{"gene":"DSC1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1993,"finding":"The human DSC1 gene encodes a type 1 desmocollin (a cadherin-related glycoprotein) expressed in the more differentiated layers of the epidermis, sharing 53% amino acid identity with the previously isolated human type 3 desmocollin (DSC3), with the N- and C-termini being more highly conserved between isoforms. The DSC1 gene was chromosomally assigned to chromosome 18, co-localizing with DSC3 and the three desmoglein genes.","method":"cDNA cloning, amino acid sequence comparison, somatic cell hybrid panel chromosomal mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — molecular cloning with chromosomal assignment, single lab","pmids":["8288219"],"is_preprint":false},{"year":1993,"finding":"DSC1 (desmocollin 1) was formally established as part of the desmosomal cadherin nomenclature, defining it as a transmembrane glycoprotein component of desmosomal junctions involved in calcium-dependent cell-cell adhesion in epithelial tissues.","method":"Nomenclature review consolidating molecular and biochemical characterization data from multiple labs","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — community consensus across multiple labs with extensive prior biochemical characterization","pmids":["8486729"],"is_preprint":false},{"year":1996,"finding":"DSC1 protein expression is closely linked to epithelial keratinization during mouse development. DSC1 protein is first detected in the outermost epithelial cells destined to form keratinized layers (stratum corneum), with DSC1 mRNA upregulation occurring after stratification onset but before keratinization begins, and in tongue coinciding with formation of keratinizing filiform papillae. Desmocollin 1 and desmoglein 1 expression patterns were not tightly coupled during embryonic development, suggesting independent regulatory mechanisms.","method":"In situ hybridization of mouse embryonic tissues, immunofluorescence with cross-reactive human DSC1 monoclonal antibodies, full-length mouse Dsc1 cDNA cloning","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — in situ hybridization combined with immunofluorescence localization, single lab","pmids":["8823356"],"is_preprint":false},{"year":1997,"finding":"Human DSC1 is the specific autoantigen for the subcorneal pustular dermatosis (SPD) subtype of IgA pemphigus. IgA autoantibodies from all six SPD-type IgA pemphigus patients reacted with the surface of COS7 cells transfected with human DSC1, but not with cells expressing DSC2 or DSC3, demonstrating isoform-specific targeting of DSC1 by pathogenic autoantibodies and implicating DSC1 in SPD pathogenesis.","method":"Transient transfection of COS7 cells with mammalian expression vectors encoding individual human Dsc isoforms, immunofluorescence with patient IgA sera","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — direct cell-surface binding assay with human patient antibodies, replicated across six SPD cases and distinguished from seven IEN cases","pmids":["9242496"],"is_preprint":false},{"year":2000,"finding":"The human DSC1 gene has a defined intron-exon structure comprising 17 exons spanning approximately 33 kb on chromosome 18q12.1, providing the genomic framework for its regulated expression and enabling mutation screening strategies.","method":"PCR-based genomic amplification, sequencing, and intron-exon boundary mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic characterization, single lab","pmids":["11027496"],"is_preprint":false},{"year":2001,"finding":"Desmocollins (including DSC1) are specifically cleaved during apoptosis by a dual mechanism: the cytoplasmic domain is cleaved by caspases, while the extracellular domain is shed from the cell surface by metalloproteinase activity. Both cleavage reactions are inhibited by caspase and metalloproteinase inhibitors, respectively, and their cleavage contributes to disruption of desmosome structure, cell rounding, and disintegration of the intermediate filament system.","method":"Western blotting with desmosomal antibodies during apoptosis induction, caspase and metalloproteinase inhibitor experiments, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical cleavage assays with specific inhibitors, multiple desmosomal proteins examined in parallel","pmids":["11500511"],"is_preprint":false},{"year":2003,"finding":"Plakophilin-3 (PKP3) physically binds desmocollin 1a (Dsc1a) as well as Dsc2a and all three desmogleins, placing DSC1 within the desmosomal plaque protein interaction network. This interaction was established by yeast two-hybrid assay and confirmed by co-immunoprecipitation and co-localization experiments.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal interaction confirmed by multiple orthogonal methods (Y2H + Co-IP + co-localization), single lab","pmids":["12707304"],"is_preprint":false},{"year":2021,"finding":"CircRAB11FIP1 directly binds to DSC1 (desmocollin 1) protein and facilitates its interaction with ATG101, a component of the autophagy initiation complex, thereby promoting autophagic flux in ovarian cancer cells. This places DSC1 at a functional interface between desmosomal adhesion and autophagy regulation.","method":"RNA pulldown, co-immunoprecipitation, overexpression and silencing experiments with autophagic flux assays in ovarian cancer cell lines","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 — single lab, Co-IP interaction between circRNA-bound DSC1 and ATG101, limited mechanistic follow-up on DSC1 specifically","pmids":["33637694"],"is_preprint":false},{"year":2025,"finding":"METTL3-mediated N6-methyladenosine (m6A) modification of DSC1 mRNA positively regulates DSC1 expression and stability. METTL3 overexpression increases DSC1 levels, and DSC1 overexpression alleviates LPS-induced apoptosis and inflammation in human periodontal ligament fibroblasts. Silencing METTL3 partially reverses the protective effect of DSC1 upregulation, establishing METTL3 as a writer for m6A modification of DSC1.","method":"m6A RNA immunoprecipitation (m6A-RIP), quantitative RT-PCR, CCK-8/EdU proliferation assays, flow cytometry (apoptosis), ELISA (inflammation markers), siRNA knockdown and overexpression experiments","journal":"International dental journal","confidence":"Medium","confidence_rationale":"Tier 2 — m6A-RIP directly demonstrates METTL3-dependent modification of DSC1 mRNA, with functional rescue experiments; single lab","pmids":["41453286"],"is_preprint":false},{"year":2024,"finding":"Ephrin-A3 (EFNA3) regulates DSC1 (desmocollin-1) expression in vaginal epithelium. Topical administration of recombinant EFNA3 promotes vaginal DSC1 expression in a biphasic dose-dependent manner and partially reverses the loss of vaginal epithelial barrier function induced by progestin (DMPA) treatment, which reduces DSC1 levels. This identifies EFNA3 signaling as an upstream regulator of DSC1-dependent desmosomal function.","method":"In vivo mouse model with DMPA and recombinant EFNA3 treatment, measurement of vaginal DSG1 and DSC1 protein levels, epithelial barrier function assays, HSV-2 infection model","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, single lab, in vivo pharmacological manipulation without direct molecular mechanism linking EFNA3 to DSC1 transcription/translation","pmids":[],"is_preprint":true}],"current_model":"DSC1 (desmocollin 1) is a cadherin-family transmembrane glycoprotein component of epithelial desmosomes expressed in differentiated/keratinizing epithelial layers, where it mediates calcium-dependent cell-cell adhesion; it serves as the specific autoantigen for SPD-type IgA pemphigus via conformation-dependent epitopes, physically interacts with the desmosomal plaque protein plakophilin-3 (via Co-IP/Y2H), is proteolytically cleaved by caspases (cytoplasmic domain) and metalloproteinases (extracellular domain) during apoptosis to disrupt desmosomes, has its mRNA stability regulated by METTL3-mediated m6A modification, and has been linked to autophagic flux through circRAB11FIP1-facilitated interaction with ATG101, while its expression in vaginal epithelium is regulated upstream by ephrin-A3 signaling."