{"gene":"PPL","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":1997,"finding":"Periplakin (PPL) was identified as a novel 195 kDa member of the plakin family of cytolinker proteins that becomes incorporated into the cornified envelope of epidermal keratinocytes. It is expressed in keratinizing and non-keratinizing stratified squamous epithelia, associates with desmosomal plaques and keratin filaments in differentiated epidermis, and co-immunoprecipitates with envoplakin. Confocal microscopy revealed that envoplakin and periplakin form a network radiating from desmosomes, suggesting they provide a scaffolding for cornified envelope assembly.","method":"cDNA sequencing, immunogold electron microscopy, co-immunoprecipitation, confocal immunofluorescence microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, immunogold EM, confocal) in a single rigorous study establishing identity, localization and binding partner","pmids":["9412476"],"is_preprint":false},{"year":2002,"finding":"Periplakin is established as a member of the plakin family of cytolinker proteins that connect cytoskeletal elements (microfilaments, microtubules, intermediate filaments) to each other and to junctional complexes including desmosomes and cell-adhesion molecules, and participates in domain-based interactions with armadillo family members. Dysfunction of plakin family members including periplakin is involved in inherited and autoimmune diseases affecting skin, neuronal tissue, and muscle.","method":"Review synthesizing domain interaction data and genetic/disease evidence","journal":"Trends in cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — review consolidating multiple experimental findings on plakin domain architecture and interactions","pmids":["11854008"],"is_preprint":false},{"year":1999,"finding":"Periplakin was identified as one of the plakin family members (together with desmoplakin, BPAG1, envoplakin, and plectin) targeted by autoantibodies in paraneoplastic pemphigus (PNP), establishing it as a cytoplasmic structural component recognized in autoimmune disease.","method":"Immunoprecipitation and autoantibody profiling in PNP patient sera","journal":"Journal of dermatological science","confidence":"Medium","confidence_rationale":"Tier 3 — single immunological method identifying PPL as autoimmune target in disease context","pmids":["10379702"],"is_preprint":false},{"year":2003,"finding":"Periplakin was identified as a component of the EPPD complex (ezrin, periplakin, periaxin, desmoyokin) in lens fiber cell cortex adhaerens junctions, where it participates together with moesin, spectrin(s) and plectin in a distinct junctional plaque ensemble on the long sides of lens fiber hexagons, separate from the cadherin-catenin complex.","method":"Biochemical fractionation, immunoprecipitation, immunolocalization microscopy across multiple species (cow, pig, rat)","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus immunolocalization across multiple species establishing complex membership and subcellular localization","pmids":["14625392"],"is_preprint":false},{"year":2015,"finding":"Periplakin interacts with the cytoplasmic tail of BTN3A1 at a membrane-proximal di-leucine motif proximal to the B30.2 domain, an interaction identified by yeast two-hybrid and confirmed functionally. Re-expression of wild-type BTN3A1 but not a periplakin-binding-deficient variant (BTN3A1Δexon5) into a BTN3A1 knockdown line restored γδ T cell responses, demonstrating that periplakin interaction is required for BTN3A1-mediated phosphoantigen presentation and Vγ9/Vδ2 T cell activation, thereby linking the cytoskeleton to innate immune surveillance.","method":"Yeast two-hybrid, knockdown cell lines, re-expression rescue assays, co-culture γδ T cell activation assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid interaction validated by functional rescue with deletion mutant, establishing mechanistic role for PPL in BTN3A1-mediated T cell activation","pmids":["25637025"],"is_preprint":false}],"current_model":"Periplakin (PPL) is a plakin-family cytolinker protein that localizes to desmosomes and cornified envelopes in stratified squamous epithelia, where it forms heterodimers with envoplakin to scaffold cornified envelope assembly; it also participates in the EPPD junctional complex of lens fiber cells, and its interaction with the di-leucine motif in the BTN3A1 cytoplasmic tail is required for phosphoantigen-dependent activation of human Vγ9/Vδ2 γδ T cells, linking the cytoskeleton to innate immune surveillance."