{"gene":"CAPN1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2016,"finding":"Calpain-1 (CAPN1) cleaves PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), and loss of this cleavage in calpain-1 KO mice results in inhibition of the Akt pro-survival pathway, leading to enhanced apoptosis of cerebellar granule cells during development. Crossing calpain-1 KO mice with PHLPP1 KO mice rescued granule cell density and motor coordination, establishing epistatic pathway placement.","method":"Calpain-1 knockout mice, genetic epistasis (calpain-1 KO × PHLPP1 KO double mutant), pharmacological Akt activation (bisperoxovanadium injection), cerebellar granule cell apoptosis assay, synaptic transmission analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis with double-KO rescue, pharmacological rescue, multiple orthogonal readouts in a single rigorous study","pmids":["27320912"],"is_preprint":false},{"year":2021,"finding":"In a DSG2-mutant ACM model, calcium overload activates CAPN1, which associates with mitochondria and cleaves mitochondrial-bound apoptosis-inducing factor (AIF). Cleaved AIF translocates to the nucleus, triggering large-scale DNA fragmentation and necrotic cell death. Overexpression of calpastatin (CAST), an endogenous CAPN1 inhibitor, protected against Ca2+-overload-induced necrosis, and pharmacological CAPN1 inhibition attenuated AIF truncation in cardiomyocytes.","method":"Dsg2 mutant mouse model (swimming exercise), co-immunoprecipitation (CAPN1 with mitochondria-associated AIF), calpain activity assay, calpastatin overexpression in cardiomyocytes, embryonic stem cell-derived cardiomyocytes with β-adrenergic stimulation and calpain inhibitor treatment, AIF-mimetic peptide blocking PPIA-mediated nuclear translocation","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, genetic KO/OE, pharmacological inhibition, rescue experiments) in a single rigorous study with defined molecular mechanism","pmids":["33597260"],"is_preprint":false},{"year":2021,"finding":"CAPN1 activation under ischemic conditions impairs lysosomal membrane integrity and cleaves autophagy regulators BECN1 (Beclin1) and ATG5, thereby suppressing autophagosome formation and blocking autophagic flux, which contributes to neuronal death.","method":"Adeno-associated virus-mediated CAPN1 knockdown in rat permanent middle cerebral artery occlusion model; pharmacological inhibition with MDL-28170; oxygen-glucose deprivation in primary neurons; lysosomal membrane permeabilization assay; autophagic substrate accumulation assay; 3-methyladenine and chloroquine co-treatment to reverse neuroprotection","journal":"Stroke","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown plus pharmacological inhibition with functional rescue, single lab, two orthogonal methods","pmids":["33874744"],"is_preprint":false},{"year":2018,"finding":"CAPN1 physically interacts with tumor suppressor NF1 (neurofibromin 1) in melanoma cells and mediates its degradation. ShRNA knockdown of CAPN1 or calpain inhibitor treatment stabilizes NF1 protein and downregulates AKT signaling.","method":"Mass spectrometry analysis of NF1 binding partners identifying CAPN1; shRNA-mediated CAPN1 knockdown; calpain inhibitor treatment; NF1 protein stability assay; AKT signaling readout; combination treatment with MEK inhibitor Trametinib","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — MS-based interaction discovery plus functional validation with shRNA and inhibitor, single lab","pmids":["30131853"],"is_preprint":false},{"year":2025,"finding":"CAPN1 inhibits NF1 (neurofibromin) protein levels in medullary thyroid cancer cells, sustaining RAS/RET-driven AKT and ERK activation; shRNA depletion or pharmacological inhibition of CAPN1 stabilizes NF1 and reduces downstream RAS/RET signaling.","method":"Proteomic profiling of MTC cells and tumors; shRNA-mediated CAPN1 depletion; calpain inhibitor treatment; xenograft tumor growth assay; Western blot for NF1, AKT, ERK; in vitro combination treatment with vandetanib/selpercatinib","journal":"Thyroid : official journal of the American Thyroid Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification plus functional genetic and pharmacological validation, single lab, multiple readouts","pmids":["39868924"],"is_preprint":false},{"year":2020,"finding":"CAPN1 degrades PTPN1 (protein tyrosine phosphatase 1) protein in lung adenocarcinoma cells; loss of PTPN1 leads to increased phosphorylation of c-Met and PIK3R2, enhancing cell proliferation, metastasis, and erlotinib resistance. Co-IP confirmed physical interaction between CAPN1 and PTPN1, and cycloheximide chase confirmed CAPN1-dependent PTPN1 protein destabilization.","method":"Co-immunoprecipitation (CAPN1–PTPN1 interaction); cycloheximide protein synthesis block assay; Western blot; CCK-8 proliferation, colony formation, and transwell invasion assays; shRNA/overexpression of CAPN1 and PTPN1","journal":"Thoracic cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus CHX chase and multiple functional readouts, single lab","pmids":["32395869"],"is_preprint":false},{"year":2022,"finding":"Cisplatin activates CAPN1/CAPN2 in esophageal cancer cells, which in turn activates BAK/BAX, leading to caspase-9 and caspase-3 activation and GSDME cleavage, resulting in pyroptosis. Calpain inhibition or CAPN1/CAPN2 knockout suppressed cisplatin-induced pyroptosis.","method":"Proteomics screening; calpain activity assay; LDH release assay; cell viability assay; CAPN1/CAPN2 knockout; Western blot for BAK/BAX, caspase-9, caspase-3, GSDME","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CAPN1/2 KO plus pharmacological inhibition with pathway-level Western blot readouts, single lab, multiple orthogonal methods","pmids":["35525317"],"is_preprint":false},{"year":2013,"finding":"A missense mutation in CAPN1 (cysteine to tyrosine at residue 115) causes spinocerebellar ataxia in Parson Russell Terrier dogs. Cysteine 115 forms part of the catalytic triad essential for cysteine protease enzymatic activity, indicating that CAPN1 catalytic activity is required for cerebellar