},"narrative":{"teleology":[{"year":1993,"claim":"Molecular cloning of human DSC1 established it as a distinct type 1 desmocollin with differentiation-linked expression, mapping it to chromosome 18 alongside other desmosomal cadherins and defining the gene family framework.","evidence":"cDNA cloning, sequence comparison, and somatic cell hybrid chromosomal mapping; community nomenclature consolidation","pmids":["8288219","8486729"],"confidence":"High","gaps":["No functional adhesion assay performed at this stage","Regulatory elements controlling differentiation-dependent expression undefined"]},{"year":1996,"claim":"Developmental expression mapping revealed that DSC1 protein appearance is tightly linked to the onset of keratinization rather than to stratification per se, and that DSC1 is regulated independently of desmoglein-1.","evidence":"In situ hybridization and immunofluorescence in mouse embryonic tissues","pmids":["8823356"],"confidence":"Medium","gaps":["Transcription factors driving DSC1 expression during keratinization not identified","Functional consequence of independent DSC1/DSG1 regulation unexplored"]},{"year":1997,"claim":"Identification of DSC1 as the specific target of IgA autoantibodies in SPD-type IgA pemphigus revealed that loss of DSC1-mediated adhesion in superficial epidermal layers underlies subcorneal blister formation.","evidence":"COS7 transfection with individual DSC isoforms, immunofluorescence with sera from six SPD patients versus seven IEN patients","pmids":["9242496"],"confidence":"High","gaps":["Precise epitope(s) on DSC1 recognized by pathogenic IgA not mapped","No passive-transfer or knockout model to confirm pathogenicity of anti-DSC1 antibodies in vivo"]},{"year":2001,"claim":"Demonstration that DSC1 is proteolytically processed during apoptosis by both caspases (cytoplasmic domain) and metalloproteinases (extracellular domain) established a mechanism for active desmosome disassembly and intermediate filament collapse during programmed cell death.","evidence":"Western blotting during apoptosis induction with caspase and metalloproteinase inhibitors, immunofluorescence","pmids":["11500511"],"confidence":"Medium","gaps":["Specific caspase(s) and metalloproteinase(s) responsible not identified","Cleavage site(s) on DSC1 not mapped"]},{"year":2003,"claim":"Yeast two-hybrid and co-immunoprecipitation identified plakophilin-3 as a direct binding partner of DSC1a, placing DSC1 within the desmosomal plaque protein interaction network.","evidence":"Yeast two-hybrid, co-immunoprecipitation, co-localization immunofluorescence","pmids":["12707304"],"confidence":"Medium","gaps":["Binding interface between PKP3 and DSC1 not structurally resolved","Functional consequence of disrupting the DSC1–PKP3 interaction on desmosome integrity not tested"]},{"year":2021,"claim":"A report linking DSC1 to autophagic flux via circRAB11FIP1-facilitated interaction with ATG101 suggested a non-canonical role for DSC1 beyond cell adhesion, though this rests on limited mechanistic evidence.","evidence":"RNA pulldown, co-immunoprecipitation, overexpression/silencing with autophagy flux assays in ovarian cancer cell lines","pmids":["33637694"],"confidence":"Low","gaps":["DSC1–ATG101 interaction not validated by reciprocal Co-IP or in non-cancer cells","Endogenous relevance of DSC1 in autophagy regulation not established","Single-lab finding without independent replication"]},{"year":2025,"claim":"METTL3-mediated m6A modification was shown to stabilize DSC1 mRNA, establishing an epitranscriptomic layer of DSC1 regulation with functional consequences for cell survival under inflammatory stress.","evidence":"m6A-RIP, qRT-PCR, proliferation/apoptosis assays, siRNA knockdown and overexpression in human periodontal ligament fibroblasts","pmids":["41453286"],"confidence":"Medium","gaps":["m6A reader protein mediating DSC1 mRNA stabilization not identified","Whether m6A regulation of DSC1 operates in epidermal keratinocytes unknown"]},{"year":null,"claim":"Key open questions include the structural basis of DSC1 homophilic and heterophilic adhesion, the identity of the specific caspase and metalloproteinase cleaving DSC1, whether DSC1 has genuine autophagy-related functions outside cancer cell lines, and the in vivo pathogenic mechanism of anti-DSC1 IgA autoantibodies.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of DSC1 extracellular domain available","In vivo loss-of-function phenotype (knockout mouse) not reported in the timeline","Pathogenic mechanism of anti-DSC1 IgA in SPD not directly demonstrated in animal models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,5]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,5,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5]}],"complexes":["desmosome"],"partners":["PKP3","ATG101"],"other_free_text":[]},"mechanistic_narrative":"DSC1 (desmocollin-1) is a cadherin-family transmembrane glycoprotein that functions as a calcium-dependent cell–cell adhesion molecule within desmosomes of differentiated and keratinizing epithelial layers [PMID:8486729, PMID:8823356]. DSC1 is the isoform-specific autoantigen in the subcorneal pustular dermatosis (SPD) subtype of IgA pemphigus, where patient IgA autoantibodies bind DSC1 but not DSC2 or DSC3 [PMID:9242496]. During apoptosis, the DSC1 cytoplasmic domain is cleaved by caspases while its extracellular domain is shed by metalloproteinases, contributing to desmosome disassembly and intermediate filament collapse [PMID:11500511]. Within the desmosomal plaque, DSC1 physically interacts with plakophilin-3, and its mRNA stability is regulated by METTL3-mediated m6A modification [PMID:12707304, PMID:41453286]."