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of periplakin as a plakin-family protein that co-immunoprecipitates with envoplakin and localizes to desmosomes in differentiated epidermis established it as a structural scaffold for cornified envelope assembly.","evidence":"cDNA cloning, co-immunoprecipitation, immunogold EM, and confocal microscopy in human keratinocytes","pmids":["9412476"],"confidence":"High","gaps":["No knockout or loss-of-function data to assess essentiality for cornified envelope integrity","Stoichiometry and direct binding surfaces of the envoplakin–periplakin heterodimer unresolved","No structural model for periplakin domain architecture"]},{"year":1999,"claim":"Recognition of periplakin as an autoantigen in paraneoplastic pemphigus linked it to an autoimmune blistering disease targeting desmosomal components.","evidence":"Immunoprecipitation and autoantibody profiling of PNP patient sera","pmids":["10379702"],"confidence":"Medium","gaps":["Single immunological method without demonstration of pathogenic role for anti-periplakin antibodies specifically","Whether anti-periplakin autoantibodies are causative or bystander is unknown"]},{"year":2003,"claim":"Discovery of periplakin within the EPPD complex at lens fiber cell junctions extended its role beyond keratinizing epithelia, revealing participation in a specialized junctional plaque distinct from the classical cadherin–catenin complex.","evidence":"Reciprocal co-immunoprecipitation and immunolocalization across bovine, porcine, and rat lens tissue","pmids":["14625392"],"confidence":"High","gaps":["Functional consequence of periplakin loss on lens fiber cell architecture not tested","Molecular basis of periplakin interaction with periaxin and desmoyokin within the EPPD complex undefined"]},{"year":2015,"claim":"Demonstration that periplakin binds the cytoplasmic di-leucine motif of BTN3A1 and that this interaction is required for phosphoantigen-dependent Vγ9/Vδ2 γδ T cell activation revealed an unexpected role for a structural cytolinker in innate immune sensing.","evidence":"Yeast two-hybrid screen, BTN3A1-knockdown and rescue with wild-type versus periplakin-binding-deficient BTN3A1, co-culture γδ T cell activation assays","pmids":["25637025"],"confidence":"High","gaps":["Mechanism by which periplakin facilitates BTN3A1-mediated antigen presentation (e.g., clustering, trafficking, cytoskeletal anchoring) not elucidated","Whether periplakin knockdown alone abrogates γδ T cell activation not directly shown","Structural basis of the periplakin–BTN3A1 interaction unresolved"]},{"year":null,"claim":"A unifying model of how periplakin's cytolinker and immune functions are coordinated — and whether periplakin is essential in vivo for either epithelial integrity or γδ T cell immunity — remains to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No periplakin-knockout animal phenotype reported in this literature","No high-resolution structure of periplakin or its complexes","Potential redundancy with envoplakin or other plakins not addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]}],"complexes":["EPPD complex"],"partners":["EVPL","BTN3A1","PRX","EZR","AHNAK"],"other_free_text":[]},"mechanistic_narrative":"Periplakin is a plakin-family cytolinker protein that localizes to desmosomes and the cornified envelope of stratified squamous epithelia, where it heterodimerizes with envoplakin to scaffold cornified envelope assembly and bridges keratin intermediate filaments to junctional complexes [PMID:9412476]. Beyond epithelia, periplakin is a component of the EPPD complex (ezrin, periplakin, periaxin, desmoyokin) at cortex adhaerens junctions of lens fiber cells, contributing to a junctional plaque distinct from the cadherin–catenin complex [PMID:14625392]. Periplakin also interacts with the cytoplasmic di-leucine motif of BTN3A1, and this interaction is required for phosphoantigen-dependent activation of Vγ9/Vδ2 γδ T cells, linking the cytoskeleton to innate immune surveillance [PMID:25637025]. Periplakin is a target of autoantibodies in paraneoplastic pemphigus [PMID:10379702]."},"prefetch_data":{"uniprot":{"accession":"O60437","full_name":"Periplakin","aliases":["190 kDa paraneoplastic pemphigus antigen","195 kDa cornified envelope precursor protein"],"length_aa":1756,"mass_kda":204.7,"function":"Component of the cornified envelope of keratinocytes. May link the cornified envelope to desmosomes and intermediate filaments. May act as a localization signal in PKB/AKT-mediated signaling","subcellular_location":"Cell junction, desmosome; Cytoplasm, cytoskeleton; Cell membrane; Lateral cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O60437/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPL","classification":"Not Classified","n_dependent_lines":47,"n_total_lines":1208,"dependency_fraction":0.03890728476821192},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PPL","total_profiled":1310},"omim":[{"mim_id":"618301","title":"KAZRIN, PERIPLAKIN-INTERACTING PROTEIN; KAZN","url":"https://www.omim.org/entry/618301"},{"mim_id":"611579","title":"TRANSMEMBRANE PROTEIN 114; TMEM114","url":"https://www.omim.org/entry/611579"},{"mim_id":"610836","title":"AUTISM, SUSCEPTIBILITY TO, 11; AUTS11","url":"https://www.omim.org/entry/610836"},{"mim_id":"609771","title":"UBINUCLEIN 1; UBN1","url":"https://www.omim.org/entry/609771"},{"mim_id":"608833","title":"REGULATOR OF TELOMERE