function.","method":"GWAS and target-enriched massively-parallel sequencing; Sanger sequencing validation; conservation analysis of catalytic triad residues across species","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic mapping with functionally annotated catalytic residue, replicated across species by subsequent human studies","pmids":["23741357"],"is_preprint":false},{"year":2013,"finding":"In μ-calpain (CAPN1) knockout mice, absence of calpain-1 leads to compensatory upregulation of m-calpain (CAPN2) protein abundance and activity, and caspase 3/7 activity; older KO mice accumulate more protein in skeletal muscle with increased fast-twitch glycolytic fiber size and number, indicating calpain-1's role in muscle protein turnover and fiber-type maintenance.","method":"Calpain-1 knockout mice; calpain activity assay; caspase 3/7 activity assay; protein:DNA and RNA:DNA ratio measurement; muscle fiber type immunohistochemistry; myoD and NCAM expression analysis","journal":"Journal of animal science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with multiple cellular phenotype readouts, single lab","pmids":["23798514"],"is_preprint":false},{"year":2021,"finding":"Calpain-1 (CAPN1) cleaves Dicer in mouse brain, generating an active Dicer fragment with RNase III activity that promotes miRNA formation. Loss of calpain-1 in KO mice reduces active Dicer levels and alters neurodegeneration-related miRNA expression; reconstitution with calpain-1 and calcium in vitro restored Dicer activity.","method":"Calpain-1 KO mouse brain homogenates; in vitro incubation of calpain-1 with calcium and brain lysates; miRNA sequencing; Dicer activity assay; Western blot for Dicer cleavage fragments","journal":"BBA advances","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of Dicer cleavage by calpain-1 plus calcium, validated in KO mouse brain, single lab","pmids":["34286311"],"is_preprint":false},{"year":2025,"finding":"CAPN1 physically interacts with TFEB (transcription factor EB) in cells infected with Pseudomonas aeruginosa and prevents TFEB nuclear translocation, thereby inhibiting the autophagy-lysosome pathway and promoting bacterial infection-induced acute lung injury. CAPN1-deficient mice show reversal of PAK-induced autolysosome suppression.","method":"Co-immunoprecipitation and GST pull-down of CAPN1–TFEB interaction; immunofluorescence for TFEB localization; Western blot; CAPN1 knockout mice; transmission electron microscopy of autolysosomes","journal":"Journal of innate immunity","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP and pull-down plus KO mouse validation and localization experiment, single lab","pmids":["40081346"],"is_preprint":false},{"year":2026,"finding":"CD99L2, a transmembrane protein, is an activating interactor of CAPN1. Loss of CD99L2 function (ablation of cytoplasmic or extracellular domains) causes its intracellular mislocalization and abrogates its interaction with CAPN1, impairing CAPN1 activation and dysregulating downstream neuronal pathways, causing spastic ataxia.","method":"Cellular interaction studies; domain deletion constructs of CD99L2; localization assays; transcriptome analysis in patient-derived fibroblasts; exome/genome sequencing of ataxia cohort","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — cellular interaction and domain-deletion experiments with functional outcome, single study","pmids":["41690933"],"is_preprint":false},{"year":2026,"finding":"Spinal overexpression of CAPN1 restricted to CaMKII neurons reproduces paclitaxel-induced neuropathic pain in naive rats. CAPN1 overexpression elevates NCS-1 (neuronal calcium sensor-1) expression, which in turn strengthens CAPN2 expression and calpain enzymatic activity, identifying a CAPN1→NCS-1→CAPN2 signaling axis in nociceptive neurons.","method":"Intraspinal viral vector-mediated CAPN1 overexpression in CaMKII neurons; pain threshold measurement; Western blot for NCS-1, CAPN2, spectrin degradation products; immunofluorescence co-localization","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neuron-specific overexpression with defined phenotypic and molecular readouts, single lab","pmids":["41482880"],"is_preprint":false},{"year":2020,"finding":"Deletion of the Capn1 gene in mice alters expression of genes in Protein Processing in ER, MAP kinase, and Alzheimer's disease KEGG pathways in brain, with most differentially expressed genes being down-regulated, implicating calpain-1 in transcriptional regulation of multiple brain function pathways.","method":"RNA-seq on brain tissue of Capn1 knockout vs. wild-type mice; Western blot validation of selected protein levels; KEGG pathway enrichment analysis","journal":"Frontiers in genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptomic profiling with limited protein-level validation, no direct mechanistic experiments on pathway placement, single lab","pmids":["32328086"],"is_preprint":false},{"year":2025,"finding":"Dexamethasone inhibits osteogenic differentiation of rat BMSCs by modulating the CAST-CAPN1 axis: DEX downregulates CAST (calpastatin) and upregulates CAPN1, reducing ATP5A1 levels and ATP activity; overexpression of CAST partially rescued osteogenic differentiation, while overexpression of CAPN1 exacerbated DEX effects and reversed CAST's rescue.","method":"qRT-PCR and Western blot for CAST, CAPN1, ATP5A1; CAPN1 and CAST overexpression plasmids; Alizarin Red S staining; ELISA for ATP activity and osteogenic markers","journal":"Discovery medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression experiments with functional readout but no direct biochemical substrate cleavage assay, single lab, single study","pmids":["40116104"],"is_preprint":false}],"current_model":"CAPN1 (calpain-1/μ-calpain) is a calcium-activated cysteine protease whose catalytic triad (including the essential C115 residue) is required for its activity; it cleaves specific substrates including PHLPP1 (activating Akt pro-survival signaling in neurons), AIF (triggering mitochondria-to-nucleus apoptotic signaling in cardiomyocytes), Dicer (generating active miRNA-processing fragments in brain), PTPN1 (relieving dephosphorylation of c-Met/PIK3R2 in cancer), and NF1 (destabilizing the RAS-GAP tumor suppressor); it is activated by the interacting protein CD99L2, is inhibited by calpastatin (CAST), and when dysregulated impairs autophagic flux through lysosomal membrane permeabilization and cleavage of Beclin1/ATG5, or by sequestering TFEB from the nucleus, collectively placing CAPN1 at the intersection of neuronal survival, cardiomyocyte death, muscle protein homeostasis, and oncogenic signaling."