pmid":"40282378","id":"PMC_40282378","title":"Arrhythmogenic Cardiomyopathy PKP2-Related: Clinical and Functional Characterization of a Pathogenic Variant Detected in Two Italian Families.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/40282378","citation_count":0,"is_preprint":false},{"pmid":"41603024","id":"PMC_41603024","title":"Generation of a PKP2 heterozygous knockout pig model of arrhythmogenic cardiomyopathy.","date":"2026","source":"Zoological research","url":"https://pubmed.ncbi.nlm.nih.gov/41603024","citation_count":0,"is_preprint":false},{"pmid":"41529851","id":"PMC_41529851","title":"[Distribution characteristics of PKP2 non-synonymous variations in protein domain and genotype-phenotype relationship in patients with arrhythmogenic right ventricular cardiomyopathy].","date":"2026","source":"Zhonghua xin xue guan bing za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/41529851","citation_count":0,"is_preprint":false},{"pmid":"41759869","id":"PMC_41759869","title":"Fibroblast growth factor 21 prevents catecholaminergic arrhythmias in a mouse model of PKP2 arrhythmogenic cardiomyopathy.","date":"2026","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/41759869","citation_count":0,"is_preprint":false},{"pmid":"41769495","id":"PMC_41769495","title":"Pediatric Stroke Associated With a Rare Pathogenic PKP2 Variant: A Diagnostic Challenge.","date":"2026","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/41769495","citation_count":0,"is_preprint":false},{"pmid":"41906570","id":"PMC_41906570","title":"Arrhythmogenic Cardiomyopathy: Exercise and Divergent Phenotypes in a Family With a Pathogenic PKP2 Variant.","date":"2026","source":"JACC. Case reports","url":"https://pubmed.ncbi.nlm.nih.gov/41906570","citation_count":0,"is_preprint":false},{"pmid":"41687845","id":"PMC_41687845","title":"NSUN6-mediated m5C RNA methylation aggravate osteosarcoma progression through promoting PKP2 mRNA stability and expression.","date":"2026","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/41687845","citation_count":0,"is_preprint":false},{"pmid":"39332132","id":"PMC_39332132","title":"Generation of human induced pluripotent stem cell lines UKJi001-A and UKJi006-A from patients with heterozygous mutation in the PKP2 gene.","date":"2024","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39332132","citation_count":0,"is_preprint":false},{"pmid":"41535644","id":"PMC_41535644","title":"Novel PKP2 compound heterozygous mutations causing neonatal early-onset arrhythmogenic cardiomyopathy: insights into the synergistic pathogenicity of biallelic inactivation.","date":"2026","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41535644","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.22.682160","title":"Cardiomyocyte-specific plakophilin-2 loss is sufficient to induce aging and senescence of nonmyocytes. Relevance to arrhythmogenic cardiomyopathy","date":"2025-10-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.22.682160","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.30.679431","title":"Single-cell sequencing of trophoblasts in preeclampsia and chemical hypoxia in BeWo b30 cells reveals EBI3, COL17A1, miR-27a-5p and miR-193b-5p as hypoxia-response markers","date":"2025-10-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.30.679431","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.02.656790","title":"PKP2 orchestrates OXPHOS expression in cardiomyocytes via a PGC1α-dependent mechanism","date":"2025-06-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.02.656790","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.09.658637","title":"The Desmoglein 2 interactome in primary neonatal cardiomyocytes","date":"2025-06-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.09.658637","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.17.633239","title":"Plakophilin-2 Coordinates Energy Metabolism and Contractility in Cardiomyocytes, Revealing Its Roles beyond Desmosomes","date":"2025-01-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.17.633239","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.12.628155","title":"Computational Modeling of Effects of<i>PKP2</i>Gene Therapy on Ventricular Conduction Properties in Arrhythmogenic Cardiomyopathy","date":"2024-12-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.12.628155","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.29.25324867","title":"Genomic and molecular evidence that the lncRNA<i>DSP-AS1</i>modulates Desmoplakin expression","date":"2025-03-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.29.25324867","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.14.618172","title":"Depleting trafficking regulator CASK promotes intercalated disc organization and ventricular function","date":"2024-10-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.14.618172","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.11.628020","title":"Interleukin-1β Drives Disease Progression in Arrhythmogenic Cardiomyopathy","date":"2024-12-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.11.628020","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40196,"output_tokens":4506,"usd":0.094089},"stage2":{"model":"claude-opus-4-6","input_tokens":7983,"output_tokens":3599,"usd":0.194835},"total_usd":0.288924,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"PKP2 (plakophilin-2) is a substrate of C-TAK1 kinase; C-TAK1 phosphorylates PKP2 generating a 14-3-3-binding site, and this phosphorylation influences PKP2 subcellular localization.