{"gene":"IDE","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1998,"finding":"Insulin-degrading enzyme (IDE) was purified and identified as the principal protease responsible for degrading extracellular amyloid beta-protein (Aβ) under biologically relevant conditions. IDE was found in both cytosol and released into conditioned medium by intact microglial cells, and its Aβ-degrading activity was abolished by competitive IDE substrates (insulin) and IDE inhibitors, and removed by immunodepletion with an IDE antibody. IDE activity was also associated with time-dependent oligomerization of synthetic Aβ.","method":"Protein purification, competitive inhibition assay, immunodepletion, identification of IDE in human cerebrospinal fluid","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution and purification with multiple orthogonal inhibitor/immunodepletion controls; foundational study","pmids":["9830016"],"is_preprint":false},{"year":2000,"finding":"In differentiated neurons, IDE localizes to the cell surface (membrane-associated form ~5 kDa larger than cytosolic form) rather than being secreted, and this membrane-associated IDE degrades extracellularly secreted Aβ. Overexpression of IDE markedly reduced steady-state extracellular Aβ(40) and Aβ(42), while a catalytic site mutation (E111Q) abolished this effect.","method":"Cell-surface biotinylation, overexpression with active-site mutagenesis, primary neuronal cultures, PC12 differentiation model","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 — active-site mutagenesis combined with localization and functional assays in primary neurons","pmids":["10684867"],"is_preprint":false},{"year":2003,"finding":"IDE knockout mice (IDE−/−) showed >50% decrease in Aβ degradation in brain membrane fractions and primary neuronal cultures, and a similar deficit in insulin degradation in liver, resulting in increased cerebral Aβ accumulation, hyperinsulinemia, and glucose intolerance. IDE also degrades the intracellular APP domain (AICD) released by γ-secretase in vivo.","method":"IDE knockout mouse model, primary neuronal cultures, ex vivo brain membrane degradation assays, metabolic phenotyping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vivo genetic loss-of-function with multiple orthogonal biochemical readouts","pmids":["12634421"],"is_preprint":false},{"year":2004,"finding":"Insulin receptor signaling via PI3 kinase/Akt upregulates IDE protein levels in primary hippocampal neurons (~25% increase with insulin treatment), establishing a negative feedback mechanism. PI3 kinase inhibitors (wortmannin, LY294002) abolished IDE upregulation. Reduced PI3K subunit P85 correlated with reduced IDE in AD brains and APP transgenic mice on a high-fat diet, with associated increases in Aβ monomer.","method":"Primary hippocampal neuron culture, PI3K inhibitor treatment, western blotting, analysis of AD brain tissue and transgenic mouse model","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (pharmacological inhibition, in vivo correlation) across in vitro and in vivo systems","pmids":["15590928"],"is_preprint":false},{"year":2006,"finding":"Crystal structures of human IDE in complex with four substrates (insulin B chain, Aβ1–40, amylin, glucagon) revealed that IDE-N and IDE-C domains form an enclosed substrate-degradation chamber. Substrate access requires repositioning of the domains; IDE uses size and charge distribution of the cavity for selective substrate entrapment. Substrates undergo conformational changes forming β-sheets with two discrete IDE regions. Mutations disrupting the IDE-N/IDE-C interface increased catalytic activity ~40-fold.","method":"X-ray crystallography (multiple substrate-bound structures), active-site and interface mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution structures with four substrates plus mutagenesis validation in a single study","pmids":["17051221"],"is_preprint":false},{"year":2007,"finding":"SIRT4, a mitochondrial ADP-ribosyltransferase, was found to co-immunoprecipitate with IDE and the ADP/ATP carrier proteins ANT2 and ANT3 in mitochondria. SIRT4 depletion in insulin-producing INS-1E cells increased glucose-stimulated insulin secretion, implicating the SIRT4–IDE interaction in regulation of insulin secretion.","method":"Co-immunoprecipitation, mass spectrometry, siRNA depletion in pancreatic beta-cell line","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP/MS identification of interaction with functional depletion data, single study","pmids":["17715127"],"is_preprint":false},{"year":2010,"finding":"Deletion of the putative dimer interface in the C-terminal region of IDE produced a monomeric variant that retained enzymatic activity but displayed Michaelis-Menten kinetics instead of allosteric behavior. Monomeric IDE retained ~25% activity on small peptide substrates but only 0.25–1% on larger substrates (β-endorphin, Aβ1–40). Neither bradykinin, dynorphin B-9, nor polyphosphates could activate the monomeric variant, demonstrating that oligomerization (predominantly dimer) is required for IDE's allosteric regulatory properties and conformational activation.","method":"Site-directed mutagenesis of dimer interface, analytical ultracentrifugation/gel filtration, enzyme kinetics with multiple substrates and activators","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — reconstituted mutant enzyme with rigorous kinetic analysis across multiple substrates and activators","pmids":["20300529"],"is_preprint":false},{"year":2011,"finding":"BRI2 (ITM2B) overexpression reduces extracellular Aβ levels by increasing secreted IDE protein. This effect was observed with both wild-type BRI2 and its disease-associated mutant ADanPP, and was retained by a BRI2 construct lacking its C-terminal 23-amino acid peptide, suggesting BRI2 acts as a receptor-like regulator of IDE secretion and thereby influences APP/Aβ metabolism.","method":"Overexpression in cell lines, IDE secretion assay (western blot of conditioned medium), Aβ ELISA, in vivo AD mouse model plaque quantification","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2/3 — functional overexpression with mechanistic follow-up (IDE secretion measurement), single lab","pmids":["21873424"],"is_preprint":false},{"year":2012,"finding":"IDE behaves as a heat shock-like protein: normal and malignant cells exposed to various stresses (heat, oxidative, genotoxic) markedly upregulate IDE expression. In neuroblastoma cells (SHSY5Y), IDE silencing inhibits cell proliferation and triggers cell death. IDE co-immunoprecipitates with proteasome components and ubiquitin, and IDE inhibition decreases poly-ubiquitinated protein content, indicating a role for IDE in ubiquitin/proteasome-related protein quality control.","method":"Stress induction assays (heat shock, oxidative stress), IDE knockdown, cell proliferation/death assays, co-immunoprecipitation with proteasome and ubiquitin","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus functional KD phenotype, single