},"narrative":{"mechanistic_narrative":"CAPN1 (calpain-1/μ-calpain) is a calcium-activated cysteine protease that acts through regulated proteolysis of specific intracellular substrates to control cell survival, death, and signaling across neuronal, cardiac, muscle, and oncogenic contexts [PMID:27320912, PMID:23741357]. Its enzymatic function depends on a catalytic triad including cysteine-115, and a C115Y mutation abolishing protease activity causes spinocerebellar ataxia [PMID:23741357]. In neurons, CAPN1 cleaves PHLPP1 to sustain Akt pro-survival signaling, and loss of this cleavage drives developmental apoptosis of cerebellar granule cells [PMID:27320912], while it also processes Dicer into an active RNase III fragment that shapes brain miRNA pools [PMID:34286311]. Conversely, pathological CAPN1 activation is destructive: under calcium overload in cardiomyocytes it associates with mitochondria and cleaves AIF, driving its nuclear translocation and necrotic death [PMID:33597260], and in ischemic neurons it permeabilizes lysosomal membranes and cleaves the autophagy regulators BECN1 and ATG5 to block autophagic flux [PMID:33874744]. CAPN1 additionally restrains autophagy by sequestering the transcription factor TFEB from the nucleus during bacterial infection [PMID:40081346]. In cancer, CAPN1 degrades the tumor suppressors NF1 and the phosphatase PTPN1, thereby sustaining RAS/RET–AKT/ERK and c-Met/PIK3R2 signaling [PMID:30131853, PMID:39868924, PMID:32395869]. CAPN1 activity is gated by the activating transmembrane interactor CD99L2 and opposed by the endogenous inhibitor calpastatin (CAST) [PMID:41690933, PMID:33597260, PMID:40116104].","teleology":[{"year":2013,"claim":"Established that CAPN1 catalytic protease activity, not merely its presence, is required for cerebellar function, by linking a catalytic-triad mutation to disease.","evidence":"GWAS and targeted sequencing of ataxic Parson Russell Terriers identifying a C115Y mutation in the catalytic triad","pmids":["23741357"],"confidence":"Medium","gaps":["Does not identify the neuronal substrate whose loss of cleavage produces ataxia","Catalytic-dead phenotype inferred from conservation rather than reconstituted enzymology"]},{"year":2013,"claim":"Defined CAPN1's homeostatic role in muscle protein turnover and revealed compensatory upregulation of CAPN2 when CAPN1 is lost.","evidence":"Calpain-1 knockout mice with calpain/caspase activity assays, protein:DNA ratios, and fiber-type immunohistochemistry","pmids":["23798514"],"confidence":"Medium","gaps":["No muscle-specific proteolytic substrate identified","Mechanism of CAPN2 compensatory upregulation unknown"]},{"year":2016,"claim":"Placed CAPN1 upstream of Akt pro-survival signaling in neurons by showing it cleaves the phosphatase PHLPP1, resolving how CAPN1 loss causes granule-cell apoptosis.","evidence":"Calpain-1 KO mice, calpain-1 × PHLPP1 double-KO genetic epistasis with rescue, pharmacological Akt activation","pmids":["27320912"],"confidence":"High","gaps":["Cleavage site within PHLPP1 not mapped biochemically","Does not address non-neuronal PHLPP1 regulation"]},{"year":2018,"claim":"Introduced an oncogenic role for CAPN1 by showing it physically binds and destabilizes the tumor suppressor NF1, linking CAPN1 to AKT-driven melanoma signaling.","evidence":"Mass-spectrometry interactor screen, shRNA knockdown, calpain inhibitor, NF1 stability assay in melanoma cells","pmids":["30131853"],"confidence":"Medium","gaps":["Direct proteolytic cleavage of NF1 by CAPN1 not demonstrated biochemically","Single lab, single cancer type"]},{"year":2020,"claim":"Extended CAPN1-mediated substrate degradation to PTPN1 in lung cancer, connecting CAPN1 to c-Met/PIK3R2 phosphorylation and drug resistance.","evidence":"Co-IP, cycloheximide chase for protein destabilization, proliferation/invasion assays with shRNA and overexpression","pmids":["32395869"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","Direct cleavage versus accelerated turnover not distinguished"]},{"year":2021,"claim":"Defined a death-effector role for CAPN1 in cardiomyocytes via mitochondrial AIF cleavage and nuclear translocation, and showed calpastatin opposes this.","evidence":"DSG2-mutant ACM mouse model, Co-IP, calpain activity assay, calpastatin overexpression, pharmacological inhibition, AIF-mimetic peptide","pmids":["33597260"],"confidence":"High","gaps":["AIF cleavage site not mapped","Generalizability beyond DSG2-mutant calcium-overload setting untested"]},{"year":2021,"claim":"Showed CAPN1 blocks autophagic flux during ischemia by permeabilizing lysosomes and cleaving BECN1 and ATG5, linking its activation to neuronal death.","evidence":"AAV-mediated knockdown in rat MCAO model, MDL-28170 inhibition, OGD in neurons, lysosomal permeabilization and autophagy substrate assays with 3-MA/chloroquine rescue","pmids":["33874744"],"confidence":"Medium","gaps":["Cleavage of BECN1/ATG5 not reconstituted in vitro","Relationship between lysosomal permeabilization and substrate cleavage order unresolved"]},{"year":2021,"claim":"Revealed a non-degradative activating proteolysis function: CAPN1 cleaves Dicer to generate an active RNase III fragment that controls brain miRNA production.","evidence":"Calpain-1 KO mouse brain, in vitro reconstitution with calpain-1 plus calcium, miRNA-seq, Dicer activity and cleavage Western blots","pmids":["34286311"],"confidence":"Medium","gaps":["Physiological consequences of altered miRNA pools not functionally tested","Single lab"]},{"year":2022,"claim":"Positioned CAPN1 (with CAPN2) as an upstream