\",\n      \"method\": \"Mutational analysis of C-TAK1 binding motifs, in vitro kinase assay, identification of 14-3-3 binding site generation, localization studies\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay with mutagenesis plus localization consequence, single rigorous paper with multiple orthogonal methods\",\n      \"pmids\": [\"12941695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Truncated PKP2 mutants (R79x and 179fs) fail to localize to sites of cell-cell apposition in cardiomyocytes; the R79x truncation prevents physical interaction of PKP2 with desmoplakin (DP) and connexin-43 (Cx43), and R79x expression reduces Cx43 abundance and HSP90 expression.\",\n      \"method\": \"Adenoviral expression of mutant PKP2 constructs in neonatal rat ventricular myocytes, co-immunoprecipitation, immunofluorescence localization, western blot\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP and localization with functional consequence, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19084810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Expression of a truncated PKP2 (PKP2-Ser329) in transgenic mice causes content-dependent reduction and remodeling of desmosomal proteins (Desmocollin-2, Plakoglobin, native PKP2, Desmin, β-Catenin) and electrical coupling proteins (Connexin-43, Nav1.5), leading to ventricular dilation, dysfunction, and arrhythmia induction.\",\n      \"method\": \"Transgenic mouse model with varying transgene content, ultrastructural analysis, western blot for protein abundance, electrocardiography, echocardiography\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean transgenic model with defined molecular and functional phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27412010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PKP2 gene is a direct transcriptional target of Wnt/β-catenin signaling in fibroblasts, induced via three TCF-binding sites in the promoter and one enhancer site ~20 kb upstream; conversely, plakophilin-2 antagonizes Wnt/β-catenin transcriptional activity, suggesting a feedback inhibitory role.\",\n      \"method\": \"Transcriptomic analysis, reporter assays with TCF binding site mutagenesis, ChIP, overexpression in HEK-293T cells\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assays with mutagenesis of binding sites plus functional transcriptional antagonism assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29044515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PKP2 is methylated at an arginine site by PRMT1; this methylation stabilizes β-catenin by recruiting USP7, which in turn induces LIG4 (a key DNA ligase for NHEJ repair), driving radioresistance in lung cancer.\",\n      \"method\": \"CRISPR/Cas9 library screen, mass spectrometry identification of arginine methylation, Co-IP for PRMT1-PKP2 and USP7 interactions, functional radioresistance assays, PRMT1 inhibitor experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mass spectrometry-identified PTM, Co-IP, functional rescue/inhibition with multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"33742119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PKP2 transcript abundance in adult cardiac myocytes is endogenously linked to transcripts participating in inflammatory/immune response pathways; loss of PKP2 in cardiomyocytes upregulates immune/inflammatory gene transcripts intrinsically, without exogenous triggers.\",\n      \"method\": \"Cardiac-specific tamoxifen-activated PKP2-knockout mice crossed with RiboTag line to isolate ribosome-resident cardiomyocyte transcriptome; RNA-seq; correlation with human cardiac GTEx transcriptomes\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cardiomyocyte-specific KO with ribosome-pulldown transcriptomics and human data correlation, single lab\",\n      \"pmids\": [\"33536940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of PKP2 in cardiomyocytes causes loss of nuclear envelope integrity, which leads to DNA damage and excess oxidant production (O2•- and H2O2); PKP2-deficient cells release H2O2 into the extracellular environment causing DNA damage in neighboring myocytes in a paracrine manner; transcriptional downregulation of electron transport chain proteins is an early event.