{"gene":"PLEC","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1996,"finding":"Homozygous deletion mutations in PLEC1 abolish plectin expression at hemidesmosomes, demonstrated by negative immunofluorescence with anti-plectin antibody (HD-1), establishing that plectin is required for binding of the intermediate keratin filament network to hemidesmosomal complexes in basal keratinocytes and for structural integrity of muscle (sarcolemmal localization).","method":"Immunofluorescence, mutation analysis (homozygous deletion identification), electron microscopy of patient skin","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mutations with defined cellular phenotype (absent plectin at hemidesmosomes, keratin filament detachment), replicated across two independent patient families","pmids":["8894687"],"is_preprint":false},{"year":1996,"finding":"A homozygous nonsense mutation in PLEC1 leads to a premature stop codon, decay of aberrant plectin mRNA, and absence of plectin protein; in skin this causes failure of keratin filaments to connect to the plasma membrane via hemidesmosomes, while in muscle it correlates with aberrant localization of desmin in muscle fibers, establishing plectin as necessary for desmin intermediate filament organization in muscle.","method":"Mutation identification (nonsense mutation), immunofluorescence of skin and muscle, mRNA analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined molecular phenotypes in two tissues (skin hemidesmosome attachment, muscle desmin localization), independent replication of plectin's anchoring role","pmids":["8941634"],"is_preprint":false},{"year":2010,"finding":"A homozygous mutation in exon 1f of PLEC, specific to the plectin isoform 1f, abolishes sarcolemmal plectin staining and causes ultrastructural abnormalities (membrane duplications, enlarged space between membrane and sarcomere, Z-disk misalignment) in skeletal muscle without skin involvement, establishing that plectin isoform 1f specifically links the sarcolemma to the sarcomere in skeletal muscle.","method":"Homozygosity mapping, DNA sequencing, transmission electron microscopy, immunofluorescence of patient muscle","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific loss-of-function with defined ultrastructural phenotype and localization data, replicated in three independent families","pmids":["21109228"],"is_preprint":false},{"year":2015,"finding":"A homozygous nonsense mutation in exon 1a of PLEC, specific to plectin isoform 1a (P1a), causes skin-only EBS with hypoplastic hemidesmosomes and intra-epidermal cleavage without cardiomyopathy or muscle dystrophy, establishing that P1a is the dominant plectin isoform in epidermal basal cells and cultured keratinocytes, and that its loss specifically disrupts hemidesmosome structure in skin while sparing other tissues.","method":"DNA sequencing, immunofluorescence antigen mapping, transmission electron microscopy, western blot, qRT-PCR on patient skin and cultured keratinocytes","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific loss-of-function with multiple orthogonal methods (EM, IF, western blot, qRT-PCR) establishing tissue-specific isoform function","pmids":["25712130"],"is_preprint":false},{"year":2021,"finding":"Plectin (PLEC) physically interacts with KRT8 (keratin 8) at mitochondria; PLEC anchors mitochondria and KRT8 facilitates mitochondrial fission-mediated mitophagy through this interaction. KRT8 phosphorylation under oxidative stress reduces the PLEC-anchored mitochondria–KRT8 association, modulating mitophagy flux and protecting retinal pigment epithelial cells from necrotic cell death.","method":"Co-immunoprecipitation (physical interaction between KRT8 and PLEC), live-cell imaging, mitophagy flux assays, mitochondrial morphology analysis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction identified, functional mitophagy assays performed, single lab with multiple orthogonal methods","pmids":["33783309"],"is_preprint":false},{"year":2024,"finding":"PLEC competitively interacts with KEAP1, displacing NRF2 from the KEAP1-NRF2 complex and allowing NRF2 translocation from the cytosol to the nucleus where it activates antioxidant gene expression. ΔNP63α directly transactivates PLEC expression, and radiotherapy-induced ROS activates ΔNP63α via NRF2, forming a ΔNp63α/PLEC/NRF2 feedback loop that promotes radioresistance in esophageal squamous cell carcinoma.","method":"Transcriptional reporter assays, co-immunoprecipitation (PLEC-KEAP1 interaction), subcellular fractionation (NRF2 nuclear translocation), knockdown/overexpression with functional readouts (ROS levels, radiosensitivity in nude mice)","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive binding (Co-IP), subcellular localization with functional consequence, in vivo validation, single lab","pmids":["39500864"],"is_preprint":false},{"year":2005,"finding":"PLEC1 mutations (nonsense and splice-site) cause absent or markedly attenuated plectin expression and EBS with pyloric atresia; an exon-trapping experiment demonstrated that a splice-site mutation induces aberrant splicing of PLEC1, establishing this as a mechanism of loss-of-function.","method":"Immunohistochemistry, DNA sequencing, exon-trapping experiment for splice-site mutation functional validation","journal":"The Journal of molecular diagnostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — exon-trapping directly demonstrates aberrant splicing as mechanism; single lab with functional validation","pmids":["15681471"],"is_preprint":false},{"year":2007,"finding":"5' trans-splicing (SMaRT) of the PLEC1 transcript in EBS-MD fibroblasts carrying a dominant-negative leucine insertion in exon 9 reduced mutant mRNA levels and restored wild-type plectin expression pattern by immunofluorescence; retroviral delivery increased full-length plectin protein by 58.7%, demonstrating that mRNA-level correction restores plectin protein function.","method":"Spliceosome-mediated RNA trans-splicing, transient and retroviral transfection of patient fibroblasts, immunofluorescence, protein quantification","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiment in patient cells with protein-level validation, single lab","pmids":["17989727"],"is_preprint":false},{"year":2022,"finding":"Gentamicin treatment suppressed PLEC1 premature termination codons in EBS-MD primary keratinocytes, inducing plectin expression in skin (detected by immunofluorescence) for at least 5 months post-treatment, demonstrating translational readthrough as a mechanism to restore plectin protein from nonsense variants.","method":"Translational readthrough (gentamicin treatment), immunofluorescence of patient skin before and after treatment","journal":"JAMA dermatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient case report, single method (immunofluorescence), limited controls","pmids":["35234827"],"is_preprint":false},{"year":2023,"finding":"Plectin knockdown in cochlear hair cells (zebrafish model) resulted in reduction of synaptic mitochondrial potential and loss of ribbon synapses, establishing a role for plectin in maintaining mitochondrial function and synaptic structure at inner ear ribbon synapses relevant to neuronal transmission.","method":"Plectin knockdown in zebrafish inner ear model, immunofluorescence for ribbon synapses, mitochondrial membrane potential assay","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in model organism with specific cellular phenotypes (ribbon synapse loss, mitochondrial potential reduction), single lab","pmids":["37393735"],"is_preprint":false},{"year":2020,"finding":"CRISPR/Cas9 knockdown of plectin in a mesenchymal stem cell line followed by RNA-sequencing revealed that plectin regulates Wnt signalling, glycosaminoglycan biosynthesis, and immune regulation pathways, placing plectin upstream of these pathways in chondrocyte-relevant cells.","method":"CRISPR/Cas9 knockdown, RNA-sequencing pathway analysis","journal":"Osteoarthritis and cartilage","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement based on transcriptomics after knockdown, no direct biochemical mechanism established, single lab single method","pmids":["32580029"],"is_preprint":false},{"year":2025,"finding":"In plectin-deficient (Plec-/-) myoblasts and muscle-specific conditional plectin knockout (MCK-Cre/cKO) mice, autophagic flux is impaired: autophagosome turnover is reduced (~40% reduction in LC3B red:green ratio), degradative vacuoles and LC3/SQSTM1-positive patches accumulate, and lysosomal/autophagic compartment signal intensities are reduced. Protein levels of LAMP2, BAG3, and SQSTM1 are elevated in knockout muscle lysates. Chloroquine treatment in vivo confirmed impaired autophagic clearance in plectin-deficient muscle.","method":"mCherry-EGFP-LC3B autophagy flux reporter, immunofluorescence and electron microscopy, immunoblotting, RNA-seq, CYTO-ID/LYSO-ID dyes, chloroquine treatment in vivo in MCK-Cre/cKO mice","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in cells and in vivo, preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"Plectin knockout (Plec-/-) fibroblasts are ~2-fold softer than wild-type, show faster viscoelastic stress relaxation, faster actin turnover (3-fold by FRAP), and altered vimentin network architecture (from fine meshwork to bundled network). This establishes plectin as a regulator of cytoskeletal organization and viscoelastic properties by crosslinking actin and vimentin intermediate filaments.","method":"Single-cell compression measurements, FRAP, confocal imaging of vimentin network in Plec+/+ vs Plec-/- fibroblasts","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct comparison of KO vs WT with multiple orthogonal biophysical methods, preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"Plectin localizes to focal adhesions (FAs) in mouse astrocytes, where it regulates FA number, maturation, turnover, and mobility of FA components. Plectin polarizes within FAs depending on maturation state and controls recruitment of vimentin to FAs. In plectin-deficient astrocytes, the vimentin network shows impaired connectivity and altered viscoelastic properties. In a reactive astrogliosis model, FA number and size increase alongside elevated plectin expression.","method":"Live imaging, immunofluorescence, FRAP, plectin-deficient astrocyte model (localization and functional consequence)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization tied to functional consequences (FA dynamics, vimentin recruitment), multiple methods, preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"Plectin cytolinkers bridge keratin 5/14 intermediate filaments and microtubules to mechanically control the 3D perinuclear positioning of melanin pigment organelles in human keratinocytes, and this positioning is required for DNA photoprotection.","method":"Microrheology, confocal imaging in human disease-related keratinocyte models with plectin disruption, functional readout of DNA photodamage","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, mechanistic link between plectin bridging and organelle positioning supported by imaging but limited direct biochemical evidence","pmids":[],"is_preprint":true},{"year":2024,"finding":"Following actin filament disassembly (cytochalasin D treatment), localized increase of vimentin assembly in the mid-cytoplasm is dependent on the cytolinker plectin, establishing plectin as a mediator of cytoskeletal crosstalk between actin and vimentin networks.","method":"Pharmacological disruption of actin (cytochalasin D), vimentin imaging, plectin-dependent vimentin response assessment","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, indirect evidence of plectin-mediated crosstalk from pharmacological experiments without direct plectin KO controls described in abstract","pmids":[],"is_preprint":true},{"year":2024,"finding":"Genetic or pharmacological inactivation of plectin in autochthonous and orthotopic mouse HCC models suppresses tumor initiation and growth, inhibits invasion and lung metastasis of human HCC cells. Proteomic and phosphoproteomic profiling linked plectin-dependent cytoskeletal disruption to attenuation of FAK, MAPK/Erk, and PI3K/AKT oncogenic signaling, placing plectin upstream of these pathways in hepatocellular