},"prefetch_data":{"uniprot":{"accession":"Q08554","full_name":"Desmocollin-1","aliases":["Cadherin family member 1","Desmosomal glycoprotein 2/3","DG2/DG3"],"length_aa":894,"mass_kda":100.0,"function":"A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion (By similarity). Required for desmosome adhesion strength between the granular layers of the epidermis, as a result moderates epidermal proliferation and differentiation (By similarity). Is therefore required to maintain postnatal epidermal barrier function and normal hair follicle morphology into adulthood (By similarity)","subcellular_location":"Cell membrane; Cell junction, desmosome","url":"https://www.uniprot.org/uniprotkb/Q08554/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DSC1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PMVK","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DSC1","total_profiled":1310},"omim":[{"mim_id":"618084","title":"PEELING SKIN SYNDROME 6; PSS6","url":"https://www.omim.org/entry/618084"},{"mim_id":"602918","title":"PHENYLALANINE-tRNA SYNTHETASE, ALPHA SUBUNIT; FARSA","url":"https://www.omim.org/entry/602918"},{"mim_id":"600271","title":"DESMOCOLLIN 3; DSC3","url":"https://www.omim.org/entry/600271"},{"mim_id":"314250","title":"DYSTONIA 3, TORSION, X-LINKED; DYT3","url":"https://www.omim.org/entry/314250"},{"mim_id":"148700","title":"PALMOPLANTAR KERATODERMA I, STRIATE, FOCAL, OR DIFFUSE; PPKS1","url":"https://www.omim.org/entry/148700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skin 1","ntpm":216.0}],"url":"https://www.proteinatlas.org/search/DSC1"},"hgnc":{"alias_symbol":["CDHF1"],"prev_symbol":[]},"alphafold":{"accession":"Q08554","domains":[{"cath_id":"2.60.40.60","chopping":"34-114","consensus_level":"high","plddt":83.3732,"start":34,"end":114},{"cath_id":"2.60.40.60","chopping":"142-234","consensus_level":"medium","plddt":93.3505,"start":142,"end":234},{"cath_id":"2.60.40.60","chopping":"242-346","consensus_level":"medium","plddt":95.6521,"start":242,"end":346},{"cath_id":"2.60.40.60","chopping":"355-445_453-462","consensus_level":"high","plddt":93.954,"start":355,"end":462},{"cath_id":"2.60.40.60","chopping":"476-569","consensus_level":"high","plddt":90.3665,"start":476,"end":569},{"cath_id":"2.60.40.60","chopping":"581-666","consensus_level":"high","plddt":88.6845,"start":581,"end":666}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08554","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q08554-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q08554-F1-predicted_aligned_error_v6.png","plddt_mean":76.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DSC1","jax_strain_url":"https://www.jax.org/strain/search?query=DSC1"},"sequence":{"accession":"Q08554","fasta_url":"https://rest.uniprot.org/uniprotkb/Q08554.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q08554/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08554"}},"corpus_meta":[{"pmid":"9242496","id":"PMC_9242496","title":"Human desmocollin 1 (Dsc1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus.","date":"1997","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/9242496","citation_count":163,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8521825","id":"PMC_8521825","title":"A yeast transcription factor bypassing the requirement for SBF and DSC1/MBF in budding yeast has homology to bacterial signal transduction proteins.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8521825","citation_count":92,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33637694","id":"PMC_33637694","title":"CircRAB11FIP1 promoted autophagy flux of ovarian cancer through DSC1 and miR-129.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33637694","citation_count":73,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8288219","id":"PMC_8288219","title":"Cloning of the cDNA (DSC1) coding for human type 1 desmocollin and its assignment to chromosome 18.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8288219","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12196396","id":"PMC_12196396","title":"The DSC1 channel, encoded by the smi60E locus, contributes to odor-guided behavior in Drosophila melanogaster.","date":"2002","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12196396","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8823356","id":"PMC_8823356","title":"Expression of the \"skin-type\" desmosomal cadherin DSC1 is closely linked to the keratinization of epithelial tissues during mouse development.","date":"1996","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/8823356","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21571069","id":"PMC_21571069","title":"Molecular characterization and functional expression of the DSC1 channel.","date":"2011","source":"Insect biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21571069","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32054439","id":"PMC_32054439","title":"The TIR-NB-LRR pair DSC1 and WRKY19 contributes to basal immunity of Arabidopsis to the root-knot nematode Meloidogyne incognita.","date":"2020","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/32054439","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23505382","id":"PMC_23505382","title":"Role of the DSC1 channel in regulating neuronal excitability in Drosophila melanogaster: extending nervous system stability under stress.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23505382","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12871901","id":"PMC_12871901","title":"The Schizosaccharomyces pombe cdt2(+) gene, a target of G1-S phase-specific transcription factor complex DSC1, is required for mitotic and premeiotic DNA replication.","date":"2003","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12871901","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25687544","id":"PMC_25687544","title":"Distinct roles of the DmNav and DSC1 channels in the action of DDT and pyrethroids.","date":"2015","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/25687544","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11795845","id":"PMC_11795845","title":"The role of DSC1 components cdc10+, rep1+ and rep2+ in MCB gene transcription at the mitotic G1-S boundary in fission yeast.","date":"2001","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11795845","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22321571","id":"PMC_22321571","title":"Molecular characterization of DSC1 orthologs in invertebrate species.","date":"2012","source":"Insect biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22321571","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12488978","id":"PMC_12488978","title":"DSC1 channels are expressed in both the central and the peripheral nervous system of adult Drosophila melanogaster.","date":"2001","source":"Invertebrate neuroscience : IN","url":"https://pubmed.ncbi.nlm.nih.gov/12488978","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14648198","id":"PMC_14648198","title":"DSC1-MCB regulation of meiotic transcription in Schizosaccharomyces pombe.","date":"2003","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/14648198","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27432995","id":"PMC_27432995","title":"Biophysical characterization of the honeybee DSC1 orthologue reveals a novel voltage-dependent Ca2+ channel subfamily: CaV4.","date":"2016","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27432995","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25987218","id":"PMC_25987218","title":"The Drosophila Sodium Channel 1 (DSC1): The founding member of a new family of voltage-gated cation channels.","date":"2014","source":"Pesticide biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25987218","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9617815","id":"PMC_9617815","title":"Phenotypic analysis and molecular cloning of discolored-1 (dsc1), a maize gene required for early kernel development.","date":"1998","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9617815","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8367276","id":"PMC_8367276","title":"Domains of p85cdc10 required for function of the fission yeast DSC-1 factor.","date":"1993","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8367276","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22666226","id":"PMC_22666226","title":"Discolored1 (DSC1) is an ADP-Ribosylation Factor-GTPase Activating Protein Required to Maintain Differentiation of Maize Kernel Structures.","date":"2012","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/22666226","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29891372","id":"PMC_29891372","title":"DSC1 channel-dependent developmental regulation of pyrethroid susceptibility in Drosophila melanogaster.","date":"2018","source":"Pesticide biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29891372","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11027496","id":"PMC_11027496","title":"Genomic organization and amplification of the human desmosomal cadherin genes DSC1 and DSC3, encoding desmocollin types 1 and 3.