\",\n      \"method\": \"High-resolution mass spectrometry, RNA-seq, transmission electron microscopy of human ARVC biopsies; cardiac-specific Pkp2-knockout mice; iPSC-derived PKP2-deficient cardiomyocytes; multiple imaging and biochemical techniques\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (proteomic, transcriptomic, ultrastructural, biochemical) in human samples and two animal/cell models, strong evidence for nuclear envelope integrity as mechanistic link\",\n      \"pmids\": [\"35959657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CASK (a trafficking regulator) functions as a repressor of PKP2 accumulation at intercalated discs; CASK depletion increases PKP2 localization at cell contacts and promotes desmosome-like structure formation and stress resistance in PKP2+/- cardiomyocytes.\",\n      \"method\": \"AAV-mediated CASK knockdown in rat hearts and iPSC-derived cardiomyocytes; proteomics; electron microscopy; high-resolution imaging; mechano-SICM; stress resistance tests\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in multiple models, preprint but mechanistically specific with functional consequence\",\n      \"pmids\": [\"bio_10.1101_2024.10.14.618172\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKP2 orchestrates oxidative phosphorylation (OXPHOS) gene expression in cardiomyocytes via a PGC1α (PPARGC1A)-dependent mechanism; PKP2 mutant cardiomyocytes have lower PPARGC1A expression leading to decreased mitochondrial spare capacity, and induction of PPARGC1A partially restores OXPHOS component expression and contractility.\",\n      \"method\": \"RNA-seq in iPSC-CMs and explanted human PKP2 mutant hearts; PPARGC1A overexpression rescue experiments; mitochondrial functional assays; contractility measurements\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptomic and functional rescue experiments in human cells and tissues, preprint with multiple orthogonal approaches\",\n      \"pmids\": [\"bio_10.1101_2025.06.02.656790\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKP2 deficiency in cardiomyocytes impairs lipid homeostasis, glycolysis, and glucose oxidation; these metabolic defects directly associate with poor contractility; AAV9:PKP2 restoration rescued contractility, electrophysiological properties, and Ca2+ transients, while metabolic enhancers improved contractility but not electrophysiology, indicating differential sensitivity of structure-mediated functions.\",\n      \"method\": \"Steady-state metabolite profiling in PKP2-deficient mouse hearts and iPSC-CMs; AAV9:PKP2 gene restoration; pharmacological metabolic enhancement; Ca2+ transient and electrophysiology measurements; contractility assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (metabolomics, gene therapy rescue, pharmacological rescue) in mouse and human cell models, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.01.17.633239\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKP2 is a membrane tension-dependent dynamic protein at the intercalated disc; in cardiomyocytes, PKP2 and plakoglobin (JUP) are the most abundant shared proteins between the DSG2 and CDH2 interactomes, placing PKP2 at the nexus of desmosomal and adherens junction complexes.\",\n      \"method\": \"Proximity labeling (BioID) combined with quantitative mass spectrometry to define DSG2 interactome in neonatal cardiomyocytes; comparison with CDH2 interactome\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling MS interactome with quantitative comparison, preprint with rigorous proteomic approach\",\n      \"pmids\": [\"bio_10.1101_2025.06.09.658637\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of PKP2 expression only in cardiomyocytes is sufficient to induce pro-inflammatory senescence (SASP) in non-myocyte cardiac resident cells and premature cardiac aging, as evidenced by senescence-associated heterochromatin foci, p21 staining, and SASP cytokines in non-myocytes.\",\n      \"method\": \"Cardiomyocyte-specific tamoxifen-activated PKP2-knockout mice; multiplex imaging; cytokine arrays; epigenetic clocks; spatial transcriptomics; expansion and structured illumination microscopy\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cardiomyocyte-specific KO with multiple orthogonal methods demonstrating non-cell-autonomous senescence induction, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.10.22.682160\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKP2 deficiency in epicardium-derived cells (EPDCs) drives emergence of a pro-inflammatory fibroblast population with senescence-associated secretory phenotype (SASP) and exaggerated inflammatory response progressing from right to biventricular predominance; B cell accumulation contributes to early inflammatory/fibrosis response.\",\n      \"method\": \"Transgenic mice lacking PKP2 in cardiomyocytes only (Pkp2-cKO) or in both cardiomyocytes and EPDCs (Pkp2-ceKO); single-cell RNA-seq of non-myocyte populations; immunohistochemistry; flow cytometry; B cell depletion experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO comparison with scRNA-seq and functional B-cell depletion, preprint with multiple orthogonal methods\",\n      \"pmids\": [\"41279609\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKP2-deficient iPSC-derived epicardial cells exhibit enhanced epithelial-to-mesenchymal transition, increased lipid accumulation, and fibrotic phenotype; RNA-seq reveals dysregulation of Wnt, interferon, and Rho GTPase signaling including upregulation of IGF2 and CEBPA; recombinant IGF2 enhances CEBPA expression in epicardial cells, implicating IGF signaling in ACM fatty-fibro remodeling.