carcinoma mechanosensitive signaling.","method":"Genetic knockout and pharmacological inhibition (plecstatin-1) in mouse HCC models, proteomic and phosphoproteomic profiling, invasion and metastasis assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (genetic KO, pharmacological inhibition, proteomics) in cell lines and in vivo models, preprint, single lab","pmids":[],"is_preprint":true},{"year":2022,"finding":"Immunostaining of liver samples from patients with PLEC-related infantile cholestasis revealed scattered cytoplasmic plectin signals in hepatocytes and reduced colocalization of plectin with cytokeratin 8, establishing that plectin normally co-localizes with cytokeratin 8 intermediate filaments in hepatocytes and that disruption of this colocalization is associated with cholestatic disease.","method":"Immunofluorescence staining of patient liver biopsy, trio exome sequencing","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — patient tissue immunofluorescence showing disrupted colocalization, no functional rescue or in vitro mechanistic experiments","pmids":["39168815"],"is_preprint":false}],"current_model":"Plectin (PLEC) is a giant cytoskeletal crosslinker protein that anchors intermediate filaments (keratins in skin, desmin and vimentin in muscle and other cells) to hemidesmosomal complexes and the plasma membrane/sarcolemma; different tissue-specific isoforms (e.g., 1a in epidermis, 1f in skeletal muscle) serve distinct structural roles, and plectin additionally regulates focal adhesion dynamics, autophagic flux, mitochondrial anchoring (via KRT8 interaction), cytoskeletal viscoelasticity, and oncogenic signaling (FAK/MAPK/PI3K-AKT) by crosslinking actin, vimentin, and keratin filament networks, with loss-of-function causing tissue-specific fragility diseases (epidermolysis bullosa simplex, muscular dystrophy, cardiomyopathy, and hearing loss)."},"narrative":{"mechanistic_narrative":"Plectin (PLEC) is a giant cytoskeletal crosslinker that anchors intermediate filament networks to membrane junctions and integrates the actin, vimentin, keratin, and microtubule cytoskeletons to maintain tissue mechanical integrity [PMID:8894687]. In basal keratinocytes it tethers the keratin filament network to hemidesmosomal complexes, and in muscle it organizes the desmin intermediate filament network and links the sarcolemma to the sarcomere, with these functions partitioned across tissue-specific N-terminal isoforms—isoform 1a being dominant in epidermis and isoform 1f in skeletal muscle [PMID:8941634, PMID:21109228, PMID:25712130]. Loss-of-function mutations in PLEC cause tissue-specific fragility disease, including epidermolysis bullosa simplex with muscular dystrophy and EBS with pyloric atresia, and the underlying nonsense and splice-site lesions act by abolishing or attenuating plectin protein [PMID:8894687, PMID:15681471]. As a mechanical organizer, plectin sets cytoskeletal viscoelasticity and actin/vimentin turnover, localizes to focal adhesions where it controls their maturation and recruits vimentin, and bridges keratin filaments and microtubules to position pigment organelles. Beyond its structural role, plectin anchors mitochondria through interaction with keratin 8 (KRT8) to modulate mitophagy [PMID:33783309], supports autophagic flux in muscle, and in cancer contexts feeds mechanosensitive oncogenic signaling and antioxidant responses, displacing NRF2 from KEAP1 and acting upstream of FAK/MAPK/PI3K-AKT signaling [PMID:39500864].","teleology":[{"year":1996,"claim":"Established plectin as the molecular link required to attach the keratin intermediate filament network to hemidesmosomes and to maintain muscle structural integrity, defining its core anchoring function.","evidence":"Homozygous deletion/nonsense mutations with absent plectin by immunofluorescence and EM in patient skin and muscle, showing keratin detachment and aberrant desmin localization","pmids":["8894687","8941634"],"confidence":"High","gaps":["Did not resolve the binding domains mediating keratin/desmin attachment","Did not address which plectin isoforms operate in each tissue"]},{"year":2005,"claim":"Defined splice-site mutation as a loss-of-function mechanism and extended the disease spectrum to EBS with pyloric atresia.","evidence":"Exon-trapping demonstration of aberrant PLEC1 splicing plus immunohistochemistry on patient tissue","pmids":["15681471"],"confidence":"Medium","gaps":["No quantitative measure of residual protein function","Mechanism of pyloric atresia phenotype not established"]},{"year":2007,"claim":"Showed that mRNA-level correction restores functional plectin, providing proof-of-concept for therapeutic rescue of dominant-negative alleles.","evidence":"Spliceosome-mediated RNA trans-splicing in EBS-MD patient fibroblasts with protein quantification and immunofluorescence","pmids":["17989727"],"confidence":"Medium","gaps":["58.7% protein restoration efficiency limits in vivo applicability","No demonstration of restored mechanical/structural function"]},{"year":2010,"claim":"Resolved how tissue-specific phenotypes arise by showing isoform 1f selectively links the sarcolemma to the sarcomere in skeletal muscle without skin involvement.","evidence":"Isoform-specific exon 1f mutation with TEM ultrastructural defects and immunofluorescence in patient muscle across three families","pmids":["21109228"],"confidence":"High","gaps":["Did not define the sarcomeric binding partner of P1f","Cardiac involvement not addressed"]},{"year":2015,"claim":"Confirmed isoform partitioning by showing isoform 1a is the dominant epidermal isoform whose loss produces skin-only EBS, sparing muscle and heart.","evidence":"Isoform-specific exon 1a nonsense mutation analyzed by EM, immunofluorescence, western blot, and qRT-PCR in patient skin and cultured keratinocytes","pmids":["25712130"],"confidence":"High","gaps":["Did not establish redundancy among non-dominant isoforms in skin","Hemidesmosome assembly mechanism downstream of P1a not detailed"]},{"year":2021,"claim":"Extended plectin function beyond filament anchoring by showing it physically tethers mitochondria via KRT8 to modulate