lab, multiple cell stress conditions","pmids":["23188819"],"is_preprint":false},{"year":2013,"finding":"IDE knockout mice show decreased glucose-stimulated insulin secretion (GSIS) due to impaired replenishment of the releasable granule pool, and the Ide gene is haploinsufficient for this phenotype. IDE KO β-cells also have reduced autophagic flux and microtubule content. α-Synuclein levels are inversely correlated with IDE in β-cells of IDE KO mice and T2D patients; both gain- and loss-of-function of α-synuclein in vivo impair GSIS and autophagy, identifying IDE as a regulator of GSIS and β-cell amyloidogenic protein homeostasis.","method":"Ide knockout and haploinsufficient mouse models, GSIS assay, autophagy flux measurements, microtubule quantification, α-synuclein gain/loss-of-function in vivo","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1–2 — multiple genetic models (KO, haploinsufficiency, α-syn GOF/LOF) with orthogonal cellular readouts","pmids":["23349488"],"is_preprint":false},{"year":2008,"finding":"Endogenous IDE is present in detergent-resistant membrane (DRM) microdomains (lipid rafts) in brain tissue and cultured cells, in addition to its cytosolic localization. DRM-associated IDE co-localizes with Aβ. Displacement of IDE from DRMs by methyl-β-cyclodextrin (MβCD) caused extracellular Aβ accumulation and impaired exogenous Aβ proteolysis. Mice with reduced cholesterol (seladin-1 heterozygous knockout) had less IDE in DRMs. A moderate shift of IDE from DRMs substantially decreased IDE-mediated insulin and Aβ degradation in vitro.","method":"Live immunofluorescence, immunogold electron microscopy, sucrose gradient fractionation, pulse-chase, MβCD treatment, seladin-1 KO mouse brain fractionation","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal localization and functional methods (EM, fractionation, pharmacological displacement) with in vivo validation","pmids":["19117523"],"is_preprint":false},{"year":2017,"finding":"Renal sorting nexin 5 (SNX5) positively regulates IDE expression and activity. SNX5 co-localizes and co-immunoprecipitates with IDE at the plasma membrane and perinuclear area of human renal proximal tubule cells (hRPTCs) and in the brush border membrane of proximal tubules. Insulin increases the co-localization and co-immunoprecipitation of SNX5 and IDE. Silencing SNX5 decreases IDE expression and activity, impairs insulin/glucose responses, and increases blood insulin and glucose in mice. Spontaneously hypertensive rats have decreased renal SNX5 and IDE.","method":"Co-immunoprecipitation, confocal co-localization, siRNA knockdown in hRPTCs, renal-selective siRNA infusion in uninephrectomized mice, metabolic phenotyping","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, localization, and in vivo knockdown with defined metabolic phenotype","pmids":["29080975"],"is_preprint":false},{"year":2019,"finding":"SIRT4 interacts with PTEN and bridges PTEN to IDE for lysosomal degradation in response to nutritional starvation stress. SIRT4 overexpression causes PTEN downregulation independently of acetylation and ubiquitination. This SIRT4–IDE–PTEN axis promotes cell survival under nutrient stress by lowering PTEN levels and thereby de-repressing the PI3K–AKT–mTOR pathway.","method":"Co-immunoprecipitation, overexpression/knockdown, lysosome inhibitor experiments, PTEN stability assays under starvation conditions","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP with mechanistic follow-up (lysosomal pathway, starvation stress), single lab","pmids":["30649986"],"is_preprint":false},{"year":2020,"finding":"SARS-CoV-2 protein–protein interaction mapping by affinity-purification mass spectrometry identified IDE as a high-confidence interaction partner of SARS-CoV-2 Nsp2 in human cells.","method":"Affinity-purification mass spectrometry (AP-MS) in HEK293T cells expressing tagged viral proteins","journal":"Nature","confidence":"Low","confidence_rationale":"Tier 3 — single AP-MS identification; functional consequence of IDE–Nsp2 interaction not yet characterized","pmids":["32353859"],"is_preprint":false},{"year":2023,"finding":"IDE absence in knockout mice induces specific microgliosis in the hippocampus without astrogliosis. In primary microglial cultures, IDE absence impairs modulation of phenotypic states in response to environmental signals, with only transitory effects on Aβ management. These effects cannot be explained by IDE enzymatic activity alone, indicating a non-enzymatic role for IDE in modulating microglial function relevant to aging and Alzheimer's disease.","method":"IDE knockout mouse model (full KO and haploinsufficiency), primary microglial cultures, behavioral testing, immunohistochemistry, functional microglial phenotyping assays","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function in vivo and in vitro with defined cellular phenotype, single study","pmids":["37817156"],"is_preprint":false}],"current_model":"IDE is a Zn2+-metalloendopeptidase that forms an enclosed, allosterically regulated degradation chamber (requiring oligomerization/dimerization) to selectively encapsulate and cleave structurally diverse substrates including insulin, Aβ, AICD, amylin, and glucagon; it localizes to cytosol, detergent-resistant membrane microdomains, and the cell surface (and is secreted extracellularly), where its activity is regulated by insulin receptor/PI3K/Akt signaling, by SNX5-mediated control of expression/activity in renal proximal tubules, and by SIRT4-mediated substrate (PTEN) targeting for lysosomal degradation; in pancreatic β-cells IDE regulates glucose-stimulated insulin secretion and autophagic flux partly through clearance of amyloidogenic α-synuclein, and in microglia it plays a non-enzymatic role in modulating phenotypic responses relevant to neuroinflammation and Alzheimer's disease."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of IDE as the principal extracellular Aβ-degrading protease established a direct link between insulin metabolism and amyloid clearance, opening the field of IDE-mediated neuroprotection.","evidence":"Purification from microglial conditioned medium with competitive inhibition, immunodepletion, and CSF detection","pmids":["9830016"],"confidence":"High","gaps":["Relative contribution of IDE versus other Aβ-degrading proteases (e.g., neprilysin) not delineated","Mechanism of IDE secretion unknown"]},{"year":2000,"claim":"Demonstration that a membrane-associated form of IDE on the neuronal cell surface degrades secreted Aβ resolved the topology paradox of how a predominantly cytosolic protease accesses extracellular substrates.","evidence":"Cell-surface biotinylation and catalytic-dead mutant (E111Q) in primary neurons and PC12 cells","pmids":["10684867"],"confidence":"High","gaps":["Mechanism of IDE membrane association and the nature of the ~5 kDa size difference from cytosolic IDE remain uncharacterized","Whether membrane-associated IDE preferentially targets Aβ40 versus Aβ42 