\",\n      \"method\": \"iPSC lines from PKP2 mutant patients and CRISPR-corrected isogenic controls; iPSC-derived epicardial cell differentiation; RNA-seq; lipid accumulation assays; IGF2 treatment experiments\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isogenic patient-derived iPSC model with transcriptomic and functional rescue experiment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41145823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Exercise in PKP2-deficient cardiomyocytes leads to reduced pool of functional β1-adrenergic receptors (β1-ARs) at the sarcolemma but preservation of intracellular (dyad-associated) receptors; OCT3 knockdown reduced norepinephrine but not isoproterenol response in trained PKP2cKO myocytes; exercise also reduces abundance and causes heterogeneous distribution of sympathetic nerve terminals in PKP2-deficient hearts.\",\n      \"method\": \"Expansion microscopy and structured illumination to quantify β1-AR in sarcolemma; shRNA-mediated OCT3 knockdown; Ca2+ transient dynamics with isoproterenol vs norepinephrine; sympathetic terminal distribution imaging\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple imaging and pharmacological methods in cardiomyocyte-specific KO model with defined mechanistic outcome, single lab\",\n      \"pmids\": [\"40383179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In PKP2-deficient arrhythmogenic cardiomyopathy, enrichment of pro-fibrotic cardiac fibroblast populations is observed; AAV9-PKP2 restoration induces phenotypic conversion of activated cardiac fibroblasts into quiescent antifibrotic states via a mechanism involving Ptprc (protein tyrosine phosphatase receptor type C) as a pivotal regulator.\",\n      \"method\": \"Single-cell RNA sequencing of Pkp2-knockout rat hearts; AAV9-PKP2 gene therapy; integrated bioinformatics to identify Ptprc; cardiac organoid HF model from hiPSCs\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — scRNA-seq in KO rat model with gene therapy rescue identifying specific fibroblast mechanism, single lab\",\n      \"pmids\": [\"40979216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYZAP stabilizes PKP2 and Nav1.5 levels in atrial tissue; overexpression of MYZAP in post-MI hearts reverses decreased PKP2 and Nav1.5 levels and reduces atrial fibrillation incidence, placing PKP2 downstream of the CCRR/MYZAP signaling axis.\",\n      \"method\": \"Cardiac-specific transgenic CCRR overexpression mice; AAV9-CCRR delivery; MYZAP overexpression experiments; western blot for PKP2 and Nav1.5 levels; AF incidence measurements\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — transgenic and AAV overexpression models with protein level measurements placing PKP2 in pathway, single lab\",\n      \"pmids\": [\"39507261\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Plakophilin-2 (PKP2) is a desmosomal scaffolding protein that serves as a substrate for C-TAK1 kinase (generating a 14-3-3 binding site that controls localization) and PRMT1 arginine methyltransferase (stabilizing β-catenin via USP7 recruitment), physically interacts with desmoplakin and connexin-43 at intercalated discs to support both mechanical coupling and gap junction function, regulates OXPHOS gene expression via PGC1α, controls nuclear envelope integrity (loss causing DNA damage and paracrine oxidative stress), and transcriptionally suppresses Wnt/β-catenin signaling as part of a feedback loop, with deficiency additionally driving metabolic impairment, pro-inflammatory senescence of non-myocytes, and remodeling of the adrenergic response in cardiomyocytes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Plakophilin-2 (PKP2) is a desmosomal armadillo-repeat protein that serves as a multifunctional scaffold at cardiac intercalated discs, integrating mechanical coupling, electrical communication, metabolic regulation, and signaling homeostasis in cardiomyocytes. PKP2 physically bridges desmosomal and adherens junction complexes by interacting with desmoplakin and connexin-43, and its loss disrupts both mechanical integrity and gap junction/sodium channel function, causing arrhythmia and ventricular dysfunction [PMID:19084810, PMID:27412010]. PKP2 subcellular localization is regulated by C-TAK1-mediated phosphorylation that creates a 14-3-3 binding site [PMID:12941695], and PRMT1-catalyzed arginine methylation stabilizes β-catenin through USP7 recruitment, linking PKP2 to DNA repair and Wnt pathway modulation [PMID:33742119, PMID:29044515]. In cardiomyocytes, PKP2 deficiency compromises nuclear envelope integrity causing DNA damage and paracrine oxidative stress, downregulates oxidative phosphorylation via reduced PGC1α expression, and non-cell-autonomously induces pro-inflammatory senescence in neighboring non-myocyte populations [PMID:35959657, PMID:33536940].