ELONGATION HELICASE 1; RTEL1","url":"https://www.omim.org/entry/608833"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"},{"location":"Basal body","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Uncertain"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":218.4},{"tissue":"esophagus","ntpm":697.4},{"tissue":"vagina","ntpm":274.1}],"url":"https://www.proteinatlas.org/search/PPL"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O60437","domains":[{"cath_id":"1.20.58.60","chopping":"23-131","consensus_level":"medium","plddt":82.8993,"start":23,"end":131},{"cath_id":"1.20.58.60","chopping":"138-185_195-294","consensus_level":"medium","plddt":88.3436,"start":138,"end":294},{"cath_id":"3.30.160.780","chopping":"1651-1754","consensus_level":"high","plddt":75.7811,"start":1651,"end":1754},{"cath_id":"1.10.287","chopping":"946-985_1006-1045_1086-1126","consensus_level":"medium","plddt":74.8488,"start":946,"end":1126},{"cath_id":"1.10.287","chopping":"1186-1223_1244-1282","consensus_level":"high","plddt":82.5814,"start":1186,"end":1282}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60437","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60437-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60437-F1-predicted_aligned_error_v6.png","plddt_mean":75.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPL","jax_strain_url":"https://www.jax.org/strain/search?query=PPL"},"sequence":{"accession":"O60437","fasta_url":"https://rest.uniprot.org/uniprotkb/O60437.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60437/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60437"}},"corpus_meta":[{"pmid":"31986282","id":"PMC_31986282","title":"Immobilization 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/11854008","citation_count":251,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15231748","id":"PMC_15231748","title":"Functional proteomics mapping of a human signaling pathway.","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15231748","citation_count":247,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19199708","id":"PMC_19199708","title":"Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).","date":"2009","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/19199708","citation_count":237,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23314748","id":"PMC_23314748","title":"Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes?","date":"2013","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/23314748","citation_count":213,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9412476","id":"PMC_9412476","title":"Periplakin, a novel component of cornified envelopes and desmosomes that belongs to the plakin family and forms complexes with envoplakin.","date":"1997","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9412476","citation_count":179,"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":"9628581","id":"PMC_9628581","title":"Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.","date":"1998","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/9628581","citation_count":156,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10379702","id":"PMC_10379702","title":"Autoimmunity against desmosomal cadherins in pemphigus.","date":"1999","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/10379702","citation_count":135,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25637025","id":"PMC_25637025","title":"Activation of human γδ T cells by cytosolic interactions of BTN3A1 with soluble phosphoantigens and the cytoskeletal adaptor periplakin.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25637025","citation_count":126,"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":"14625392","id":"PMC_14625392","title":"A novel cell-cell junction system: the cortex adhaerens mosaic of lens fiber cells.","date":"2003","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/14625392","citation_count":101,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16508,"output_tokens":403,"usd":0.027785},"stage2":{"model":"","input_tokens":0,"output_tokens":0,"usd":0.0},"total_usd":0.176195,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":29395,"output_tokens":1422,"usd":0.054758},"round2_rules_fired":"R1","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4897,"output_tokens":1518,"usd":0.093652}},"stage1_raw":"Looking at the corpus, I need to identify the human/mammalian gene PPL. Based on the preponderance of the corpus (paper 21 mentions PPL in context of epithelial cell structure, adhesion, and differentiation in HNSCC; paper 27 mentions PPL in context of endometrial maturation), PPL in the human context refers to Periplakin, a cornified envelope precursor protein involved in epithelial structure.