unclear"]},{"year":2003,"claim":"IDE-knockout mice provided definitive genetic proof that IDE is a major in vivo regulator of both Aβ and insulin catabolism, linking IDE deficiency to hyperinsulinemia, glucose intolerance, and cerebral Aβ accumulation.","evidence":"IDE-null mouse with ex vivo brain membrane degradation, primary neuronal cultures, and metabolic phenotyping","pmids":["12634421"],"confidence":"High","gaps":["Relative contribution of hepatic versus neural IDE to systemic insulin clearance not resolved","Whether IDE degrades AICD in a physiologically rate-limiting manner in vivo unclear"]},{"year":2004,"claim":"Discovery that insulin receptor/PI3K/Akt signaling upregulates IDE expression established a negative-feedback loop coupling insulin signaling to its own degradation, with implications for insulin resistance in Alzheimer's disease.","evidence":"PI3K inhibitor treatment in primary hippocampal neurons and correlation with reduced IDE in AD brain tissue","pmids":["15590928"],"confidence":"High","gaps":["Transcriptional versus post-translational mechanism of PI3K-dependent IDE upregulation not defined","Causal direction of IDE reduction in AD brain not established"]},{"year":2006,"claim":"Crystal structures of IDE bound to insulin B chain, Aβ, amylin, and glucagon revealed the enclosed degradation chamber architecture and explained substrate selectivity through size/charge complementarity and β-sheet-mediated capture.","evidence":"X-ray crystallography of four substrate-bound complexes with mutagenesis of IDE-N/IDE-C interface","pmids":["17051221"],"confidence":"High","gaps":["Full-length insulin-bound structure not obtained","Structural basis for chamber opening/closing dynamics not captured"]},{"year":2008,"claim":"Localization of IDE to detergent-resistant membrane microdomains (lipid rafts) and the demonstration that raft displacement impairs Aβ and insulin degradation revealed that IDE's proteolytic function is spatially regulated by membrane cholesterol.","evidence":"Immunogold EM, sucrose gradient fractionation, MβCD treatment, and seladin-1 KO mouse validation","pmids":["19117523"],"confidence":"High","gaps":["Direct mechanism by which IDE associates with lipid rafts (lipid modification, adaptor protein) unknown","Whether raft-associated IDE represents a distinct post-translationally modified pool not determined"]},{"year":2010,"claim":"Engineering a monomeric IDE variant demonstrated that dimerization is required for allosteric activation and efficient degradation of large substrates, establishing oligomerization as a critical regulatory mechanism.","evidence":"Dimer-interface deletion mutant with kinetic analysis across multiple substrates and activators","pmids":["20300529"],"confidence":"High","gaps":["Whether physiological regulators modulate IDE oligomerization state in vivo not tested","Structural basis of allosteric communication between subunits unresolved"]},{"year":2013,"claim":"IDE-knockout and haploinsufficient β-cells revealed that IDE maintains glucose-stimulated insulin secretion by sustaining autophagic flux and clearing α-synuclein, linking IDE to β-cell proteostasis beyond its known catabolic role.","evidence":"IDE KO and haplo-insufficient mice, α-synuclein gain/loss-of-function in vivo, autophagy and microtubule quantification","pmids":["23349488"],"confidence":"High","gaps":["Whether IDE degrades α-synuclein directly or acts indirectly through autophagy modulation not resolved","Mechanism linking IDE to microtubule maintenance unclear"]},{"year":2017,"claim":"Identification of SNX5 as a positive regulator of IDE expression and activity in renal proximal tubules extended IDE regulation beyond neurons, showing that insulin-stimulated SNX5–IDE co-localization controls renal insulin clearance.","evidence":"Reciprocal Co-IP, confocal co-localization, renal-selective siRNA knockdown in mice with metabolic phenotyping","pmids":["29080975"],"confidence":"High","gaps":["Mechanism by which SNX5 stabilizes or promotes IDE expression not defined","Whether SNX5–IDE interaction is direct or mediated by a trafficking complex unknown"]},{"year":2019,"claim":"The finding that SIRT4 bridges PTEN to IDE for lysosomal degradation under starvation stress revealed a non-canonical IDE function in which the protease participates in targeted protein disposal through the lysosomal pathway, coupling nutrient sensing to PI3K–AKT–mTOR signaling.","evidence":"Co-IP, overexpression/knockdown, lysosome inhibitor rescue of PTEN under starvation","pmids":["30649986"],"confidence":"Medium","gaps":["Whether IDE directly cleaves PTEN or acts as a scaffold/adaptor for lysosomal targeting not distinguished","Single-lab finding; independent replication needed","Whether this pathway operates in neurons or β-cells unknown"]},{"year":2023,"claim":"IDE knockout induces hippocampal microgliosis and impairs microglial phenotypic switching through a mechanism independent of its enzymatic activity, establishing a non-catalytic scaffolding or signaling role in neuroinflammation.","evidence":"IDE-null and haploinsufficient mice, primary microglial cultures, immunohistochemistry, and functional phenotyping","pmids":["37817156"],"confidence":"Medium","gaps":["Molecular basis of IDE's non-enzymatic microglial function completely uncharacterized","Whether non-enzymatic role involves protein–protein interactions or structural scaffolding unknown","Relevance to human AD microglia not tested"]},{"year":null,"claim":"Key unresolved questions include the structural dynamics of IDE chamber gating in vivo, the molecular basis of its non-enzymatic functions in microglia and protein quality control, whether IDE oligomerization state is physiologically regulated, and the direct mechanism linking IDE to autophagic flux in β-cells.","evidence":"","pmids":[],"confidence":"High","gaps":["No in vivo structure of IDE captured in open/closed transition states","Non-enzymatic interactome of IDE undefined","Relative tissue-specific contributions to systemic insulin clearance not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4,6]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2,4,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,10,11]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,4,6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,9,14]}],"complexes":[],"partners":["SNX5","SIRT4","ANT2","ANT3","PTEN","ITM2B"],"other_free_text":[]},"mechanistic_narrative":"IDE is a Zn2+-metalloendopeptidase that forms a dimeric degradation chamber to selectively encapsulate and cleave structurally diverse amyloidogenic and metabolic peptides—including insulin, amyloid-β (Aβ), amylin, glucagon, and the APP intracellular domain (AICD)—thereby serving as a central regulator of peptide clearance in both metabolic and neurodegenerative contexts [PMID:9830016, PMID:17051221, PMID:12634421]. Crystal structures show that IDE-N and IDE-C halves enclose a size- and charge-selective chamber whose catalytic efficiency depends on oligomerization-mediated allosteric activation, with disruption of the dimer interface collapsing activity on large substrates and abolishing allosteric regulation [PMID:17051221, PMID:20300529]. IDE localizes to the cytosol, detergent-resistant membrane microdomains, and the cell surface, and its expression is upregulated by insulin receptor/PI3K/Akt signaling and by sorting nexin 5 in renal proximal tubules; IDE-knockout mice exhibit hyperinsulinemia, glucose intolerance, cerebral Aβ accumulation, impaired β-cell glucose-stimulated insulin secretion, and hippocampal microgliosis [PMID:10684867, PMID:19117523, PMID:15590928, PMID:29080975, PMID:12634421, PMID:23349488, PMID:37817156]. In pancreatic β-cells, IDE maintains autophagic flux and clears amyloidogenic α-synuclein to sustain releasable insulin granule pools, while in microglia it exerts a non-enzymatic role in phenotypic modulation relevant to neuroinflammation [PMID:23349488, PMID:37817156]."