activator of mitochondrial apoptosis and GSDME-dependent pyroptosis in response to cisplatin.","evidence":"Proteomics, CAPN1/CAPN2 knockout, calpain inhibition, LDH/viability assays, Western blot for BAK/BAX, caspases, GSDME in esophageal cancer cells","pmids":["35525317"],"confidence":"Medium","gaps":["Direct calpain substrate triggering BAK/BAX activation not identified","CAPN1 versus CAPN2 specific contributions not separated"]},{"year":2025,"claim":"Generalized CAPN1's NF1-destabilizing oncogenic function to medullary thyroid cancer, sustaining RAS/RET–AKT/ERK signaling.","evidence":"Proteomic profiling, shRNA depletion, calpain inhibitor, xenograft assays, combination with vandetanib/selpercatinib","pmids":["39868924"],"confidence":"Medium","gaps":["Direct NF1 cleavage by CAPN1 not biochemically demonstrated","In vivo on-target specificity of inhibitor not established"]},{"year":2025,"claim":"Linked CAPN1 to autophagy suppression during infection through physical sequestration of TFEB, preventing its nuclear translocation.","evidence":"Co-IP and GST pull-down of CAPN1–TFEB, TFEB localization imaging, CAPN1 KO mice, autolysosome electron microscopy in P. aeruginosa lung injury","pmids":["40081346"],"confidence":"Medium","gaps":["Whether TFEB is cleaved or only bound is unresolved","Calcium dependence of the interaction not tested"]},{"year":2026,"claim":"Identified CD99L2 as an activating, localization-dependent interactor of CAPN1, defining how upstream input regulates CAPN1 activity in neurons.","evidence":"Cellular interaction and domain-deletion constructs, localization assays, patient fibroblast transcriptomics, exome/genome sequencing of a spastic ataxia cohort","pmids":["41690933"],"confidence":"Medium","gaps":["Mechanism by which CD99L2 binding activates CAPN1 unknown","Downstream neuronal substrates not defined"]},{"year":2026,"claim":"Demonstrated CAPN1 as a sufficient driver of neuropathic pain via a CAPN1→NCS-1→CAPN2 amplification axis in spinal neurons.","evidence":"Neuron-specific intraspinal CAPN1 overexpression in rats, pain threshold measurement, Western blot for NCS-1/CAPN2/spectrin breakdown","pmids":["41482880"],"confidence":"Medium","gaps":["Direct substrate underlying nociceptive signaling not identified","Whether NCS-1 is a CAPN1 substrate or transcriptional target unclear"]},{"year":null,"claim":"How CAPN1 selects between non-degradative activating cleavage (Dicer), substrate destruction (PHLPP1, NF1, PTPN1, AIF, BECN1/ATG5), and non-proteolytic sequestration (TFEB) in different cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying determinant of substrate fate identified","Cleavage sites for most substrates not mapped","Spatial/calcium-threshold control of substrate choice uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,5,7,9]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,10]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,4,5]}],"complexes":[],"partners":["PHLPP1","AIF","DICER","NF1","PTPN1","TFEB","CD99L2","CAST"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07384","full_name":"Calpain-1 catalytic subunit","aliases":["Calcium-activated neutral proteinase 1","CANP 1","Calpain mu-type","Calpain-1 large subunit","Cell proliferation-inducing gene 30 protein","Micromolar-calpain","muCANP"],"length_aa":714,"mass_kda":81.9,"function":"Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction (PubMed:19617626, PubMed:21531719, PubMed:2400579). Proteolytically cleaves CTBP1 at 'Asn-375', 'Gly-387' and 'His-409' (PubMed:23707407). Cleaves and activates caspase-7 (CASP7) (PubMed:19617626)","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P07384/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CAPN1","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MAP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CAPN1","total_profiled":1310},"omim":[{"mim_id":"617632","title":"EF-HAND CALCIUM-BINDING DOMAIN-CONTAINING PROTEIN 7; EFCAB7","url":"https://www.omim.org/entry/617632"},{"mim_id":"616907","title":"SPASTIC PARAPLEGIA 76, AUTOSOMAL RECESSIVE; SPG76","url":"https://www.omim.org/entry/616907"},{"mim_id":"616293","title":"HORNERIN; HRNR","url":"https://www.omim.org/entry/616293"},{"mim_id":"616284","title":"FILAGGRIN FAMILY MEMBER 2; FLG2","url":"https://www.omim.org/entry/616284"},{"mim_id":"608633","title":"CASPASE 12, APOPTOSIS-RELATED CYSTEINE PROTEASE; CASP12","url":"https://www.omim.org/entry/608633"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"esophagus","ntpm":267.3}],"url":"https://www.proteinatlas.org/search/CAPN1"},"hgnc":{"alias_symbol":["muCANP","muCL","CANP","CANPL1"],"prev_symbol":[]},"alphafold":{"accession":"P07384","domains":[{"cath_id":"-","chopping":"28-218","consensus_level":"high","plddt":95.3275,"start":28,"end":218},{"cath_id":"3.90.70.10","chopping":"222-353","consensus_level":"high","plddt":91.1739,"start":222,"end":353},{"cath_id":"2.60.120.380","chopping":"367-406_415-430_440-526","consensus_level":"high","plddt":91.8831,"start":367,"end":526},{"cath_id":"1.10.238.10","chopping":"541-714","consensus_level":"high","plddt":88.75,"start":541,"end":714}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07384","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07384-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07384-F1-predicted_aligned_error_v6.png","plddt_mean":89.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAPN1","jax_strain_url":"https://www.jax.org/strain/search?query=CAPN1"},"sequence":{"accession":"P07384","fasta_url":"https://rest.uniprot.org/uniprotkb/P07384.