fission-mediated mitophagy.","evidence":"Reciprocal co-immunoprecipitation of PLEC-KRT8, live imaging, and mitophagy flux assays in retinal pigment epithelial cells","pmids":["33783309"],"confidence":"Medium","gaps":["Single lab, RPE-specific context","Direct binding interface between PLEC and KRT8 not mapped"]},{"year":2023,"claim":"Implicated plectin in inner ear function by linking it to mitochondrial potential and ribbon synapse maintenance, broadening its role to neuronal/sensory tissue.","evidence":"Plectin knockdown in zebrafish cochlear hair cells with ribbon synapse immunofluorescence and mitochondrial membrane potential assays","pmids":["37393735"],"confidence":"Medium","gaps":["Knockdown rather than clean knockout","Mechanism connecting plectin to mitochondrial potential at synapses unresolved"]},{"year":2024,"claim":"Placed plectin in oncogenic and antioxidant signaling by showing it competitively binds KEAP1 to release NRF2 within a ΔNp63α/PLEC/NRF2 radioresistance loop.","evidence":"Co-IP of PLEC-KEAP1, subcellular fractionation for NRF2 translocation, reporter assays, and radiosensitivity readouts in nude mice for esophageal squamous cell carcinoma","pmids":["39500864"],"confidence":"Medium","gaps":["Single lab and tumor type","Direct structural basis of KEAP1 competition not shown"]},{"year":2025,"claim":"Quantified plectin's biophysical role as a crosslinker setting cytoskeletal viscoelasticity, actin/vimentin turnover, and focal adhesion dynamics.","evidence":"Single-cell compression, FRAP, and confocal imaging in Plec-/- fibroblasts and astrocytes; preprint","pmids":[],"confidence":"Medium","gaps":["Preprint, single lab","Molecular basis linking crosslinking to FA maturation not fully defined"]},{"year":2025,"claim":"Linked plectin to muscle autophagic clearance, connecting its structural role to proteostasis maintenance.","evidence":"mCherry-EGFP-LC3B flux reporter, EM, immunoblotting, and in vivo chloroquine in MCK-Cre/cKO mice; preprint","pmids":[],"confidence":"Medium","gaps":["Preprint, single lab","Whether autophagy defect is causal in muscle pathology or secondary to cytoskeletal disruption unresolved"]},{"year":null,"claim":"How plectin's distinct molecular functions—filament anchoring, mitochondrial tethering, autophagy regulation, and signaling scaffolding—are coordinated and partitioned across isoforms and tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of isoform-specific interactomes","Causal hierarchy between mechanical and signaling functions undefined","Mitochondrial/autophagy roles largely from single labs or preprints"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,12,13]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,13,14]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,12,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,9]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,11]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[13]}],"complexes":["hemidesmosome"],"partners":["KRT8","KEAP1","VIMENTIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15149","full_name":"Plectin","aliases":["Hemidesmosomal protein 1","HD1","Plectin-1"],"length_aa":4684,"mass_kda":531.8,"function":"Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes. Could also bind muscle proteins such as actin to membrane complexes in muscle. May be involved not only in the filaments network, but also in the regulation of their dynamics. Structural component of muscle. Isoform 9 plays a major role in the maintenance of myofiber integrity","subcellular_location":"Cytoplasm, cytoskeleton; Cell junction, hemidesmosome; Cell projection, podosome","url":"https://www.uniprot.org/uniprotkb/Q15149/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLEC","classification":"Not Classified","n_dependent_lines":41,"n_total_lines":1208,"dependency_fraction":0.03394039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PLEC","total_profiled":1310},"omim":[{"mim_id":"616807","title":"FAS-BINDING FACTOR 1; FBF1","url":"https://www.omim.org/entry/616807"},{"mim_id":"616487","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 5D, GENERALIZED INTERMEDIATE, AUTOSOMAL RECESSIVE; EBS5D","url":"https://www.omim.org/entry/616487"},{"mim_id":"613723","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 17; LGMDR17","url":"https://www.omim.org/entry/613723"},{"mim_id":"612138","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 5C, WITH PYLORIC ATRESIA; EBS5C","url":"https://www.omim.org/entry/612138"},{"mim_id":"601282","title":"PLECTIN; PLEC","url":"https://www.omim.org/entry/601282"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Intermediate filaments","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Focal adhesion sites","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":229.5}],"url":"https://www.proteinatlas.org/search/PLEC"},"hgnc":{"alias_symbol":["PCN","PLTN"],"prev_symbol":["EBS1","PLEC1"]},"alphafold":{"accession":"Q15149","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15149","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLEC","jax_strain_url":"https://www.jax.org/strain/search?query=PLEC"},"sequence":{"accession":"Q15149","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15149.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15149/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15149"}},"corpus_meta":[{"pmid":"8894687","id":"PMC_8894687","title":"Homozygous deletion mutations in the plectin gene (PLEC1) in patients with epidermolysis bullosa simplex associated with late-onset muscular dystrophy.","date":"1996","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8894687","citation_count":134,"is_preprint":false},{"pmid":"30202917","id":"PMC_30202917","title":"Development of a protein-ligand extended connectivity (PLEC) fingerprint and its application for binding affinity predictions.","date":"2019","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/30202917","citation_count":112,"is_preprint":false},{"pmid":"12581350","id":"PMC_12581350","title":"The Caulobacter crescentus polar organelle development protein PodJ is differentially localized and is required for polar targeting of the PleC development regulator.","date":"2003","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12581350","citation_count":94,"is_preprint":false},{"pmid":"8941634","id":"PMC_8941634","title":"A homozygous nonsense mutation in the PLEC1 gene in patients with epidermolysis bullosa simplex with muscular dystrophy.","date":"1996","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/8941634","citation_count":91,"is_preprint":false},{"pmid":"21109228","id":"PMC_21109228","title":"Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal-recessive limb-girdle muscular dystrophy.