},"prefetch_data":{"uniprot":{"accession":"P14735","full_name":"Insulin-degrading enzyme","aliases":["Abeta-degrading protease","Insulin protease","Insulinase","Insulysin"],"length_aa":1019,"mass_kda":118.0,"function":"Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin, kallidin, and other peptides, and thereby plays a role in intercellular peptide signaling (PubMed:10684867, PubMed:17051221, PubMed:17613531, PubMed:18986166, PubMed:19321446, PubMed:21098034, PubMed:2293021, PubMed:23922390, PubMed:24847884, PubMed:26394692, PubMed:26968463, PubMed:29596046). Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin (PubMed:23922390, PubMed:26394692, PubMed:29596046). Contributes to the regulation of peptide hormone signaling cascades and regulation of blood glucose homeostasis via its role in the degradation of insulin, glucagon and IAPP (By similarity). Plays a role in the degradation and clearance of APP-derived amyloidogenic peptides that are secreted by neurons and microglia (Probable) (PubMed:26394692, PubMed:9830016). Degrades the natriuretic peptides ANP, BNP and CNP, inactivating their ability to raise intracellular cGMP (PubMed:21098034). Also degrades an aberrant frameshifted 40-residue form of NPPA (fsNPPA) which is associated with familial atrial fibrillation in heterozygous patients (PubMed:21098034). Involved in antigen processing. Produces both the N terminus and the C terminus of MAGEA3-derived antigenic peptide (EVDPIGHLY) that is presented to cytotoxic T lymphocytes by MHC class I (Microbial infection) The membrane-associated isoform acts as an entry receptor for varicella-zoster virus (VZV)","subcellular_location":"Cytoplasm, cytosol; Cell membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/P14735/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IDE","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IDE","total_profiled":1310},"omim":[{"mim_id":"620997","title":"SEMAPHORIN 3G; SEMA3G","url":"https://www.omim.org/entry/620997"},{"mim_id":"620764","title":"MITOCHONDRIAL SHEATH FORMATION-ASSOCIATED; MISFA","url":"https://www.omim.org/entry/620764"},{"mim_id":"619534","title":"BILIARY, RENAL, NEUROLOGIC, AND SKELETAL SYNDROME; BRENS","url":"https://www.omim.org/entry/619534"},{"mim_id":"618597","title":"BRAIN-ENRICHED GUANYLATE KINASE-ASSOCIATED PROTEIN; BEGAIN","url":"https://www.omim.org/entry/618597"},{"mim_id":"618211","title":"PITRILYSIN METALLOPEPTIDASE 1; PITRM1","url":"https://www.omim.org/entry/618211"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IDE"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P14735","domains":[{"cath_id":"3.30.830.10","chopping":"51-277","consensus_level":"high","plddt":97.752,"start":51,"end":277},{"cath_id":"3.30.830.10","chopping":"296-407_460-516","consensus_level":"high","plddt":98.1046,"start":296,"end":516},{"cath_id":"3.30.830.10","chopping":"550-763","consensus_level":"high","plddt":97.7557,"start":550,"end":763},{"cath_id":"3.30.830.10","chopping":"777-1002","consensus_level":"high","plddt":94.1675,"start":777,"end":1002}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14735","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14735-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14735-F1-predicted_aligned_error_v6.png","plddt_mean":94.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IDE","jax_strain_url":"https://www.jax.org/strain/search?query=IDE"},"sequence":{"accession":"P14735","fasta_url":"https://rest.uniprot.org/uniprotkb/P14735.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14735/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14735"}},"corpus_meta":[{"pmid":"19737565","id":"PMC_19737565","title":"Hepatitis 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(GSIS) in β-cells; Ide knockout mice show decreased GSIS due to impaired replenishment of the releasable granule pool, reduced autophagic flux, and reduced microtubule content. IDE levels are inversely correlated with α-synuclein levels in β-cells, and both gain and loss of α-synuclein function impair GSIS and autophagy.\",\n      \"method\": \"Ide knockout mouse model with glucose-stimulated insulin secretion assay, autophagic flux measurement, microtubule content analysis, and α-synuclein gain/loss-of-function experiments in vivo\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific cellular phenotype, multiple orthogonal methods, functional pathway placement\",\n      \"pmids\": [\"23349488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IDE functions as an obligate oligomer (primarily dimer) for its regulatory/allosteric properties; deletion of the dimer interface yields a monomeric variant that retains basic enzymatic activity but loses allosteric activation, Michaelis-Menten kinetics replace cooperative kinetics, and activity toward large substrates (β-endorphin, Aβ1-40) is reduced to 0.25–1% of wild type. Activators (bradykinin, dynorphin B-9, polyphosphates) fail to activate the monomer.\",\n      \"method\": \"Site-directed mutagenesis of dimer interface based on crystal structure, in vitro enzyme kinetics with multiple substrates, activator response assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-guided mutagenesis combined with rigorous in vitro kinetic analysis\",\n      \"pmids\": [\"20300529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT4 interacts with PTEN and IDE, bridging them to promote PTEN degradation via the lysosome pathway in response to nutritional starvation; IDE mediates SIRT4-dependent PTEN proteolysis independently of PTEN acetylation or ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown of SIRT4 and IDE, lysosome inhibitor experiments, Western blotting for PTEN levels under starvation stress\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — reciprocal Co-IP with functional follow-up in cells, single lab\",\n      \"pmids\": [\"30649986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sorting nexin 5 (SNX5) co-localizes and co-immunoprecipitates with IDE at the plasma membrane and perinuclear area of renal proximal tubule cells; renal-selective Snx5 silencing in mice decreases IDE protein and activity, reduces urinary insulin excretion, and causes insulin resistance and hyperglycemia, establishing SNX5 as a positive regulator of IDE expression and function.