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07384/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07384"}},"corpus_meta":[{"pmid":"12542147","id":"PMC_12542147","title":"Evaluation of single-nucleotide polymorphisms in CAPN1 for association with meat tenderness in cattle.","date":"2002","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/12542147","citation_count":123,"is_preprint":false},{"pmid":"16100054","id":"PMC_16100054","title":"A new single nucleotide polymorphism in CAPN1 extends the current tenderness marker test to include cattle of Bos indicus, Bos taurus, and crossbred descent.","date":"2005","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/16100054","citation_count":110,"is_preprint":false},{"pmid":"27320912","id":"PMC_27320912","title":"Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27320912","citation_count":91,"is_preprint":false},{"pmid":"33597260","id":"PMC_33597260","title":"Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy.","date":"2021","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33597260","citation_count":82,"is_preprint":false},{"pmid":"15537766","id":"PMC_15537766","title":"Association of markers in the bovine CAPN1 gene with meat tenderness in large crossbred populations that sample influential industry sires.","date":"2004","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/15537766","citation_count":73,"is_preprint":false},{"pmid":"34879549","id":"PMC_34879549","title":"Chlorpyrifos triggers epithelioma papulosum cyprini cell pyroptosis via miR-124-3p/CAPN1 axis.","date":"2021","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/34879549","citation_count":67,"is_preprint":false},{"pmid":"23741357","id":"PMC_23741357","title":"Missense mutation in CAPN1 is associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23741357","citation_count":55,"is_preprint":false},{"pmid":"15621511","id":"PMC_15621511","title":"Identification and molecular characterization of the rainbow trout calpains (Capn1 and Capn2): their expression in muscle wasting during starvation.","date":"2005","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15621511","citation_count":47,"is_preprint":false},{"pmid":"35525317","id":"PMC_35525317","title":"Cisplatin-induced pyroptosis is mediated via the CAPN1/CAPN2-BAK/BAX-caspase-9-caspase-3-GSDME axis in esophageal cancer.","date":"2022","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/35525317","citation_count":45,"is_preprint":false},{"pmid":"21450414","id":"PMC_21450414","title":"Investigation on CAST, CAPN1 and CAPN3 porcine gene polymorphisms and expression in relation to post-mortem calpain activity in muscle and meat quality.","date":"2011","source":"Meat science","url":"https://pubmed.ncbi.nlm.nih.gov/21450414","citation_count":44,"is_preprint":false},{"pmid":"11048924","id":"PMC_11048924","title":"Bovine CAPN1 maps to a region of BTA29 containing a quantitative trait locus for meat tenderness.","date":"2000","source":"Journal of animal 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Crossing calpain-1 KO mice with PHLPP1 KO mice rescued granule cell density and motor coordination, establishing epistatic pathway placement.\",\n      \"method\": \"Calpain-1 knockout mice, genetic epistasis (calpain-1 KO × PHLPP1 KO double mutant), pharmacological Akt activation (bisperoxovanadium injection), cerebellar granule cell apoptosis assay, synaptic transmission analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis with double-KO rescue, pharmacological rescue, multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"27320912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In a DSG2-mutant ACM model, calcium overload activates CAPN1, which associates with mitochondria and cleaves mitochondrial-bound apoptosis-inducing factor (AIF). Cleaved AIF translocates to the nucleus, triggering large-scale DNA fragmentation and necrotic cell death. Overexpression of calpastatin (CAST), an endogenous CAPN1 inhibitor, protected against Ca2+-overload-induced necrosis, and pharmacological CAPN1 inhibition attenuated AIF truncation in cardiomyocytes.\",\n      \"method\": \"Dsg2 mutant mouse model (swimming exercise), co-immunoprecipitation (CAPN1 with mitochondria-associated AIF), calpain activity assay, calpastatin overexpression in cardiomyocytes, embryonic stem cell-derived cardiomyocytes with β-adrenergic stimulation and calpain inhibitor treatment, AIF-mimetic peptide blocking PPIA-mediated nuclear translocation\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, genetic KO/OE, pharmacological inhibition, rescue experiments) in a single rigorous study with defined molecular mechanism\",\n      \"pmids\": [\"33597260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CAPN1 activation under ischemic conditions impairs lysosomal membrane integrity and cleaves autophagy regulators BECN1 (Beclin1) and ATG5, thereby suppressing autophagosome formation and blocking autophagic flux, which contributes to neuronal death.\",\n      \"method\": \"Adeno-associated virus-mediated CAPN1 knockdown in rat permanent middle cerebral artery occlusion model; pharmacological inhibition with MDL-28170; oxygen-glucose deprivation in primary neurons; lysosomal membrane permeabilization assay; autophagic substrate accumulation assay; 3-methyladenine and chloroquine co-treatment to reverse neuroprotection\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown plus pharmacological inhibition with functional rescue, single lab, two orthogonal methods\",\n      \"pmids\": [\"33874744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CAPN1 physically interacts with tumor suppressor NF1 (neurofibromin 1) in melanoma cells and mediates its degradation. ShRNA knockdown of CAPN1 or calpain inhibitor treatment stabilizes NF1 protein and downregulates AKT signaling.\",\n      \"method\": \"Mass spectrometry analysis of NF1 binding partners identifying CAPN1; shRNA-mediated CAPN1 knockdown; calpain inhibitor treatment; NF1 protein stability assay; AKT signaling readout; combination treatment with MEK inhibitor Trametinib\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — MS-based interaction discovery plus functional validation with shRNA and inhibitor, single lab\",\n      \"pmids\": [\"30131853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAPN1 inhibits NF1 (neurofibromin) protein levels in medullary thyroid cancer cells, sustaining RAS/RET-driven AKT and ERK activation; shRNA depletion or pharmacological inhibition of CAPN1 stabilizes NF1 and reduces downstream RAS/RET signaling.