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11027496","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17014956","id":"PMC_17014956","title":"Association of DSC1, a gene modulated by adrenergic stimulation, with Alzheimer's disease.","date":"2006","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/17014956","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24155671","id":"PMC_24155671","title":"Molecular characterization and alternative splicing of a sodium channel and DSC1 ortholog genes in Liposcelis bostrychophila Badonnel (Psocoptera: Liposcelididae).","date":"2013","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24155671","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16460890","id":"PMC_16460890","title":"Transcription of the Schizosaccharomyces pombe gene cdc18+: roles of MCB elements and the DSC1 complex.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/16460890","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41453286","id":"PMC_41453286","title":"METTL3-Mediated m6A Modification of DSC1 Alleviates Inflammation and Cellular Dysfunction in Periodontitis.","date":"2025","source":"International dental journal","url":"https://pubmed.ncbi.nlm.nih.gov/41453286","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.11.06.686738","title":"Tear fluid as noninvasive liquid biopsy reveals proteins associated with malignant transformation of oral lesions","date":"2025-11-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.06.686738","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.10.29.620915","title":"Exogenous ephrin-A3 administration restores vaginal epithelial barrier function in progestin-treated mice","date":"2024-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.29.620915","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.08.09.607388","title":"Lipidomic and Proteomic Insights from Extracellular Vesicles in Postmortem Dorsolateral Prefrontal Cortex Reveal Substance Use Disorder-Induced Brain Changes","date":"2024-08-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.09.607388","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22190034","id":"PMC_22190034","title":"Global landscape of HIV-human protein complexes.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22190034","citation_count":593,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33845483","id":"PMC_33845483","title":"Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/33845483","citation_count":532,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15951569","id":"PMC_15951569","title":"Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules.","date":"2005","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/15951569","citation_count":434,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18464913","id":"PMC_18464913","title":"A genome-wide association study identifies protein quantitative trait loci (pQTLs).","date":"2008","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18464913","citation_count":390,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23251661","id":"PMC_23251661","title":"Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23251661","citation_count":312,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8486729","id":"PMC_8486729","title":"Nomenclature of the desmosomal cadherins.","date":"1993","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8486729","citation_count":268,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29568061","id":"PMC_29568061","title":"An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29568061","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25544563","id":"PMC_25544563","title":"Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/25544563","citation_count":173,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32807901","id":"PMC_32807901","title":"UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32807901","citation_count":168,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25468996","id":"PMC_25468996","title":"E-cadherin interactome complexity and robustness resolved by quantitative proteomics.","date":"2014","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25468996","citation_count":162,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12707304","id":"PMC_12707304","title":"Defining desmosomal plakophilin-3 interactions.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12707304","citation_count":138,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27591049","id":"PMC_27591049","title":"SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling.","date":"2016","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/27591049","citation_count":134,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24457600","id":"PMC_24457600","title":"The central role of EED in the orchestration of polycomb group complexes.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24457600","citation_count":131,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30639242","id":"PMC_30639242","title":"The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/30639242","citation_count":124,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11500511","id":"PMC_11500511","title":"The fate of desmosomal proteins in apoptotic cells.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11500511","citation_count":109,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20379614","id":"PMC_20379614","title":"Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.","date":"2010","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/20379614","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36739287","id":"PMC_36739287","title":"ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36739287","citation_count":104,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19717567","id":"PMC_19717567","title":"Desmocollin 3-mediated binding is crucial for keratinocyte cohesion and is impaired in pemphigus.