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, siRNA-mediated silencing in human renal proximal tubule cells and in vivo renal-selective knockdown via osmotic mini-pump, insulin/glucose tolerance tests\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, in vivo loss-of-function with defined metabolic phenotype, orthogonal localization data\",\n      \"pmids\": [\"29080975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IDE behaves as a heat shock-like protein: normal and malignant cells upregulate IDE under various stresses in an HSP-like manner; IDE co-immunoprecipitates with proteasome and ubiquitin in neuroblastoma cells, and IDE silencing inhibits proliferation and triggers cell death while decreasing poly-ubiquitinated protein content.\",\n      \"method\": \"Stress induction assays, IDE silencing (siRNA), Co-immunoprecipitation with proteasome/ubiquitin, cell viability/proliferation assays, in vivo tumor expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP with functional KD phenotype but limited mechanistic resolution\",\n      \"pmids\": [\"23188819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRI2 (ITM2B) overexpression reduces extracellular Aβ by increasing levels of secreted IDE; this effect requires neither the C-terminal 23-amino acid peptide of BRI2 nor direct modulation of APP cleavage, suggesting BRI2 acts as a receptor-like protein that upregulates IDE secretion to influence Aβ metabolism.\",\n      \"method\": \"BRI2 and ADanPP overexpression in cell lines, measurement of secreted IDE by Western blot/ELISA, Aβ quantification, BRI2 truncation mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanistic follow-up with truncation mutants but no direct binding assay for BRI2-IDE interaction\",\n      \"pmids\": [\"21873424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IDE associates with detergent-resistant membrane microdomains (DRMs/lipid rafts) in brain tissue and cultured cells; disruption of DRM integrity by methyl-β-cyclodextrin mislocalizes IDE away from DRMs and impairs degradation of both extracellular Aβ and insulin, identifying DRM association as functionally important for IDE substrate degradation.\",\n      \"method\": \"Live immunofluorescence, immunogold electron microscopy, sucrose gradient fractionation, pulse-chase experiments, methyl-β-cyclodextrin treatment, in vitro IDE activity assays, seladin-1 heterozygous knockout mouse brain fractionation\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal localization methods tied to functional consequence, validated in vivo\",\n      \"pmids\": [\"19117523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IDE absence in mice induces hippocampal microgliosis without astrogliosis or hippocampal volume changes; IDE-KO primary microglial cultures show impaired modulation of phenotypic states in response to environmental signals, with only transitory effects on Aβ management, indicating a non-enzymatic role for IDE in modulating microglial function.\",\n      \"method\": \"IDE knockout mouse model, histological/immunofluorescence analysis, hippocampal-dependent memory tests, primary microglial culture functional assays\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific cellular phenotype in multiple contexts, single lab\",\n      \"pmids\": [\"37817156\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IDE (insulin-degrading enzyme) is a zinc metallopeptidase that functions as an obligate oligomer (primarily dimer) whose allosteric activation and efficient degradation of large substrates (insulin, Aβ, PTEN) depend on its oligomeric state and association with detergent-resistant membrane microdomains; in β-cells it is required for glucose-stimulated insulin secretion and autophagic flux, in kidney proximal tubules it is positively regulated by SNX5 to control circulating insulin, and it also participates in SIRT4-mediated lysosomal degradation of PTEN under nutrient stress and in non-enzymatic modulation of microglial phenotypic states.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Insulin-degrading enzyme (IDE) was purified and identified as the principal protease responsible for degrading extracellular amyloid beta-protein (Aβ) under biologically relevant conditions. IDE was found in both cytosol and released into conditioned medium by intact microglial cells, and its Aβ-degrading activity was abolished by competitive IDE substrates (insulin) and IDE inhibitors, and removed by immunodepletion with an IDE antibody. IDE activity was also associated with time-dependent oligomerization of synthetic Aβ.\",\n      \"method\": \"Protein purification, competitive inhibition assay, immunodepletion, identification of IDE in human cerebrospinal fluid\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution and purification with multiple orthogonal inhibitor/immunodepletion controls; foundational study\",\n      \"pmids\": [\"9830016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In differentiated neurons, IDE localizes to the cell surface (membrane-associated form ~5 kDa larger than cytosolic form) rather than being secreted, and this membrane-associated IDE degrades extracellularly secreted Aβ. Overexpression of IDE markedly reduced steady-state extracellular Aβ(40) and Aβ(42), while a catalytic site mutation (E111Q) abolished this effect.\",\n      \"method\": \"Cell-surface biotinylation, overexpression with active-site mutagenesis, primary neuronal cultures, PC12 differentiation model\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis combined with localization and functional assays in primary neurons\",\n      \"pmids\": [\"10684867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IDE knockout mice (IDE−/−) showed >50% decrease in Aβ degradation in brain membrane fractions and primary neuronal cultures, and a similar deficit in insulin degradation in liver, resulting in increased cerebral Aβ accumulation, hyperinsulinemia, and glucose intolerance. IDE also degrades the intracellular APP domain (AICD) released by γ-secretase in vivo.\",\n      \"method\": \"IDE knockout mouse model, primary neuronal cultures, ex vivo brain membrane degradation assays, metabolic phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vivo genetic loss-of-function with multiple orthogonal biochemical readouts\",\n      \"pmids\": [\"12634421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Insulin receptor signaling via PI3 kinase/Akt upregulates IDE protein levels in primary hippocampal neurons (~25% increase with insulin treatment), establishing a negative feedback mechanism. PI3 kinase inhibitors (wortmannin, LY294002) abolished IDE upregulation. Reduced PI3K subunit P85 correlated with reduced IDE in AD brains and APP transgenic mice on a high-fat diet, with associated increases in Aβ monomer.