\",\n      \"method\": \"Proteomic profiling of MTC cells and tumors; shRNA-mediated CAPN1 depletion; calpain inhibitor treatment; xenograft tumor growth assay; Western blot for NF1, AKT, ERK; in vitro combination treatment with vandetanib/selpercatinib\",\n      \"journal\": \"Thyroid : official journal of the American Thyroid Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification plus functional genetic and pharmacological validation, single lab, multiple readouts\",\n      \"pmids\": [\"39868924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CAPN1 degrades PTPN1 (protein tyrosine phosphatase 1) protein in lung adenocarcinoma cells; loss of PTPN1 leads to increased phosphorylation of c-Met and PIK3R2, enhancing cell proliferation, metastasis, and erlotinib resistance. Co-IP confirmed physical interaction between CAPN1 and PTPN1, and cycloheximide chase confirmed CAPN1-dependent PTPN1 protein destabilization.\",\n      \"method\": \"Co-immunoprecipitation (CAPN1–PTPN1 interaction); cycloheximide protein synthesis block assay; Western blot; CCK-8 proliferation, colony formation, and transwell invasion assays; shRNA/overexpression of CAPN1 and PTPN1\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus CHX chase and multiple functional readouts, single lab\",\n      \"pmids\": [\"32395869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cisplatin activates CAPN1/CAPN2 in esophageal cancer cells, which in turn activates BAK/BAX, leading to caspase-9 and caspase-3 activation and GSDME cleavage, resulting in pyroptosis. Calpain inhibition or CAPN1/CAPN2 knockout suppressed cisplatin-induced pyroptosis.\",\n      \"method\": \"Proteomics screening; calpain activity assay; LDH release assay; cell viability assay; CAPN1/CAPN2 knockout; Western blot for BAK/BAX, caspase-9, caspase-3, GSDME\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CAPN1/2 KO plus pharmacological inhibition with pathway-level Western blot readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35525317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A missense mutation in CAPN1 (cysteine to tyrosine at residue 115) causes spinocerebellar ataxia in Parson Russell Terrier dogs. Cysteine 115 forms part of the catalytic triad essential for cysteine protease enzymatic activity, indicating that CAPN1 catalytic activity is required for cerebellar function.\",\n      \"method\": \"GWAS and target-enriched massively-parallel sequencing; Sanger sequencing validation; conservation analysis of catalytic triad residues across species\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic mapping with functionally annotated catalytic residue, replicated across species by subsequent human studies\",\n      \"pmids\": [\"23741357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In μ-calpain (CAPN1) knockout mice, absence of calpain-1 leads to compensatory upregulation of m-calpain (CAPN2) protein abundance and activity, and caspase 3/7 activity; older KO mice accumulate more protein in skeletal muscle with increased fast-twitch glycolytic fiber size and number, indicating calpain-1's role in muscle protein turnover and fiber-type maintenance.\",\n      \"method\": \"Calpain-1 knockout mice; calpain activity assay; caspase 3/7 activity assay; protein:DNA and RNA:DNA ratio measurement; muscle fiber type immunohistochemistry; myoD and NCAM expression analysis\",\n      \"journal\": \"Journal of animal science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with multiple cellular phenotype readouts, single lab\",\n      \"pmids\": [\"23798514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Calpain-1 (CAPN1) cleaves Dicer in mouse brain, generating an active Dicer fragment with RNase III activity that promotes miRNA formation. Loss of calpain-1 in KO mice reduces active Dicer levels and alters neurodegeneration-related miRNA expression; reconstitution with calpain-1 and calcium in vitro restored Dicer activity.\",\n      \"method\": \"Calpain-1 KO mouse brain homogenates; in vitro incubation of calpain-1 with calcium and brain lysates; miRNA sequencing; Dicer activity assay; Western blot for Dicer cleavage fragments\",\n      \"journal\": \"BBA advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of Dicer cleavage by calpain-1 plus calcium, validated in KO mouse brain, single lab\",\n      \"pmids\": [\"34286311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAPN1 physically interacts with TFEB (transcription factor EB) in cells infected with Pseudomonas aeruginosa and prevents TFEB nuclear translocation, thereby inhibiting the autophagy-lysosome pathway and promoting bacterial infection-induced acute lung injury. CAPN1-deficient mice show reversal of PAK-induced autolysosome suppression.\",\n      \"method\": \"Co-immunoprecipitation and GST pull-down of CAPN1–TFEB interaction; immunofluorescence for TFEB localization; Western blot; CAPN1 knockout mice; transmission electron microscopy of autolysosomes\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP and pull-down plus KO mouse validation and localization experiment, single lab\",\n      \"pmids\": [\"40081346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CD99L2, a transmembrane protein, is an activating interactor of CAPN1. Loss of CD99L2 function (ablation of cytoplasmic or extracellular domains) causes its intracellular mislocalization and abrogates its interaction with CAPN1, impairing CAPN1 activation and dysregulating downstream neuronal pathways, causing spastic ataxia.\",\n      \"method\": \"Cellular interaction studies; domain deletion constructs of CD99L2; localization assays; transcriptome analysis in patient-derived fibroblasts; exome/genome sequencing of ataxia cohort\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — cellular interaction and domain-deletion experiments with functional outcome, single study\",\n      \"pmids\": [\"41690933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Spinal overexpression of CAPN1 restricted to CaMKII neurons reproduces paclitaxel-induced neuropathic pain in naive rats. CAPN1 overexpression elevates NCS-1 (neuronal calcium sensor-1) expression, which in turn strengthens CAPN2 expression and calpain enzymatic activity, identifying a CAPN1→NCS-1→CAPN2 signaling axis in nociceptive neurons.