\n\nHowever, reviewing all 34 papers carefully:\n- Papers 1-2: Porcine pancreatic lipase (PPL) — symbol collision, not the human gene\n- Paper 3: Legionella pneumophila Ppl — bacterial gene, not ortholog\n- Papers 4-6: Various PPL acronyms/proteins — collisions\n- Papers 7, 18-19: PPL-101/103/138 = drug compound names, not the gene\n- Paper 9: PPL Therapeutics company name\n- Papers 10-14, 16-17, 20-29: Various unrelated uses of \"PPL\"\n- Paper 21: Mentions PPL (Periplakin) protein in HNSCC tissue — expression study only, no mechanism\n- Paper 22: E. coli Ppl defense system — bacterial gene, symbol collision\n- Paper 27: PPL mentioned as a gene in preeclampsia context — computational/transcriptomic, no mechanism\n\nNone of the papers in this corpus describe mechanistic experiments on the human PPL (Periplakin) gene. The papers either describe symbol collisions or purely expression-based findings.\n\n```json\n{\n  \"discoveries\": [],\n  \"current_model\": \"No mechanistic findings in the available literature.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Periplakin (PPL) was identified as a novel 195 kDa member of the plakin family of cytolinker proteins that becomes incorporated into the cornified envelope of epidermal keratinocytes. It is expressed in keratinizing and non-keratinizing stratified squamous epithelia, associates with desmosomal plaques and keratin filaments in differentiated epidermis, and co-immunoprecipitates with envoplakin. Confocal microscopy revealed that envoplakin and periplakin form a network radiating from desmosomes, suggesting they provide a scaffolding for cornified envelope assembly.\",\n      \"method\": \"cDNA sequencing, immunogold electron microscopy, co-immunoprecipitation, confocal immunofluorescence microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, immunogold EM, confocal) in a single rigorous study establishing identity, localization and binding partner\",\n      \"pmids\": [\"9412476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Periplakin is established as a member of the plakin family of cytolinker proteins that connect cytoskeletal elements (microfilaments, microtubules, intermediate filaments) to each other and to junctional complexes including desmosomes and cell-adhesion molecules, and participates in domain-based interactions with armadillo family members. Dysfunction of plakin family members including periplakin is involved in inherited and autoimmune diseases affecting skin, neuronal tissue, and muscle.\",\n      \"method\": \"Review synthesizing domain interaction data and genetic/disease evidence\",\n      \"journal\": \"Trends in cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review consolidating multiple experimental findings on plakin domain architecture and interactions\",\n      \"pmids\": [\"11854008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Periplakin was identified as one of the plakin family members (together with desmoplakin, BPAG1, envoplakin, and plectin) targeted by autoantibodies in paraneoplastic pemphigus (PNP), establishing it as a cytoplasmic structural component recognized in autoimmune disease.\",\n      \"method\": \"Immunoprecipitation and autoantibody profiling in PNP patient sera\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single immunological method identifying PPL as autoimmune target in disease context\",\n      \"pmids\": [\"10379702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Periplakin was identified as a component of the EPPD complex (ezrin, periplakin, periaxin, desmoyokin) in lens fiber cell cortex adhaerens junctions, where it participates together with moesin, spectrin(s) and plectin in a distinct junctional plaque ensemble on the long sides of lens fiber hexagons, separate from the cadherin-catenin complex.\",\n      \"method\": \"Biochemical fractionation, immunoprecipitation, immunolocalization microscopy across multiple species (cow, pig, rat)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus immunolocalization across multiple species establishing complex membership and subcellular localization\",\n      \"pmids\": [\"14625392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Periplakin interacts with the cytoplasmic tail of BTN3A1 at a membrane-proximal di-leucine motif proximal to the B30.2 domain, an interaction identified by yeast two-hybrid and confirmed functionally. Re-expression of wild-type BTN3A1 but not a periplakin-binding-deficient variant (BTN3A1Δexon5) into a BTN3A1 knockdown line restored γδ T cell responses, demonstrating that periplakin interaction is required for BTN3A1-mediated phosphoantigen presentation and Vγ9/Vδ2 T cell activation, thereby linking the cytoskeleton to innate immune surveillance.\",\n      \"method\": \"Yeast two-hybrid, knockdown cell lines, re-expression rescue assays, co-culture γδ T cell activation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid interaction validated by functional rescue with deletion mutant, establishing mechanistic role for PPL in BTN3A1-mediated T cell activation\",\n      \"pmids\": [\"25637025\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Periplakin (PPL) is a plakin-family cytolinker protein that localizes to desmosomes and cornified envelopes in stratified squamous epithelia, where it forms heterodimers with envoplakin to scaffold cornified envelope assembly; it also participates in the EPPD junctional complex of lens fiber cells, and its interaction with the di-leucine motif in the BTN3A1 cytoplasmic tail is required for phosphoantigen-dependent activation of human Vγ9/Vδ2 γδ T cells, linking the cytoskeleton to innate immune surveillance.