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19717567","citation_count":96,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16168112","id":"PMC_16168112","title":"Epigenetic silencing of DSC3 is a common event in human breast cancer.","date":"2005","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/16168112","citation_count":93,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23897914","id":"PMC_23897914","title":"A genome-wide association study (GWAS) for bronchopulmonary dysplasia.","date":"2013","source":"Pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/23897914","citation_count":93,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29467282","id":"PMC_29467282","title":"Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function.","date":"2018","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/29467282","citation_count":92,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32707033","id":"PMC_32707033","title":"Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/32707033","citation_count":88,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14794,"output_tokens":1641,"usd":0.034499},"stage2":{"model":"claude-opus-4-6","input_tokens":4890,"output_tokens":1494,"usd":0.0927},"total_usd":0.322854,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":28201,"output_tokens":4470,"usd":0.075827},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6242,"output_tokens":1947,"usd":0.119828}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Human DSC1 (desmocollin 1) is the autoantigen specifically recognized by IgA autoantibodies in the subcorneal pustular dermatosis (SPD) type of IgA pemphigus; IgA antibodies from all SPD-type patients reacted with the surface of COS7 cells expressing human DSC1, but not DSC2 or DSC3, demonstrating conformation-dependent epitope recognition on the cell surface.\",\n      \"method\": \"Transient transfection of COS7 cells with human DSC1/DSC2/DSC3 expression vectors followed by immunofluorescence with patient IgA antibodies\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-surface antigen identification with functional specificity, replicated across 6 patient sera with appropriate controls (DSC2, DSC3 negative)\",\n      \"pmids\": [\"9242496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Human DSC1 encodes a type 1 desmocollin cadherin-related glycoprotein expressed in the more differentiated (suprabasal) layers of human epidermis, with 53% amino acid identity to the type 3 desmocollin; the DSC1 gene was mapped to chromosome 18.\",\n      \"method\": \"cDNA cloning, sequence analysis, somatic cell hybrid panel mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — molecular cloning with sequence characterization and chromosomal mapping; foundational identity paper\",\n      \"pmids\": [\"8288219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"DSC1 protein is first expressed in the outermost epithelial cells destined to form the keratinized layers (stratum corneum) during mouse development, and its expression is closely linked to keratinization; DSC1 and DSG1 mRNA upregulation precedes keratinization at embryonic day 15.5.\",\n      \"method\": \"In situ hybridization during murine embryonic development, cross-reactive monoclonal antibody immunostaining\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with developmental functional context, single lab\",\n      \"pmids\": [\"8823356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DSC1 (desmocollin 1) binds to circRAB11FIP1 and facilitates the interaction of DSC1 with ATG101, placing DSC1 in a complex that promotes autophagic flux in ovarian cancer cells.\",\n      \"method\": \"Co-immunoprecipitation and RNA pulldown assays in SKOV3/A2780 ovarian cancer cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/pulldown without mutagenesis validation or reconstitution\",\n      \"pmids\": [\"33637694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The human DSC1 gene comprises 17 exons spanning approximately 33 kb on chromosome 18q12.1, defining its complete intron-exon organization.\",\n      \"method\": \"Genomic sequencing and PCR-based exon mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct genomic characterization; single lab but comprehensive\",\n      \"pmids\": [\"11027496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3 positively regulates DSC1 (desmocollin 1) expression and mRNA stability through m6A modification; m6A RNA immunoprecipitation confirmed METTL3-dependent m6A modification of DSC1 mRNA, and DSC1 overexpression alleviated LPS-induced apoptosis and inflammation in human periodontal ligament fibroblasts.\",\n      \"method\": \"m6A RNA immunoprecipitation (MeRIP), siRNA knockdown of METTL3, DSC1 overexpression, CCK-8/flow cytometry/ELISA assays in HPLF cells\",\n      \"journal\": \"International dental journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct m6A modification demonstrated by MeRIP with functional rescue assays; single lab\",\n      \"pmids\": [\"41453286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ephrin-A3 (EFNA3) is identified as a regulator of DSC1 (desmocollin-1) gene expression in vaginal epithelium; topical administration of recombinant EFNA3 promotes vaginal DSC1 expression in a biphasic dose-dependent manner and partially reverses DMPA-induced loss of vaginal epithelial barrier function.\",\n      \"method\": \"Mouse model with DMPA treatment and recombinant EFNA3 topical administration, gene expression analysis, epithelial barrier function assay, viral challenge model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, in vivo pharmacological experiment without direct molecular mechanism of EFNA3→DSC1 regulation\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DSC1 (desmocollin 1) is a desmosomal cadherin expressed in suprabasal/keratinizing layers of stratified epithelia where it mediates cell-cell adhesion, functions as the autoantigen for SPD-type IgA pemphigus through conformation-dependent surface epitopes, has its mRNA stability regulated by METTL3-mediated m6A modification, and can interact with ATG101 (facilitated by circRAB11FIP1) to promote autophagic flux; its expression is regulated upstream by ephrin-A3 signaling in vaginal epithelium.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\n**Retrieved Papers:**\n1. PMID:9242496 — Human DSC1 (desmocollin 1) as autoantigen → KEEP\n2. PMID:8521825 — Yeast DSC1/MBF transcription factor → EXCLUDE (symbol collision: yeast transcription factor, not desmocollin)\n3. PMID:33637694 — CircRAB11FIP1/DSC1 in ovarian cancer → KEEP (mentions desmocollin 1 binding to ATG101)\n4. PMID:8288219 — Human DSC1 cDNA cloning → KEEP\n5. PMID:12196396 — Drosophila DSC1 ion channel → EXCLUDE (symbol collision: insect sodium channel)\n6. PMID:8823356 — Mouse desmocollin 1 expression → KEEP\n7. PMID:21571069 — Drosophila DSC1 channel molecular characterization → EXCLUDE (insect ion channel)\n8. PMID:32054439 — Arabidopsis DSC1 TIR-NB-LRR → EXCLUDE (plant immune receptor)\n9. PMID:23505382 — Drosophila DSC1 knockout neuronal excitability → EXCLUDE (insect ion channel)\n10. PMID:12871901 — S. pombe DSC1 transcription factor → EXCLUDE (symbol collision: yeast transcription complex)\n11. PMID:25687544 — Drosophila DSC1 and DDT/pyrethroids → EXCLUDE (insect ion channel)\n12. PMID:11795845 — S. pombe DSC1 MCB transcription → EXCLUDE (yeast transcription factor)\n13. PMID:22321571 — Invertebrate DSC1 cation channels → EXCLUDE (insect ion channel)\n14. PMID:12488978 — Drosophila DSC1 channel expression → EXCLUDE (insect ion