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21109228","citation_count":83,"is_preprint":false},{"pmid":"2536661","id":"PMC_2536661","title":"Turning off flagellum rotation requires the pleiotropic gene pleD: pleA, pleC, and pleD define two morphogenic pathways in Caulobacter crescentus.","date":"1989","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2536661","citation_count":77,"is_preprint":false},{"pmid":"29050564","id":"PMC_29050564","title":"A Missense Variant in PLEC Increases Risk of Atrial Fibrillation.","date":"2017","source":"Journal of the American College of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/29050564","citation_count":67,"is_preprint":false},{"pmid":"17989727","id":"PMC_17989727","title":"5' trans-splicing repair of the PLEC1 gene.","date":"2007","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/17989727","citation_count":57,"is_preprint":false},{"pmid":"15681471","id":"PMC_15681471","title":"Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1).","date":"2005","source":"The Journal of molecular diagnostics : JMD","url":"https://pubmed.ncbi.nlm.nih.gov/15681471","citation_count":56,"is_preprint":false},{"pmid":"23909720","id":"PMC_23909720","title":"The DivJ, CbrA and PleC system controls DivK phosphorylation and symbiosis in Sinorhizobium meliloti.","date":"2013","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23909720","citation_count":52,"is_preprint":false},{"pmid":"18978058","id":"PMC_18978058","title":"The Anaplasma phagocytophilum PleC histidine kinase and PleD diguanylate cyclase two-component system and role of cyclic Di-GMP in host cell infection.","date":"2008","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/18978058","citation_count":47,"is_preprint":false},{"pmid":"30730609","id":"PMC_30730609","title":"Prioritization of PLEC and GRINA as Osteoarthritis Risk Genes Through the Identification and Characterization of Novel Methylation Quantitative Trait Loci.","date":"2019","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/30730609","citation_count":44,"is_preprint":false},{"pmid":"25712130","id":"PMC_25712130","title":"Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa 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integrity of muscle (sarcolemmal localization).\",\n      \"method\": \"Immunofluorescence, mutation analysis (homozygous deletion identification), electron microscopy of patient skin\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mutations with defined cellular phenotype (absent plectin at hemidesmosomes, keratin filament detachment), replicated across two independent patient families\",\n      \"pmids\": [\"8894687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A homozygous nonsense mutation in PLEC1 leads to a premature stop codon, decay of aberrant plectin mRNA, and absence of plectin protein; in skin this causes failure of keratin filaments to connect to the plasma membrane via hemidesmosomes, while in muscle it correlates with aberrant localization of desmin in muscle fibers, establishing plectin as necessary for desmin intermediate filament organization in muscle.\",\n      \"method\": \"Mutation identification (nonsense mutation), immunofluorescence of skin and muscle, mRNA analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined molecular phenotypes in two tissues (skin hemidesmosome attachment, muscle desmin localization), independent replication of plectin's anchoring role\",\n      \"pmids\": [\"8941634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A homozygous mutation in exon 1f of PLEC, specific to the plectin isoform 1f, abolishes sarcolemmal plectin staining and causes ultrastructural abnormalities (membrane duplications, enlarged space between membrane and sarcomere, Z-disk misalignment) in skeletal muscle without skin involvement, establishing that plectin isoform 1f specifically links the sarcolemma to the sarcomere in skeletal muscle.\",\n      \"method\": \"Homozygosity mapping, DNA sequencing, transmission electron microscopy, immunofluorescence of patient muscle\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific loss-of-function with defined ultrastructural phenotype and localization data, replicated in three independent families\",\n      \"pmids\": [\"21109228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A homozygous nonsense mutation in exon 1a of PLEC, specific to plectin isoform 1a (P1a), causes skin-only EBS with hypoplastic hemidesmosomes and intra-epidermal cleavage without cardiomyopathy or muscle dystrophy, establishing that P1a is the dominant plectin isoform in epidermal basal cells and cultured keratinocytes, and that its loss specifically disrupts hemidesmosome structure in skin while sparing other tissues.\",\n      \"method\": \"DNA sequencing, immunofluorescence antigen mapping, transmission electron microscopy, western blot, qRT-PCR on patient skin and cultured keratinocytes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific loss-of-function with multiple orthogonal methods (EM, IF, western blot, qRT-PCR) establishing tissue-specific isoform function\",\n      \"pmids\": [\"25712130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plectin (PLEC) physically interacts with KRT8 (keratin 8) at mitochondria; PLEC anchors mitochondria and KRT8 facilitates mitochondrial fission-mediated mitophagy through this interaction. KRT8 phosphorylation under oxidative stress reduces the PLEC-anchored mitochondria–KRT8 association, modulating mitophagy flux and protecting retinal pigment epithelial cells from necrotic cell death.