\"\n}\n```","stage2_raw":"\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Periplakin is a plakin-family cytolinker protein that localizes to desmosomes and the cornified envelope of stratified squamous epithelia, where it heterodimerizes with envoplakin to scaffold cornified envelope assembly and bridges keratin intermediate filaments to junctional complexes [PMID:9412476]. Beyond epithelia, periplakin is a component of the EPPD complex (ezrin, periplakin, periaxin, desmoyokin) at cortex adhaerens junctions of lens fiber cells, contributing to a junctional plaque distinct from the cadherin–catenin complex [PMID:14625392]. Periplakin also interacts with the cytoplasmic di-leucine motif of BTN3A1, and this interaction is required for phosphoantigen-dependent activation of Vγ9/Vδ2 γδ T cells, linking the cytoskeleton to innate immune surveillance [PMID:25637025]. Periplakin is a target of autoantibodies in paraneoplastic pemphigus [PMID:10379702].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of periplakin as a plakin-family protein that co-immunoprecipitates with envoplakin and localizes to desmosomes in differentiated epidermis established it as a structural scaffold for cornified envelope assembly.\",\n      \"evidence\": \"cDNA cloning, co-immunoprecipitation, immunogold EM, and confocal microscopy in human keratinocytes\",\n      \"pmids\": [\"9412476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No knockout or loss-of-function data to assess essentiality for cornified envelope integrity\",\n        \"Stoichiometry and direct binding surfaces of the envoplakin–periplakin heterodimer unresolved\",\n        \"No structural model for periplakin domain architecture\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Recognition of periplakin as an autoantigen in paraneoplastic pemphigus linked it to an autoimmune blistering disease targeting desmosomal components.\",\n      \"evidence\": \"Immunoprecipitation and autoantibody profiling of PNP patient sera\",\n      \"pmids\": [\"10379702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single immunological method without demonstration of pathogenic role for anti-periplakin antibodies specifically\",\n        \"Whether anti-periplakin autoantibodies are causative or bystander is unknown\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery of periplakin within the EPPD complex at lens fiber cell junctions extended its role beyond keratinizing epithelia, revealing participation in a specialized junctional plaque distinct from the classical cadherin–catenin complex.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation and immunolocalization across bovine, porcine, and rat lens tissue\",\n      \"pmids\": [\"14625392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of periplakin loss on lens fiber cell architecture not tested\",\n        \"Molecular basis of periplakin interaction with periaxin and desmoyokin within the EPPD complex undefined\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstration that periplakin binds the cytoplasmic di-leucine motif of BTN3A1 and that this interaction is required for phosphoantigen-dependent Vγ9/Vδ2 γδ T cell activation revealed an unexpected role for a structural cytolinker in innate immune sensing.\",\n      \"evidence\": \"Yeast two-hybrid screen, BTN3A1-knockdown and rescue with wild-type versus periplakin-binding-deficient BTN3A1, co-culture γδ T cell activation assays\",\n      \"pmids\": [\"25637025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which periplakin facilitates BTN3A1-mediated antigen presentation (e.g., clustering, trafficking, cytoskeletal anchoring) not elucidated\",\n        \"Whether periplakin knockdown alone abrogates γδ T cell activation not directly shown\",\n        \"Structural basis of the periplakin–BTN3A1 interaction unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying model of how periplakin's cytolinker and immune functions are coordinated — and whether periplakin is essential in vivo for either epithelial integrity or γδ T cell immunity — remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No periplakin-knockout animal phenotype reported in this literature\",\n        \"No high-resolution structure of periplakin or its complexes\",\n        \"Potential redundancy with envoplakin or other plakins not addressed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"EPPD complex\"\n    ],\n    \"partners\": [\n      \"EVPL\",\n      \"BTN3A1\",\n      \"PRX\",\n      \"EZR\",\n      \"AHNAK\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}