channel)\n15. PMID:14648198 — S. pombe DSC1 meiotic transcription → EXCLUDE (yeast)\n16. PMID:27432995 — Honeybee DSC1 Ca2+ channel → EXCLUDE (insect ion channel)\n17. PMID:25987218 — Drosophila DSC1 review → EXCLUDE (insect ion channel)\n18. PMID:9617815 — Maize dsc1 kernel development → EXCLUDE (plant gene)\n19. PMID:8367276 — S. pombe DSC-1 complex domains → EXCLUDE (yeast)\n20. PMID:22666226 — Maize DSC1 ARF-GAP → EXCLUDE (plant gene)\n21. PMID:29891372 — Drosophila DSC1 pyrethroid susceptibility → EXCLUDE (insect ion channel)\n22. PMID:11027496 — Human DSC1 and DSC3 genomic organization → KEEP\n23. PMID:17014956 — Human DSC1/desmocollin 1 and Alzheimer's → KEEP (expression-based; check for mechanism)\n24. PMID:24155671 — Liposcelis DSC1 ortholog (insect) → EXCLUDE (insect ion channel)\n25. PMID:16460890 — S. pombe DSC1 complex → EXCLUDE (yeast)\n26. PMID:41453286 — METTL3 m6A modification of DSC1 → KEEP\n27. bio_10.1101_2025.11.06.686738 — Tear fluid proteomics, DSC1 as marker → EXCLUDE (expression/biomarker only)\n28. bio_10.1101_2024.10.29.620915 — Ephrin-A3 regulates DSC1 in vaginal epithelium → KEEP\n29. bio_10.1101_2024.08.09.607388 — Proteomics/DSC1 in SUD EVs → EXCLUDE (expression only)\n\n**Gene2pubmed Papers:**\n- PMID:28514442 — BioPlex interactome (DSC1 appears in network) → KEEP (interaction data)\n- PMID:14702039 — Full-length cDNA sequencing → EXCLUDE (no mechanism)\n- PMID:33961781 — BioPlex 3.0 interactome → KEEP (interaction data)\n- PMID:15951569 — EGFR phosphoproteomics → EXCLUDE (no DSC1-specific mechanism)\n- PMID:35271311 — OpenCell localization → KEEP (localization data)\n- PMID:16344560 — Alternative promoters → EXCLUDE (no mechanism)\n- PMID:18464913 — GWAS pQTLs → EXCLUDE\n- PMID:34079125 — BioID proximity map → KEEP (localization)\n- PMID:23251661 — GWAS childhood obesity → EXCLUDE\n- PMID:8486729 — Desmosomal cadherin nomenclature → KEEP (foundational)\n- PMID:22190034 — HIV-human complexes → EXCLUDE (no DSC1-specific)\n- PMID:33845483 — SARS-CoV-2 proteomics → EXCLUDE\n- PMID:12707304 — Plakophilin-3 interactions with Dsc1 → KEEP\n- PMID:31871319 — Rho GTPase proximity network → EXCLUDE\n- PMID:27591049 — SPATA2/CYLD/LUBAC → EXCLUDE\n- PMID:24457600 — EED/PRC → EXCLUDE\n- PMID:30639242 — Ras/mTORC2 → EXCLUDE\n- PMID:11500511 — Desmosomal proteins in apoptosis → KEEP\n- PMID:20379614 — Smoking cessation GWAS → EXCLUDE\n- PMID:36739287 — STING degradation → EXCLUDE\n- PMID:19717567 — Dsc3-mediated binding, keratinocyte cohesion → KEEP (mentions Dsc1 context)\n- PMID:16168112 — DSC3 epigenetic silencing → EXCLUDE (DSC3, not DSC1)\n- PMID:23897914 — BPD GWAS → EXCLUDE\n- PMID:29467282 — VCP substrates → EXCLUDE\n- PMID:32707033 — Kinase interaction network → EXCLUDE\n- PMID:29568061 — MAC-tag AP-MS/BioID → EXCLUDE\n- PMID:25468996 — E-cadherin interactome → EXCLUDE\n- PMID:21873635 — GO phylogenetic propagation → EXCLUDE\n- PMID:32807901 — UFMylation/p53 → EXCLUDE\n- PMID:13085486 — not listed explicitly\n\nNow extracting discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"The human DSC1 gene encodes a type 1 desmocollin (a cadherin-related glycoprotein) expressed in the more differentiated layers of the epidermis, sharing 53% amino acid identity with the previously isolated human type 3 desmocollin (DSC3), with the N- and C-termini being more highly conserved between isoforms. The DSC1 gene was chromosomally assigned to chromosome 18, co-localizing with DSC3 and the three desmoglein genes.\",\n      \"method\": \"cDNA cloning, amino acid sequence comparison, somatic cell hybrid panel chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular cloning with chromosomal assignment, single lab\",\n      \"pmids\": [\"8288219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"DSC1 (desmocollin 1) was formally established as part of the desmosomal cadherin nomenclature, defining it as a transmembrane glycoprotein component of desmosomal junctions involved in calcium-dependent cell-cell adhesion in epithelial tissues.\",\n      \"method\": \"Nomenclature review consolidating molecular and biochemical characterization data from multiple labs\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — community consensus across multiple labs with extensive prior biochemical characterization\",\n      \"pmids\": [\"8486729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"DSC1 protein expression is closely linked to epithelial keratinization during mouse development. DSC1 protein is first detected in the outermost epithelial cells destined to form keratinized layers (stratum corneum), with DSC1 mRNA upregulation occurring after stratification onset but before keratinization begins, and in tongue coinciding with formation of keratinizing filiform papillae. Desmocollin 1 and desmoglein 1 expression patterns were not tightly coupled during embryonic development, suggesting independent regulatory mechanisms.\",\n      \"method\": \"In situ hybridization of mouse embryonic tissues, immunofluorescence with cross-reactive human DSC1 monoclonal antibodies, full-length mouse Dsc1 cDNA cloning\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in situ hybridization combined with immunofluorescence localization, single lab\",\n      \"pmids\": [\"8823356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human DSC1 is the specific autoantigen for the subcorneal pustular dermatosis (SPD) subtype of IgA pemphigus. IgA autoantibodies from all six SPD-type IgA pemphigus patients reacted with the surface of COS7 cells transfected with human DSC1, but not with cells expressing DSC2 or DSC3, demonstrating isoform-specific targeting of DSC1 by pathogenic autoantibodies and implicating DSC1 in SPD pathogenesis.\",\n      \"method\": \"Transient transfection of COS7 cells with mammalian expression vectors encoding individual human Dsc isoforms, immunofluorescence with patient IgA sera\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct cell-surface binding assay with human patient antibodies, replicated across six SPD cases and distinguished from seven IEN cases\",\n      \"pmids\": [\"9242496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The human DSC1 gene has a defined intron-exon structure comprising 17 exons spanning approximately 33 kb on chromosome 18q12.1, providing the genomic framework for its regulated expression and enabling mutation screening strategies.\",\n      \"method\": \"PCR-based genomic amplification, sequencing, and intron-exon boundary mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic characterization, single lab\",\n      \"pmids\": [\"11027496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Desmocollins (including DSC1) are specifically cleaved during apoptosis by a dual mechanism: the cytoplasmic domain is cleaved by caspases, while the extracellular domain is shed from the cell surface by metalloproteinase activity. Both cleavage reactions are inhibited by caspase and metalloproteinase inhibitors, respectively, and their cleavage contributes to disruption of desmosome structure, cell rounding, and disintegration of the intermediate filament system.