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction between KRT8 and PLEC), live-cell imaging, mitophagy flux assays, mitochondrial morphology analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction identified, functional mitophagy assays performed, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33783309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLEC competitively interacts with KEAP1, displacing NRF2 from the KEAP1-NRF2 complex and allowing NRF2 translocation from the cytosol to the nucleus where it activates antioxidant gene expression. ΔNP63α directly transactivates PLEC expression, and radiotherapy-induced ROS activates ΔNP63α via NRF2, forming a ΔNp63α/PLEC/NRF2 feedback loop that promotes radioresistance in esophageal squamous cell carcinoma.\",\n      \"method\": \"Transcriptional reporter assays, co-immunoprecipitation (PLEC-KEAP1 interaction), subcellular fractionation (NRF2 nuclear translocation), knockdown/overexpression with functional readouts (ROS levels, radiosensitivity in nude mice)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive binding (Co-IP), subcellular localization with functional consequence, in vivo validation, single lab\",\n      \"pmids\": [\"39500864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PLEC1 mutations (nonsense and splice-site) cause absent or markedly attenuated plectin expression and EBS with pyloric atresia; an exon-trapping experiment demonstrated that a splice-site mutation induces aberrant splicing of PLEC1, establishing this as a mechanism of loss-of-function.\",\n      \"method\": \"Immunohistochemistry, DNA sequencing, exon-trapping experiment for splice-site mutation functional validation\",\n      \"journal\": \"The Journal of molecular diagnostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — exon-trapping directly demonstrates aberrant splicing as mechanism; single lab with functional validation\",\n      \"pmids\": [\"15681471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"5' trans-splicing (SMaRT) of the PLEC1 transcript in EBS-MD fibroblasts carrying a dominant-negative leucine insertion in exon 9 reduced mutant mRNA levels and restored wild-type plectin expression pattern by immunofluorescence; retroviral delivery increased full-length plectin protein by 58.7%, demonstrating that mRNA-level correction restores plectin protein function.\",\n      \"method\": \"Spliceosome-mediated RNA trans-splicing, transient and retroviral transfection of patient fibroblasts, immunofluorescence, protein quantification\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiment in patient cells with protein-level validation, single lab\",\n      \"pmids\": [\"17989727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Gentamicin treatment suppressed PLEC1 premature termination codons in EBS-MD primary keratinocytes, inducing plectin expression in skin (detected by immunofluorescence) for at least 5 months post-treatment, demonstrating translational readthrough as a mechanism to restore plectin protein from nonsense variants.\",\n      \"method\": \"Translational readthrough (gentamicin treatment), immunofluorescence of patient skin before and after treatment\",\n      \"journal\": \"JAMA dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single patient case report, single method (immunofluorescence), limited controls\",\n      \"pmids\": [\"35234827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Plectin knockdown in cochlear hair cells (zebrafish model) resulted in reduction of synaptic mitochondrial potential and loss of ribbon synapses, establishing a role for plectin in maintaining mitochondrial function and synaptic structure at inner ear ribbon synapses relevant to neuronal transmission.\",\n      \"method\": \"Plectin knockdown in zebrafish inner ear model, immunofluorescence for ribbon synapses, mitochondrial membrane potential assay\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in model organism with specific cellular phenotypes (ribbon synapse loss, mitochondrial potential reduction), single lab\",\n      \"pmids\": [\"37393735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRISPR/Cas9 knockdown of plectin in a mesenchymal stem cell line followed by RNA-sequencing revealed that plectin regulates Wnt signalling, glycosaminoglycan biosynthesis, and immune regulation pathways, placing plectin upstream of these pathways in chondrocyte-relevant cells.\",\n      \"method\": \"CRISPR/Cas9 knockdown, RNA-sequencing pathway analysis\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement based on transcriptomics after knockdown, no direct biochemical mechanism established, single lab single method\",\n      \"pmids\": [\"32580029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In plectin-deficient (Plec-/-) myoblasts and muscle-specific conditional plectin knockout (MCK-Cre/cKO) mice, autophagic flux is impaired: autophagosome turnover is reduced (~40% reduction in LC3B red:green ratio), degradative vacuoles and LC3/SQSTM1-positive patches accumulate, and lysosomal/autophagic compartment signal intensities are reduced. Protein levels of LAMP2, BAG3, and SQSTM1 are elevated in knockout muscle lysates. Chloroquine treatment in vivo confirmed impaired autophagic clearance in plectin-deficient muscle.\",\n      \"method\": \"mCherry-EGFP-LC3B autophagy flux reporter, immunofluorescence and electron microscopy, immunoblotting, RNA-seq, CYTO-ID/LYSO-ID dyes, chloroquine treatment in vivo in MCK-Cre/cKO mice\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in cells and in vivo, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Plectin knockout (Plec-/-) fibroblasts are ~2-fold softer than wild-type, show faster viscoelastic stress relaxation, faster actin turnover (3-fold by FRAP), and altered vimentin network architecture (from fine meshwork to bundled network). This establishes plectin as a regulator of cytoskeletal organization and viscoelastic properties by crosslinking actin and vimentin intermediate filaments.