\",\n      \"method\": \"Intraspinal viral vector-mediated CAPN1 overexpression in CaMKII neurons; pain threshold measurement; Western blot for NCS-1, CAPN2, spectrin degradation products; immunofluorescence co-localization\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neuron-specific overexpression with defined phenotypic and molecular readouts, single lab\",\n      \"pmids\": [\"41482880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Deletion of the Capn1 gene in mice alters expression of genes in Protein Processing in ER, MAP kinase, and Alzheimer's disease KEGG pathways in brain, with most differentially expressed genes being down-regulated, implicating calpain-1 in transcriptional regulation of multiple brain function pathways.\",\n      \"method\": \"RNA-seq on brain tissue of Capn1 knockout vs. wild-type mice; Western blot validation of selected protein levels; KEGG pathway enrichment analysis\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptomic profiling with limited protein-level validation, no direct mechanistic experiments on pathway placement, single lab\",\n      \"pmids\": [\"32328086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Dexamethasone inhibits osteogenic differentiation of rat BMSCs by modulating the CAST-CAPN1 axis: DEX downregulates CAST (calpastatin) and upregulates CAPN1, reducing ATP5A1 levels and ATP activity; overexpression of CAST partially rescued osteogenic differentiation, while overexpression of CAPN1 exacerbated DEX effects and reversed CAST's rescue.\",\n      \"method\": \"qRT-PCR and Western blot for CAST, CAPN1, ATP5A1; CAPN1 and CAST overexpression plasmids; Alizarin Red S staining; ELISA for ATP activity and osteogenic markers\",\n      \"journal\": \"Discovery medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression experiments with functional readout but no direct biochemical substrate cleavage assay, single lab, single study\",\n      \"pmids\": [\"40116104\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAPN1 (calpain-1/μ-calpain) is a calcium-activated cysteine protease whose catalytic triad (including the essential C115 residue) is required for its activity; it cleaves specific substrates including PHLPP1 (activating Akt pro-survival signaling in neurons), AIF (triggering mitochondria-to-nucleus apoptotic signaling in cardiomyocytes), Dicer (generating active miRNA-processing fragments in brain), PTPN1 (relieving dephosphorylation of c-Met/PIK3R2 in cancer), and NF1 (destabilizing the RAS-GAP tumor suppressor); it is activated by the interacting protein CD99L2, is inhibited by calpastatin (CAST), and when dysregulated impairs autophagic flux through lysosomal membrane permeabilization and cleavage of Beclin1/ATG5, or by sequestering TFEB from the nucleus, collectively placing CAPN1 at the intersection of neuronal survival, cardiomyocyte death, muscle protein homeostasis, and oncogenic signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CAPN1 (calpain-1/\\u03bc-calpain) is a calcium-activated cysteine protease that acts through regulated proteolysis of specific intracellular substrates to control cell survival, death, and signaling across neuronal, cardiac, muscle, and oncogenic contexts [#0, #7]. Its enzymatic function depends on a catalytic triad including cysteine-115, and a C115Y mutation abolishing protease activity causes spinocerebellar ataxia [#7]. In neurons, CAPN1 cleaves PHLPP1 to sustain Akt pro-survival signaling, and loss of this cleavage drives developmental apoptosis of cerebellar granule cells [#0], while it also processes Dicer into an active RNase III fragment that shapes brain miRNA pools [#9]. Conversely, pathological CAPN1 activation is destructive: under calcium overload in cardiomyocytes it associates with mitochondria and cleaves AIF, driving its nuclear translocation and necrotic death [#1], and in ischemic neurons it permeabilizes lysosomal membranes and cleaves the autophagy regulators BECN1 and ATG5 to block autophagic flux [#2]. CAPN1 additionally restrains autophagy by sequestering the transcription factor TFEB from the nucleus during bacterial infection [#10]. In cancer, CAPN1 degrades the tumor suppressors NF1 and the phosphatase PTPN1, thereby sustaining RAS/RET\\u2013AKT/ERK and c-Met/PIK3R2 signaling [#3, #4, #5]. CAPN1 activity is gated by the activating transmembrane interactor CD99L2 and opposed by the endogenous inhibitor calpastatin (CAST) [#11, #1, #14].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that CAPN1 catalytic protease activity, not merely its presence, is required for cerebellar function, by linking a catalytic-triad mutation to disease.\",\n      \"evidence\": \"GWAS and targeted sequencing of ataxic Parson Russell Terriers identifying a C115Y mutation in the catalytic triad\",\n      \"pmids\": [\"23741357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the neuronal substrate whose loss of cleavage produces ataxia\", \"Catalytic-dead phenotype inferred from conservation rather than reconstituted enzymology\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined CAPN1's homeostatic role in muscle protein turnover and revealed compensatory upregulation of CAPN2 when CAPN1 is lost.\",\n      \"evidence\": \"Calpain-1 knockout mice with calpain/caspase activity assays, protein:DNA ratios, and fiber-type immunohistochemistry\",\n      \"pmids\": [\"23798514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No muscle-specific proteolytic substrate identified\", \"Mechanism of CAPN2 compensatory upregulation unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed CAPN1 upstream of Akt pro-survival signaling in neurons by showing it cleaves the phosphatase PHLPP1, resolving how CAPN1 loss causes granule-cell apoptosis.