\",\n      \"method\": \"Western blotting with desmosomal antibodies during apoptosis induction, caspase and metalloproteinase inhibitor experiments, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical cleavage assays with specific inhibitors, multiple desmosomal proteins examined in parallel\",\n      \"pmids\": [\"11500511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Plakophilin-3 (PKP3) physically binds desmocollin 1a (Dsc1a) as well as Dsc2a and all three desmogleins, placing DSC1 within the desmosomal plaque protein interaction network. This interaction was established by yeast two-hybrid assay and confirmed by co-immunoprecipitation and co-localization experiments.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmed by multiple orthogonal methods (Y2H + Co-IP + co-localization), single lab\",\n      \"pmids\": [\"12707304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CircRAB11FIP1 directly binds to DSC1 (desmocollin 1) protein and facilitates its interaction with ATG101, a component of the autophagy initiation complex, thereby promoting autophagic flux in ovarian cancer cells. This places DSC1 at a functional interface between desmosomal adhesion and autophagy regulation.\",\n      \"method\": \"RNA pulldown, co-immunoprecipitation, overexpression and silencing experiments with autophagic flux assays in ovarian cancer cell lines\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP interaction between circRNA-bound DSC1 and ATG101, limited mechanistic follow-up on DSC1 specifically\",\n      \"pmids\": [\"33637694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3-mediated N6-methyladenosine (m6A) modification of DSC1 mRNA positively regulates DSC1 expression and stability. METTL3 overexpression increases DSC1 levels, and DSC1 overexpression alleviates LPS-induced apoptosis and inflammation in human periodontal ligament fibroblasts. Silencing METTL3 partially reverses the protective effect of DSC1 upregulation, establishing METTL3 as a writer for m6A modification of DSC1.\",\n      \"method\": \"m6A RNA immunoprecipitation (m6A-RIP), quantitative RT-PCR, CCK-8/EdU proliferation assays, flow cytometry (apoptosis), ELISA (inflammation markers), siRNA knockdown and overexpression experiments\",\n      \"journal\": \"International dental journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — m6A-RIP directly demonstrates METTL3-dependent modification of DSC1 mRNA, with functional rescue experiments; single lab\",\n      \"pmids\": [\"41453286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ephrin-A3 (EFNA3) regulates DSC1 (desmocollin-1) expression in vaginal epithelium. Topical administration of recombinant EFNA3 promotes vaginal DSC1 expression in a biphasic dose-dependent manner and partially reverses the loss of vaginal epithelial barrier function induced by progestin (DMPA) treatment, which reduces DSC1 levels. This identifies EFNA3 signaling as an upstream regulator of DSC1-dependent desmosomal function.\",\n      \"method\": \"In vivo mouse model with DMPA and recombinant EFNA3 treatment, measurement of vaginal DSG1 and DSC1 protein levels, epithelial barrier function assays, HSV-2 infection model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, in vivo pharmacological manipulation without direct molecular mechanism linking EFNA3 to DSC1 transcription/translation\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DSC1 (desmocollin 1) is a cadherin-family transmembrane glycoprotein component of epithelial desmosomes expressed in differentiated/keratinizing epithelial layers, where it mediates calcium-dependent cell-cell adhesion; it serves as the specific autoantigen for SPD-type IgA pemphigus via conformation-dependent epitopes, physically interacts with the desmosomal plaque protein plakophilin-3 (via Co-IP/Y2H), is proteolytically cleaved by caspases (cytoplasmic domain) and metalloproteinases (extracellular domain) during apoptosis to disrupt desmosomes, has its mRNA stability regulated by METTL3-mediated m6A modification, and has been linked to autophagic flux through circRAB11FIP1-facilitated interaction with ATG101, while its expression in vaginal epithelium is regulated upstream by ephrin-A3 signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DSC1 (desmocollin 1) is a type 1 desmosomal cadherin glycoprotein that mediates cell–cell adhesion in the suprabasal, keratinizing layers of stratified epithelia, with its expression tightly linked to the onset of keratinization during embryonic development [PMID:8288219, PMID:8823356]. DSC1 is the specific autoantigen recognized by IgA autoantibodies in the subcorneal pustular dermatosis (SPD) type of IgA pemphigus, with patient antibodies binding conformation-dependent epitopes on the DSC1 cell surface but not on DSC2 or DSC3 [PMID:9242496]. DSC1 mRNA stability is regulated by METTL3-mediated m6A modification, and DSC1 overexpression protects human periodontal ligament fibroblasts from LPS-induced apoptosis and inflammation [PMID:41453286].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Molecular cloning of DSC1 established it as a cadherin-family desmosomal glycoprotein on chromosome 18, distinct from the type 3 desmocollin, resolving the identity and gene family placement of desmocollin subtypes.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and somatic cell hybrid panel mapping in human tissues\",\n      \"pmids\": [\"8288219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No functional adhesion assays performed\",\n        \"Tissue-specific expression pattern not yet mapped beyond epidermis\",\n        \"Relationship to desmosome assembly not tested\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Developmental expression analysis showed DSC1 upregulation precedes and marks the onset of keratinization in mouse embryonic epidermis, linking DSC1 specifically to terminal differentiation rather than generic desmosome function.\",\n      \"evidence\": \"In situ hybridization and immunostaining during murine embryonic development\",\n      \"pmids\": [\"8823356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No loss-of-function experiment to test whether DSC1 is required for keratinization\",\n        \"Cross-reactivity of monoclonal antibody not fully excluded\",\n        \"Regulation of DSC1 expression during differentiation unknown\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of DSC1 as the specific autoantigen in SPD-type IgA pemphigus resolved which desmosomal cadherin is targeted in this blistering disease and demonstrated that pathogenic epitopes are conformation-dependent and surface-exposed.\",\n      \"evidence\": \"Immunofluorescence of patient IgA sera on COS7 cells transfected with DSC1, DSC2, or DSC3\",\n      \"pmids\": [\"9242496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Pathogenic mechanism of IgA binding (desmosome disruption vs. signaling) not determined\",\n        \"Epitope mapping not performed\",\n        \"Animal model of disease not established\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Complete genomic characterization of DSC1 (17 exons, ~33 kb, chromosome 18q12.1) provided the structural framework for mutation screening and regulatory element analysis.