\",\n      \"method\": \"Primary hippocampal neuron culture, PI3K inhibitor treatment, western blotting, analysis of AD brain tissue and transgenic mouse model\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (pharmacological inhibition, in vivo correlation) across in vitro and in vivo systems\",\n      \"pmids\": [\"15590928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structures of human IDE in complex with four substrates (insulin B chain, Aβ1–40, amylin, glucagon) revealed that IDE-N and IDE-C domains form an enclosed substrate-degradation chamber. Substrate access requires repositioning of the domains; IDE uses size and charge distribution of the cavity for selective substrate entrapment. Substrates undergo conformational changes forming β-sheets with two discrete IDE regions. Mutations disrupting the IDE-N/IDE-C interface increased catalytic activity ~40-fold.\",\n      \"method\": \"X-ray crystallography (multiple substrate-bound structures), active-site and interface mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution structures with four substrates plus mutagenesis validation in a single study\",\n      \"pmids\": [\"17051221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SIRT4, a mitochondrial ADP-ribosyltransferase, was found to co-immunoprecipitate with IDE and the ADP/ATP carrier proteins ANT2 and ANT3 in mitochondria. SIRT4 depletion in insulin-producing INS-1E cells increased glucose-stimulated insulin secretion, implicating the SIRT4–IDE interaction in regulation of insulin secretion.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, siRNA depletion in pancreatic beta-cell line\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP/MS identification of interaction with functional depletion data, single study\",\n      \"pmids\": [\"17715127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Deletion of the putative dimer interface in the C-terminal region of IDE produced a monomeric variant that retained enzymatic activity but displayed Michaelis-Menten kinetics instead of allosteric behavior. Monomeric IDE retained ~25% activity on small peptide substrates but only 0.25–1% on larger substrates (β-endorphin, Aβ1–40). Neither bradykinin, dynorphin B-9, nor polyphosphates could activate the monomeric variant, demonstrating that oligomerization (predominantly dimer) is required for IDE's allosteric regulatory properties and conformational activation.\",\n      \"method\": \"Site-directed mutagenesis of dimer interface, analytical ultracentrifugation/gel filtration, enzyme kinetics with multiple substrates and activators\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted mutant enzyme with rigorous kinetic analysis across multiple substrates and activators\",\n      \"pmids\": [\"20300529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRI2 (ITM2B) overexpression reduces extracellular Aβ levels by increasing secreted IDE protein. This effect was observed with both wild-type BRI2 and its disease-associated mutant ADanPP, and was retained by a BRI2 construct lacking its C-terminal 23-amino acid peptide, suggesting BRI2 acts as a receptor-like regulator of IDE secretion and thereby influences APP/Aβ metabolism.\",\n      \"method\": \"Overexpression in cell lines, IDE secretion assay (western blot of conditioned medium), Aβ ELISA, in vivo AD mouse model plaque quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — functional overexpression with mechanistic follow-up (IDE secretion measurement), single lab\",\n      \"pmids\": [\"21873424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IDE behaves as a heat shock-like protein: normal and malignant cells exposed to various stresses (heat, oxidative, genotoxic) markedly upregulate IDE expression. In neuroblastoma cells (SHSY5Y), IDE silencing inhibits cell proliferation and triggers cell death. IDE co-immunoprecipitates with proteasome components and ubiquitin, and IDE inhibition decreases poly-ubiquitinated protein content, indicating a role for IDE in ubiquitin/proteasome-related protein quality control.\",\n      \"method\": \"Stress induction assays (heat shock, oxidative stress), IDE knockdown, cell proliferation/death assays, co-immunoprecipitation with proteasome and ubiquitin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus functional KD phenotype, single lab, multiple cell stress conditions\",\n      \"pmids\": [\"23188819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IDE knockout mice show decreased glucose-stimulated insulin secretion (GSIS) due to impaired replenishment of the releasable granule pool, and the Ide gene is haploinsufficient for this phenotype. IDE KO β-cells also have reduced autophagic flux and microtubule content. α-Synuclein levels are inversely correlated with IDE in β-cells of IDE KO mice and T2D patients; both gain- and loss-of-function of α-synuclein in vivo impair GSIS and autophagy, identifying IDE as a regulator of GSIS and β-cell amyloidogenic protein homeostasis.\",\n      \"method\": \"Ide knockout and haploinsufficient mouse models, GSIS assay, autophagy flux measurements, microtubule quantification, α-synuclein gain/loss-of-function in vivo\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple genetic models (KO, haploinsufficiency, α-syn GOF/LOF) with orthogonal cellular readouts\",\n      \"pmids\": [\"23349488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Endogenous IDE is present in detergent-resistant membrane (DRM) microdomains (lipid rafts) in brain tissue and cultured cells, in addition to its cytosolic localization. DRM-associated IDE co-localizes with Aβ. Displacement of IDE from DRMs by methyl-β-cyclodextrin (MβCD) caused extracellular Aβ accumulation and impaired exogenous Aβ proteolysis. Mice with reduced cholesterol (seladin-1 heterozygous knockout) had less IDE in DRMs. A moderate shift of IDE from DRMs substantially decreased IDE-mediated insulin and Aβ degradation in vitro.\",\n      \"method\": \"Live immunofluorescence, immunogold electron microscopy, sucrose gradient fractionation, pulse-chase, MβCD treatment, seladin-1 KO mouse brain fractionation\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal localization and functional methods (EM, fractionation, pharmacological displacement) with in vivo validation\",\n      \"pmids\": [\"19117523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Renal sorting nexin 5 (SNX5) positively regulates IDE expression and activity. SNX5 co-localizes and co-immunoprecipitates with IDE at the plasma membrane and perinuclear area of human renal proximal tubule cells (hRPTCs) and in the brush border membrane of proximal tubules. Insulin increases the co-localization and co-immunoprecipitation of SNX5 and IDE. Silencing SNX5 decreases IDE expression and activity, impairs insulin/glucose responses, and increases blood insulin and glucose in mice. Spontaneously hypertensive rats have decreased renal SNX5 and IDE.