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that PKP2 is post-translationally regulated by phosphorylation revealed how its subcellular distribution is controlled: C-TAK1 phosphorylation generates a 14-3-3 docking site that governs PKP2 localization.\",\n      \"evidence\": \"In vitro kinase assay with mutagenesis of C-TAK1 binding motifs and localization studies\",\n      \"pmids\": [\"12941695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Upstream signals that regulate C-TAK1-PKP2 phosphorylation remain undefined\",\n        \"Functional consequence of 14-3-3 binding on desmosome assembly not tested\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that disease-associated PKP2 truncations disrupt interactions with desmoplakin and connexin-43 established PKP2 as a nexus linking desmosomal adhesion to gap junction and ion channel function in cardiomyocytes.\",\n      \"evidence\": \"Adenoviral expression of R79x and 179fs PKP2 mutants in neonatal rat ventricular myocytes with co-immunoprecipitation and immunofluorescence\",\n      \"pmids\": [\"19084810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Studies used overexpression of truncated constructs rather than endogenous mutation knock-in\",\n        \"Whether Cx43 loss is due to direct binding loss or secondary remodeling was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"An in vivo transgenic model demonstrated that truncated PKP2 causes dose-dependent remodeling of desmosomal, gap junction, and sodium channel proteins with progressive ventricular dysfunction and arrhythmia, confirming PKP2 as a master organizer of intercalated disc integrity.\",\n      \"evidence\": \"Transgenic mice expressing PKP2-Ser329 at varying content levels with ultrastructural, protein-level, and electrophysiological characterization\",\n      \"pmids\": [\"27412010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which truncated PKP2 dominantly destabilizes native full-length PKP2 not defined\",\n        \"Contribution of individual downstream targets (Cx43 vs Nav1.5 vs desmosomal proteins) to arrhythmogenesis not dissected\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of PKP2 as both a direct transcriptional target of Wnt/β-catenin signaling and an antagonist of Wnt/β-catenin transcriptional activity revealed a negative feedback loop through which PKP2 constrains Wnt pathway output.\",\n      \"evidence\": \"Reporter assays with TCF binding site mutagenesis, ChIP, and overexpression in HEK-293T cells\",\n      \"pmids\": [\"29044515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Feedback loop not validated in cardiomyocytes\",\n        \"Molecular mechanism by which PKP2 protein antagonizes β-catenin transcriptional activity not identified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that PRMT1-mediated arginine methylation of PKP2 recruits USP7 to stabilize β-catenin, thereby inducing LIG4 and radioresistance, expanded PKP2's role beyond structural scaffolding to signaling-dependent regulation of DNA repair.\",\n      \"evidence\": \"CRISPR screen, mass spectrometry identification of arginine methylation, Co-IP for PRMT1-PKP2 and USP7, functional radioresistance assays in lung cancer cells\",\n      \"pmids\": [\"33742119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relevance of PRMT1-PKP2-USP7 axis in cardiomyocytes not tested\",\n        \"Whether other armadillo proteins are similarly methylated by PRMT1 is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cardiomyocyte-specific PKP2 knockout revealed that PKP2 loss cell-autonomously upregulates inflammatory/immune transcripts in cardiomyocytes, establishing an intrinsic inflammatory program independent of immune cell infiltration.\",\n      \"evidence\": \"Cardiac-specific tamoxifen-activated Pkp2-KO mice with RiboTag ribosome-resident transcriptomics; correlation with human GTEx data\",\n      \"pmids\": [\"33536940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Transcription factor(s) driving cardiomyocyte-intrinsic inflammatory gene induction not identified\",\n        \"Causal relationship between inflammatory gene expression and disease phenotype not established\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that PKP2 deficiency compromises nuclear envelope integrity, causing DNA damage and extracellular H₂O₂ release that damages neighboring cells, revealed a non-cell-autonomous paracrine injury mechanism and identified nuclear envelope disruption as an early mechanistic node.\",\n      \"evidence\": \"High-resolution mass spectrometry, RNA-seq, TEM of human ARVC biopsies, cardiac-specific Pkp2-KO mice, and iPSC-derived PKP2-deficient cardiomyocytes\",\n      \"pmids\": [\"35959657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular link between desmosomal PKP2 loss and nuclear envelope destabilization not fully defined\",\n        \"Whether antioxidant intervention can prevent disease progression in vivo not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of MYZAP as a stabilizer of PKP2 and Nav1.5 levels, and CASK as a repressor of PKP2 accumulation at intercalated discs, defined upstream regulators that control PKP2 protein abundance and localization at cell contacts.