\",\n      \"evidence\": \"Genomic sequencing and PCR-based exon mapping\",\n      \"pmids\": [\"11027496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Promoter and regulatory elements not characterized\",\n        \"No disease-causing mutations identified in DSC1 at this time\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that METTL3-dependent m6A modification stabilizes DSC1 mRNA revealed an epitranscriptomic layer of DSC1 regulation and showed that DSC1 overexpression counteracts LPS-induced inflammation and apoptosis in periodontal ligament fibroblasts.\",\n      \"evidence\": \"MeRIP, METTL3 knockdown, DSC1 overexpression rescue in human periodontal ligament fibroblasts\",\n      \"pmids\": [\"41453286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific m6A sites on DSC1 mRNA not mapped\",\n        \"Reader protein mediating m6A-dependent stabilization not identified\",\n        \"Relevance of this regulatory axis to epidermal DSC1 function not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The adhesive mechanism of DSC1 at the molecular level, its binding partners within the desmosomal plaque, and how autoantibody binding leads to epidermal blistering remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of DSC1 homophilic or heterophilic binding interface\",\n        \"Dsc1-knockout phenotype in stratified epithelia not fully characterized\",\n        \"Mechanism by which IgA autoantibodies cause subcorneal pustule formation unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DSG1\", \"ATG101\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"DSC1 (desmocollin-1) is a cadherin-family transmembrane glycoprotein that functions as a calcium-dependent cell–cell adhesion molecule within desmosomes of differentiated and keratinizing epithelial layers [PMID:8486729, PMID:8823356]. DSC1 is the isoform-specific autoantigen in the subcorneal pustular dermatosis (SPD) subtype of IgA pemphigus, where patient IgA autoantibodies bind DSC1 but not DSC2 or DSC3 [PMID:9242496]. During apoptosis, the DSC1 cytoplasmic domain is cleaved by caspases while its extracellular domain is shed by metalloproteinases, contributing to desmosome disassembly and intermediate filament collapse [PMID:11500511]. Within the desmosomal plaque, DSC1 physically interacts with plakophilin-3, and its mRNA stability is regulated by METTL3-mediated m6A modification [PMID:12707304, PMID:41453286].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Molecular cloning of human DSC1 established it as a distinct type 1 desmocollin with differentiation-linked expression, mapping it to chromosome 18 alongside other desmosomal cadherins and defining the gene family framework.\",\n      \"evidence\": \"cDNA cloning, sequence comparison, and somatic cell hybrid chromosomal mapping; community nomenclature consolidation\",\n      \"pmids\": [\"8288219\", \"8486729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional adhesion assay performed at this stage\", \"Regulatory elements controlling differentiation-dependent expression undefined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Developmental expression mapping revealed that DSC1 protein appearance is tightly linked to the onset of keratinization rather than to stratification per se, and that DSC1 is regulated independently of desmoglein-1.\",\n      \"evidence\": \"In situ hybridization and immunofluorescence in mouse embryonic tissues\",\n      \"pmids\": [\"8823356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors driving DSC1 expression during keratinization not identified\", \"Functional consequence of independent DSC1/DSG1 regulation unexplored\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of DSC1 as the specific target of IgA autoantibodies in SPD-type IgA pemphigus revealed that loss of DSC1-mediated adhesion in superficial epidermal layers underlies subcorneal blister formation.\",\n      \"evidence\": \"COS7 transfection with individual DSC isoforms, immunofluorescence with sera from six SPD patients versus seven IEN patients\",\n      \"pmids\": [\"9242496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise epitope(s) on DSC1 recognized by pathogenic IgA not mapped\", \"No passive-transfer or knockout model to confirm pathogenicity of anti-DSC1 antibodies in vivo\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstration that DSC1 is proteolytically processed during apoptosis by both caspases (cytoplasmic domain) and metalloproteinases (extracellular domain) established a mechanism for active desmosome disassembly and intermediate filament collapse during programmed cell death.\",\n      \"evidence\": \"Western blotting during apoptosis induction with caspase and metalloproteinase inhibitors, immunofluorescence\",\n      \"pmids\": [\"11500511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific caspase(s) and metalloproteinase(s) responsible not identified\", \"Cleavage site(s) on DSC1 not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Yeast two-hybrid and co-immunoprecipitation identified plakophilin-3 as a direct binding partner of DSC1a, placing DSC1 within the desmosomal plaque protein interaction network.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization immunofluorescence\",\n      \"pmids\": [\"12707304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface between PKP3 and DSC1 not structurally resolved\", \"Functional consequence of disrupting the DSC1–PKP3 interaction on desmosome integrity not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A report linking DSC1 to autophagic flux via circRAB11FIP1-facilitated interaction with ATG101 suggested a non-canonical role for DSC1 beyond cell adhesion, though this rests on limited mechanistic evidence.\",\n      \"evidence\": \"RNA pulldown, co-immunoprecipitation, overexpression/silencing with autophagy flux assays in ovarian cancer cell lines\",\n      \"pmids\": [\"33637694\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"DSC1–ATG101 interaction not validated by reciprocal Co-IP or in non-cancer cells\", \"Endogenous relevance of DSC1 in autophagy regulation not established\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"METTL3-mediated m6A modification was shown to stabilize DSC1 mRNA, establishing an epitranscriptomic layer of DSC1 regulation with functional consequences for cell survival under inflammatory stress.\",\n      \"evidence\": \"m6A-RIP, qRT-PCR, proliferation/apoptosis assays, siRNA knockdown and overexpression in human periodontal ligament fibroblasts\",\n      \"pmids\": [\"41453286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A reader protein mediating DSC1 mRNA stabilization not identified\", \"Whether m6A regulation of DSC1 operates in epidermal keratinocytes unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of DSC1 homophilic and heterophilic adhesion, the identity of the specific caspase and metalloproteinase cleaving DSC1, whether DSC1 has genuine autophagy-related functions outside cancer cell lines, and the in vivo pathogenic mechanism of anti-DSC1 IgA autoantibodies.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of DSC1 extracellular domain available\", \"In vivo loss-of-function phenotype (knockout mouse) not reported in the timeline\", \"Pathogenic mechanism of anti-DSC1 IgA in SPD not directly demonstrated in animal models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"desmosome\"\n    ],\n    \"partners\": [\n      \"PKP3\",\n      \"ATG101\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}