\",\n      \"method\": \"Co-immunoprecipitation, confocal co-localization, siRNA knockdown in hRPTCs, renal-selective siRNA infusion in uninephrectomized mice, metabolic phenotyping\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, localization, and in vivo knockdown with defined metabolic phenotype\",\n      \"pmids\": [\"29080975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT4 interacts with PTEN and bridges PTEN to IDE for lysosomal degradation in response to nutritional starvation stress. SIRT4 overexpression causes PTEN downregulation independently of acetylation and ubiquitination. This SIRT4–IDE–PTEN axis promotes cell survival under nutrient stress by lowering PTEN levels and thereby de-repressing the PI3K–AKT–mTOR pathway.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, lysosome inhibitor experiments, PTEN stability assays under starvation conditions\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP with mechanistic follow-up (lysosomal pathway, starvation stress), single lab\",\n      \"pmids\": [\"30649986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SARS-CoV-2 protein–protein interaction mapping by affinity-purification mass spectrometry identified IDE as a high-confidence interaction partner of SARS-CoV-2 Nsp2 in human cells.\",\n      \"method\": \"Affinity-purification mass spectrometry (AP-MS) in HEK293T cells expressing tagged viral proteins\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single AP-MS identification; functional consequence of IDE–Nsp2 interaction not yet characterized\",\n      \"pmids\": [\"32353859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IDE absence in knockout mice induces specific microgliosis in the hippocampus without astrogliosis. In primary microglial cultures, IDE absence impairs modulation of phenotypic states in response to environmental signals, with only transitory effects on Aβ management. These effects cannot be explained by IDE enzymatic activity alone, indicating a non-enzymatic role for IDE in modulating microglial function relevant to aging and Alzheimer's disease.\",\n      \"method\": \"IDE knockout mouse model (full KO and haploinsufficiency), primary microglial cultures, behavioral testing, immunohistochemistry, functional microglial phenotyping assays\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in vivo and in vitro with defined cellular phenotype, single study\",\n      \"pmids\": [\"37817156\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IDE is a Zn2+-metalloendopeptidase that forms an enclosed, allosterically regulated degradation chamber (requiring oligomerization/dimerization) to selectively encapsulate and cleave structurally diverse substrates including insulin, Aβ, AICD, amylin, and glucagon; it localizes to cytosol, detergent-resistant membrane microdomains, and the cell surface (and is secreted extracellularly), where its activity is regulated by insulin receptor/PI3K/Akt signaling, by SNX5-mediated control of expression/activity in renal proximal tubules, and by SIRT4-mediated substrate (PTEN) targeting for lysosomal degradation; in pancreatic β-cells IDE regulates glucose-stimulated insulin secretion and autophagic flux partly through clearance of amyloidogenic α-synuclein, and in microglia it plays a non-enzymatic role in modulating phenotypic responses relevant to neuroinflammation and Alzheimer's disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IDE is a zinc metallopeptidase that functions as an obligate dimer whose allosteric activation and efficient degradation of large substrates such as insulin and amyloid-β depend on its oligomeric state and association with detergent-resistant membrane microdomains (lipid rafts) [PMID:20300529, PMID:19117523]. In pancreatic β-cells, IDE is required for glucose-stimulated insulin secretion through maintenance of the releasable granule pool, autophagic flux, and microtubule content [PMID:23349488], while in kidney proximal tubules its expression and activity are positively regulated by sorting nexin 5 (SNX5) to control circulating insulin levels [PMID:29080975]. IDE also participates in SIRT4-mediated lysosomal degradation of PTEN under nutrient stress [PMID:30649986] and exerts non-enzymatic functions in modulating microglial phenotypic states, as IDE-knockout mice develop hippocampal microgliosis with impaired microglial responses to environmental signals [PMID:37817156].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that IDE's subcellular localization to lipid rafts is functionally required for substrate degradation answered how IDE accesses extracellular insulin and Aβ in a membrane-associated context.\",\n      \"evidence\": \"Sucrose gradient fractionation, immunogold EM, and methyl-β-cyclodextrin disruption in brain tissue and cultured cells\",\n      \"pmids\": [\"19117523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which IDE is targeted to detergent-resistant microdomains is undefined\",\n        \"Whether lipid raft association differs across cell types remains untested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that IDE functions as an obligate dimer for allosteric activation and efficient degradation of large substrates resolved how its cooperative kinetics and activator responsiveness arise.\",\n      \"evidence\": \"Structure-guided deletion of the dimer interface followed by in vitro kinetic analysis with multiple substrates and activators\",\n      \"pmids\": [\"20300529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether higher-order oligomers (tetramers) contribute distinct regulatory properties in vivo is not resolved\",\n        \"Structural basis of allosteric communication between subunits remains incomplete\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing that BRI2 overexpression lowers extracellular Aβ by increasing secreted IDE levels revealed a trans-acting regulator of IDE secretion relevant to Aβ clearance.\",\n      \"evidence\": \"BRI2 and truncation mutant overexpression in cell lines with quantification of secreted IDE and Aβ\",\n      \"pmids\": [\"21873424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct BRI2–IDE binding assay was performed\",\n        \"Mechanism by which BRI2 promotes IDE secretion is unknown\",\n        \"Single-lab finding not independently confirmed\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying IDE as a stress-inducible protein that co-immunoprecipitates with proteasome and ubiquitin, and whose silencing inhibits proliferation, suggested a non-canonical role in protein homeostasis beyond peptide degradation.\",\n      \"evidence\": \"Stress induction, IDE siRNA knockdown, Co-IP with proteasome/ubiquitin in neuroblastoma cells\",\n      \"pmids\": [\"23188819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic basis for IDE–proteasome interaction is unresolved\",\n        \"Whether IDE has chaperone-like activity independent of its peptidase activity was not tested\",\n        \"Single-lab Co-IP without reciprocal validation for proteasome interaction\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that IDE knockout impairs glucose-stimulated insulin secretion via defective granule replenishment, autophagy, and microtubule content established IDE as a cell-autonomous regulator of β-cell function beyond insulin degradation.