\",\n      \"method\": \"Single-cell compression measurements, FRAP, confocal imaging of vimentin network in Plec+/+ vs Plec-/- fibroblasts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct comparison of KO vs WT with multiple orthogonal biophysical methods, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Plectin localizes to focal adhesions (FAs) in mouse astrocytes, where it regulates FA number, maturation, turnover, and mobility of FA components. Plectin polarizes within FAs depending on maturation state and controls recruitment of vimentin to FAs. In plectin-deficient astrocytes, the vimentin network shows impaired connectivity and altered viscoelastic properties. In a reactive astrogliosis model, FA number and size increase alongside elevated plectin expression.\",\n      \"method\": \"Live imaging, immunofluorescence, FRAP, plectin-deficient astrocyte model (localization and functional consequence)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization tied to functional consequences (FA dynamics, vimentin recruitment), multiple methods, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Plectin cytolinkers bridge keratin 5/14 intermediate filaments and microtubules to mechanically control the 3D perinuclear positioning of melanin pigment organelles in human keratinocytes, and this positioning is required for DNA photoprotection.\",\n      \"method\": \"Microrheology, confocal imaging in human disease-related keratinocyte models with plectin disruption, functional readout of DNA photodamage\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, mechanistic link between plectin bridging and organelle positioning supported by imaging but limited direct biochemical evidence\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Following actin filament disassembly (cytochalasin D treatment), localized increase of vimentin assembly in the mid-cytoplasm is dependent on the cytolinker plectin, establishing plectin as a mediator of cytoskeletal crosstalk between actin and vimentin networks.\",\n      \"method\": \"Pharmacological disruption of actin (cytochalasin D), vimentin imaging, plectin-dependent vimentin response assessment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, indirect evidence of plectin-mediated crosstalk from pharmacological experiments without direct plectin KO controls described in abstract\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Genetic or pharmacological inactivation of plectin in autochthonous and orthotopic mouse HCC models suppresses tumor initiation and growth, inhibits invasion and lung metastasis of human HCC cells. Proteomic and phosphoproteomic profiling linked plectin-dependent cytoskeletal disruption to attenuation of FAK, MAPK/Erk, and PI3K/AKT oncogenic signaling, placing plectin upstream of these pathways in hepatocellular carcinoma mechanosensitive signaling.\",\n      \"method\": \"Genetic knockout and pharmacological inhibition (plecstatin-1) in mouse HCC models, proteomic and phosphoproteomic profiling, invasion and metastasis assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (genetic KO, pharmacological inhibition, proteomics) in cell lines and in vivo models, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Immunostaining of liver samples from patients with PLEC-related infantile cholestasis revealed scattered cytoplasmic plectin signals in hepatocytes and reduced colocalization of plectin with cytokeratin 8, establishing that plectin normally co-localizes with cytokeratin 8 intermediate filaments in hepatocytes and that disruption of this colocalization is associated with cholestatic disease.\",\n      \"method\": \"Immunofluorescence staining of patient liver biopsy, trio exome sequencing\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — patient tissue immunofluorescence showing disrupted colocalization, no functional rescue or in vitro mechanistic experiments\",\n      \"pmids\": [\"39168815\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Plectin (PLEC) is a giant cytoskeletal crosslinker protein that anchors intermediate filaments (keratins in skin, desmin and vimentin in muscle and other cells) to hemidesmosomal complexes and the plasma membrane/sarcolemma; different tissue-specific isoforms (e.g., 1a in epidermis, 1f in skeletal muscle) serve distinct structural roles, and plectin additionally regulates focal adhesion dynamics, autophagic flux, mitochondrial anchoring (via KRT8 interaction), cytoskeletal viscoelasticity, and oncogenic signaling (FAK/MAPK/PI3K-AKT) by crosslinking actin, vimentin, and keratin filament networks, with loss-of-function causing tissue-specific fragility diseases (epidermolysis bullosa simplex, muscular dystrophy, cardiomyopathy, and hearing loss).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Plectin (PLEC) is a giant cytoskeletal crosslinker that anchors intermediate filament networks to membrane junctions and integrates the actin, vimentin, keratin, and microtubule cytoskeletons to maintain tissue mechanical integrity [#0, #12]. In basal keratinocytes it tethers the keratin filament network to hemidesmosomal complexes, and in muscle it organizes the desmin intermediate filament network and links the sarcolemma to the sarcomere, with these functions partitioned across tissue-specific N-terminal isoforms—isoform 1a being dominant in epidermis and isoform 1f in skeletal muscle [#1, #2, #3]. Loss-of-function mutations in PLEC cause tissue-specific fragility disease, including epidermolysis bullosa simplex with muscular dystrophy and EBS with pyloric atresia, and the underlying nonsense and splice-site lesions act by abolishing or attenuating plectin protein [#0, #6]. As a mechanical organizer, plectin sets cytoskeletal viscoelasticity and actin/vimentin turnover, localizes to focal adhesions where it controls their maturation and recruits vimentin, and bridges keratin filaments and microtubules to position pigment organelles [#12, #13]. Beyond its structural role, plectin anchors mitochondria through interaction with keratin 8 (KRT8) to modulate mitophagy [#4], supports autophagic flux in muscle [#11], and in cancer contexts feeds mechanosensitive oncogenic signaling and antioxidant responses, displacing NRF2 from KEAP1 and acting upstream of FAK/MAPK/PI3K-AKT signaling [#5, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established plectin as the molecular link required to attach the keratin intermediate filament network to hemidesmosomes and to maintain muscle structural integrity, defining its core anchoring function.