\",\n      \"evidence\": \"Calpain-1 KO mice, calpain-1 \\u00d7 PHLPP1 double-KO genetic epistasis with rescue, pharmacological Akt activation\",\n      \"pmids\": [\"27320912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site within PHLPP1 not mapped biochemically\", \"Does not address non-neuronal PHLPP1 regulation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Introduced an oncogenic role for CAPN1 by showing it physically binds and destabilizes the tumor suppressor NF1, linking CAPN1 to AKT-driven melanoma signaling.\",\n      \"evidence\": \"Mass-spectrometry interactor screen, shRNA knockdown, calpain inhibitor, NF1 stability assay in melanoma cells\",\n      \"pmids\": [\"30131853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct proteolytic cleavage of NF1 by CAPN1 not demonstrated biochemically\", \"Single lab, single cancer type\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended CAPN1-mediated substrate degradation to PTPN1 in lung cancer, connecting CAPN1 to c-Met/PIK3R2 phosphorylation and drug resistance.\",\n      \"evidence\": \"Co-IP, cycloheximide chase for protein destabilization, proliferation/invasion assays with shRNA and overexpression\",\n      \"pmids\": [\"32395869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Direct cleavage versus accelerated turnover not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a death-effector role for CAPN1 in cardiomyocytes via mitochondrial AIF cleavage and nuclear translocation, and showed calpastatin opposes this.\",\n      \"evidence\": \"DSG2-mutant ACM mouse model, Co-IP, calpain activity assay, calpastatin overexpression, pharmacological inhibition, AIF-mimetic peptide\",\n      \"pmids\": [\"33597260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"AIF cleavage site not mapped\", \"Generalizability beyond DSG2-mutant calcium-overload setting untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed CAPN1 blocks autophagic flux during ischemia by permeabilizing lysosomes and cleaving BECN1 and ATG5, linking its activation to neuronal death.\",\n      \"evidence\": \"AAV-mediated knockdown in rat MCAO model, MDL-28170 inhibition, OGD in neurons, lysosomal permeabilization and autophagy substrate assays with 3-MA/chloroquine rescue\",\n      \"pmids\": [\"33874744\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage of BECN1/ATG5 not reconstituted in vitro\", \"Relationship between lysosomal permeabilization and substrate cleavage order unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a non-degradative activating proteolysis function: CAPN1 cleaves Dicer to generate an active RNase III fragment that controls brain miRNA production.\",\n      \"evidence\": \"Calpain-1 KO mouse brain, in vitro reconstitution with calpain-1 plus calcium, miRNA-seq, Dicer activity and cleavage Western blots\",\n      \"pmids\": [\"34286311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequences of altered miRNA pools not functionally tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned CAPN1 (with CAPN2) as an upstream activator of mitochondrial apoptosis and GSDME-dependent pyroptosis in response to cisplatin.\",\n      \"evidence\": \"Proteomics, CAPN1/CAPN2 knockout, calpain inhibition, LDH/viability assays, Western blot for BAK/BAX, caspases, GSDME in esophageal cancer cells\",\n      \"pmids\": [\"35525317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct calpain substrate triggering BAK/BAX activation not identified\", \"CAPN1 versus CAPN2 specific contributions not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Generalized CAPN1's NF1-destabilizing oncogenic function to medullary thyroid cancer, sustaining RAS/RET\\u2013AKT/ERK signaling.\",\n      \"evidence\": \"Proteomic profiling, shRNA depletion, calpain inhibitor, xenograft assays, combination with vandetanib/selpercatinib\",\n      \"pmids\": [\"39868924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NF1 cleavage by CAPN1 not biochemically demonstrated\", \"In vivo on-target specificity of inhibitor not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked CAPN1 to autophagy suppression during infection through physical sequestration of TFEB, preventing its nuclear translocation.\",\n      \"evidence\": \"Co-IP and GST pull-down of CAPN1\\u2013TFEB, TFEB localization imaging, CAPN1 KO mice, autolysosome electron microscopy in P. aeruginosa lung injury\",\n      \"pmids\": [\"40081346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TFEB is cleaved or only bound is unresolved\", \"Calcium dependence of the interaction not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified CD99L2 as an activating, localization-dependent interactor of CAPN1, defining how upstream input regulates CAPN1 activity in neurons.\",\n      \"evidence\": \"Cellular interaction and domain-deletion constructs, localization assays, patient fibroblast transcriptomics, exome/genome sequencing of a spastic ataxia cohort\",\n      \"pmids\": [\"41690933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CD99L2 binding activates CAPN1 unknown\", \"Downstream neuronal substrates not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated CAPN1 as a sufficient driver of neuropathic pain via a CAPN1\\u2192NCS-1\\u2192CAPN2 amplification axis in spinal neurons.\",\n      \"evidence\": \"Neuron-specific intraspinal CAPN1 overexpression in rats, pain threshold measurement, Western blot for NCS-1/CAPN2/spectrin breakdown\",\n      \"pmids\": [\"41482880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate underlying nociceptive signaling not identified\", \"Whether NCS-1 is a CAPN1 substrate or transcriptional target unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CAPN1 selects between non-degradative activating cleavage (Dicer), substrate destruction (PHLPP1, NF1, PTPN1, AIF, BECN1/ATG5), and non-proteolytic sequestration (TFEB) in different cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying determinant of substrate fate identified\", \"Cleavage sites for most substrates not mapped\", \"Spatial/calcium-threshold control of substrate choice uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 5, 7, 9]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PHLPP1\", \"AIF\", \"Dicer\", \"NF1\", \"PTPN1\", \"TFEB\", \"CD99L2\", \"CAST\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}