\",\n      \"evidence\": \"AAV-mediated CASK knockdown in rat hearts and iPSC-CMs with proteomics and electron microscopy (preprint); cardiac-specific CCRR/MYZAP transgenic and AAV models with protein level measurements\",\n      \"pmids\": [\"39507261\", \"bio_10.1101_2024.10.14.618172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"CASK mechanism is from a preprint awaiting peer review\",\n        \"Direct physical interaction between MYZAP and PKP2 not demonstrated\",\n        \"Whether CASK and MYZAP pathways converge or act independently is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple studies converged to show that PKP2 deficiency causes broad metabolic dysfunction — reduced OXPHOS gene expression via PGC1α, impaired lipid homeostasis and glycolysis — and that metabolic restoration partially rescues contractility but not electrophysiological defects, separating metabolic from structural functions of PKP2.\",\n      \"evidence\": \"RNA-seq and PGC1α rescue in iPSC-CMs and human PKP2 mutant hearts (preprint); metabolite profiling and AAV9:PKP2 vs metabolic enhancer rescue in mouse and iPSC-CM models (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.02.656790\", \"bio_10.1101_2025.01.17.633239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Both metabolic studies are preprints awaiting peer review\",\n        \"Mechanism linking PKP2 protein to PGC1α transcriptional regulation is unknown\",\n        \"Whether metabolic impairment is downstream of nuclear envelope disruption or independent is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"PKP2 deficiency in cardiomyocytes was shown to non-cell-autonomously induce pro-inflammatory senescence (SASP) in neighboring non-myocyte populations including fibroblasts and epicardium-derived cells, with B cell infiltration contributing to early fibrosis, and AAV9-PKP2 gene therapy reversing fibroblast activation via Ptprc.\",\n      \"evidence\": \"Cardiomyocyte-specific Pkp2-KO mice with multiplex imaging, scRNA-seq, cytokine arrays, epigenetic clocks (preprints); scRNA-seq of Pkp2-KO rat hearts with AAV9-PKP2 rescue and B cell depletion; iPSC-derived epicardial cells with isogenic controls\",\n      \"pmids\": [\"bio_10.1101_2025.10.22.682160\", \"41279609\", \"40979216\", \"41145823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Most senescence studies are preprints\",\n        \"Whether paracrine H₂O₂ from cardiomyocytes is the direct trigger for non-myocyte senescence is not confirmed\",\n        \"Ptprc mechanism of fibroblast phenotypic conversion is correlative\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Exercise-induced remodeling of β1-adrenergic receptor distribution and sympathetic innervation in PKP2-deficient hearts revealed a previously unknown link between desmosomal integrity and adrenergic signaling that may explain exercise-triggered arrhythmias.\",\n      \"evidence\": \"Expansion and structured illumination microscopy of β1-AR localization; OCT3 knockdown and pharmacological dissection of catecholamine response in cardiomyocyte-specific Pkp2-KO mice\",\n      \"pmids\": [\"40383179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which PKP2 loss causes β1-AR redistribution not defined\",\n        \"OCT3 role is based on shRNA knockdown without genetic confirmation\",\n        \"Whether β1-AR remodeling is a direct structural consequence or secondary to metabolic/inflammatory changes is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular link between desmosomal PKP2 loss and nuclear envelope disruption — the central early node connecting structural, metabolic, oxidative, and inflammatory pathologies — remains uncharacterized, and whether distinct PKP2 functions (scaffolding, signaling, metabolic regulation) are mediated by separate protein domains or interaction surfaces is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of PKP2 in complex with nuclear envelope components exists\",\n        \"Domain-function mapping for PKP2's non-desmosomal roles (metabolic, signaling) has not been performed\",\n        \"Therapeutic thresholds for PKP2 restoration (how much protein is sufficient) are not defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 7, 10, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 2, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 11, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 8, 9]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [\n      \"desmosome\",\n      \"intercalated disc complex\"\n    ],\n    \"partners\": [\n      \"DSP\",\n      \"GJA1\",\n      \"JUP\",\n      \"PRMT1\",\n      \"USP7\",\n      \"CTNNB1\",\n      \"CASK\",\n      \"MYZAP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}