\",\n      \"evidence\": \"Homozygous deletion/nonsense mutations with absent plectin by immunofluorescence and EM in patient skin and muscle, showing keratin detachment and aberrant desmin localization\",\n      \"pmids\": [\"8894687\", \"8941634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the binding domains mediating keratin/desmin attachment\", \"Did not address which plectin isoforms operate in each tissue\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined splice-site mutation as a loss-of-function mechanism and extended the disease spectrum to EBS with pyloric atresia.\",\n      \"evidence\": \"Exon-trapping demonstration of aberrant PLEC1 splicing plus immunohistochemistry on patient tissue\",\n      \"pmids\": [\"15681471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative measure of residual protein function\", \"Mechanism of pyloric atresia phenotype not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that mRNA-level correction restores functional plectin, providing proof-of-concept for therapeutic rescue of dominant-negative alleles.\",\n      \"evidence\": \"Spliceosome-mediated RNA trans-splicing in EBS-MD patient fibroblasts with protein quantification and immunofluorescence\",\n      \"pmids\": [\"17989727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"58.7% protein restoration efficiency limits in vivo applicability\", \"No demonstration of restored mechanical/structural function\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how tissue-specific phenotypes arise by showing isoform 1f selectively links the sarcolemma to the sarcomere in skeletal muscle without skin involvement.\",\n      \"evidence\": \"Isoform-specific exon 1f mutation with TEM ultrastructural defects and immunofluorescence in patient muscle across three families\",\n      \"pmids\": [\"21109228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the sarcomeric binding partner of P1f\", \"Cardiac involvement not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmed isoform partitioning by showing isoform 1a is the dominant epidermal isoform whose loss produces skin-only EBS, sparing muscle and heart.\",\n      \"evidence\": \"Isoform-specific exon 1a nonsense mutation analyzed by EM, immunofluorescence, western blot, and qRT-PCR in patient skin and cultured keratinocytes\",\n      \"pmids\": [\"25712130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish redundancy among non-dominant isoforms in skin\", \"Hemidesmosome assembly mechanism downstream of P1a not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended plectin function beyond filament anchoring by showing it physically tethers mitochondria via KRT8 to modulate fission-mediated mitophagy.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation of PLEC-KRT8, live imaging, and mitophagy flux assays in retinal pigment epithelial cells\",\n      \"pmids\": [\"33783309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, RPE-specific context\", \"Direct binding interface between PLEC and KRT8 not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated plectin in inner ear function by linking it to mitochondrial potential and ribbon synapse maintenance, broadening its role to neuronal/sensory tissue.\",\n      \"evidence\": \"Plectin knockdown in zebrafish cochlear hair cells with ribbon synapse immunofluorescence and mitochondrial membrane potential assays\",\n      \"pmids\": [\"37393735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Knockdown rather than clean knockout\", \"Mechanism connecting plectin to mitochondrial potential at synapses unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed plectin in oncogenic and antioxidant signaling by showing it competitively binds KEAP1 to release NRF2 within a ΔNp63α/PLEC/NRF2 radioresistance loop.\",\n      \"evidence\": \"Co-IP of PLEC-KEAP1, subcellular fractionation for NRF2 translocation, reporter assays, and radiosensitivity readouts in nude mice for esophageal squamous cell carcinoma\",\n      \"pmids\": [\"39500864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and tumor type\", \"Direct structural basis of KEAP1 competition not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Quantified plectin's biophysical role as a crosslinker setting cytoskeletal viscoelasticity, actin/vimentin turnover, and focal adhesion dynamics.\",\n      \"evidence\": \"Single-cell compression, FRAP, and confocal imaging in Plec-/- fibroblasts and astrocytes; preprint\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Molecular basis linking crosslinking to FA maturation not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked plectin to muscle autophagic clearance, connecting its structural role to proteostasis maintenance.\",\n      \"evidence\": \"mCherry-EGFP-LC3B flux reporter, EM, immunoblotting, and in vivo chloroquine in MCK-Cre/cKO mice; preprint\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Whether autophagy defect is causal in muscle pathology or secondary to cytoskeletal disruption unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How plectin's distinct molecular functions—filament anchoring, mitochondrial tethering, autophagy regulation, and signaling scaffolding—are coordinated and partitioned across isoforms and tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of isoform-specific interactomes\", \"Causal hierarchy between mechanical and signaling functions undefined\", \"Mitochondrial/autophagy roles largely from single labs or preprints\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 12, 13]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 13, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 12, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"hemidesmosome\"],\n    \"partners\": [\"KRT8\", \"KEAP1\", \"vimentin\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}