\",\n      \"evidence\": \"Ide-KO mouse model with GSIS assays, autophagic flux measurement, microtubule staining, and α-synuclein gain/loss-of-function experiments\",\n      \"pmids\": [\"23349488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether IDE's enzymatic activity or a scaffolding function mediates effects on autophagy and microtubules is unknown\",\n        \"The molecular link between IDE and α-synuclein levels is not defined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying SNX5 as a positive regulator that co-localizes with IDE and controls its expression in renal proximal tubules connected IDE to systemic insulin clearance via a kidney-specific regulatory axis.\",\n      \"evidence\": \"Co-IP and co-localization in renal cells, renal-selective Snx5 knockdown in mice with metabolic phenotyping\",\n      \"pmids\": [\"29080975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SNX5 stabilizes IDE protein or promotes its trafficking is not distinguished\",\n        \"Relevance beyond kidney proximal tubule cells untested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that SIRT4 bridges IDE to PTEN for ubiquitination-independent lysosomal degradation under starvation revealed a non-canonical proteolytic function for IDE in tumor-suppressor turnover.\",\n      \"evidence\": \"Co-IP of SIRT4–IDE–PTEN, overexpression/knockdown with lysosome inhibitors under starvation in cultured cells\",\n      \"pmids\": [\"30649986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether IDE directly cleaves PTEN or facilitates its lysosomal targeting is not distinguished\",\n        \"In vivo validation of SIRT4–IDE–PTEN axis is lacking\",\n        \"Single-lab finding\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that IDE-KO mice develop hippocampal microgliosis with impaired microglial phenotypic modulation, largely independent of Aβ effects, established a non-enzymatic role for IDE in neuroinflammation.\",\n      \"evidence\": \"IDE-KO mouse histology, primary microglial culture functional assays, hippocampal-dependent memory tests\",\n      \"pmids\": [\"37817156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular basis for IDE's non-enzymatic microglial modulation is unidentified\",\n        \"Whether the microglial phenotype contributes to cognitive outcomes is not established\",\n        \"Single-lab finding\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A central unresolved question is whether IDE's non-catalytic functions — in autophagy, microtubule maintenance, proteasome association, and microglial modulation — reflect a common scaffolding or chaperone-like mechanism separable from its peptidase activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No catalytic-dead knock-in has been used to dissect enzymatic versus non-enzymatic functions in vivo\",\n        \"Structural basis for IDE's interactions with SIRT4, SNX5, and proteasome components is unknown\",\n        \"Tissue-specific regulatory mechanisms controlling IDE oligomerization in vivo are uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SNX5\",\n      \"SIRT4\",\n      \"PTEN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"IDE is a Zn2+-metalloendopeptidase that forms a dimeric degradation chamber to selectively encapsulate and cleave structurally diverse amyloidogenic and metabolic peptides—including insulin, amyloid-β (Aβ), amylin, glucagon, and the APP intracellular domain (AICD)—thereby serving as a central regulator of peptide clearance in both metabolic and neurodegenerative contexts [PMID:9830016, PMID:17051221, PMID:12634421]. Crystal structures show that IDE-N and IDE-C halves enclose a size- and charge-selective chamber whose catalytic efficiency depends on oligomerization-mediated allosteric activation, with disruption of the dimer interface collapsing activity on large substrates and abolishing allosteric regulation [PMID:17051221, PMID:20300529]. IDE localizes to the cytosol, detergent-resistant membrane microdomains, and the cell surface, and its expression is upregulated by insulin receptor/PI3K/Akt signaling and by sorting nexin 5 in renal proximal tubules; IDE-knockout mice exhibit hyperinsulinemia, glucose intolerance, cerebral Aβ accumulation, impaired β-cell glucose-stimulated insulin secretion, and hippocampal microgliosis [PMID:10684867, PMID:19117523, PMID:15590928, PMID:29080975, PMID:12634421, PMID:23349488, PMID:37817156]. In pancreatic β-cells, IDE maintains autophagic flux and clears amyloidogenic α-synuclein to sustain releasable insulin granule pools, while in microglia it exerts a non-enzymatic role in phenotypic modulation relevant to neuroinflammation [PMID:23349488, PMID:37817156].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of IDE as the principal extracellular Aβ-degrading protease established a direct link between insulin metabolism and amyloid clearance, opening the field of IDE-mediated neuroprotection.\",\n      \"evidence\": \"Purification from microglial conditioned medium with competitive inhibition, immunodepletion, and CSF detection\",\n      \"pmids\": [\"9830016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of IDE versus other Aβ-degrading proteases (e.g., neprilysin) not delineated\", \"Mechanism of IDE secretion unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstration that a membrane-associated form of IDE on the neuronal cell surface degrades secreted Aβ resolved the topology paradox of how a predominantly cytosolic protease accesses extracellular substrates.\",\n      \"evidence\": \"Cell-surface biotinylation and catalytic-dead mutant (E111Q) in primary neurons and PC12 cells\",\n      \"pmids\": [\"10684867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of IDE membrane association and the nature of the ~5 kDa size difference from cytosolic IDE remain uncharacterized\", \"Whether membrane-associated IDE preferentially targets Aβ40 versus Aβ42 unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"IDE-knockout mice provided definitive genetic proof that IDE is a major in vivo regulator of both Aβ and insulin catabolism, linking IDE deficiency to hyperinsulinemia, glucose intolerance, and cerebral Aβ accumulation.\",\n      \"evidence\": \"IDE-null mouse with ex vivo brain membrane degradation, primary neuronal cultures, and metabolic phenotyping\",\n      \"pmids\": [\"12634421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of hepatic versus neural IDE to systemic insulin clearance not resolved\", \"Whether IDE degrades AICD in a physiologically rate-limiting manner in vivo unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that insulin receptor/PI3K/Akt signaling upregulates IDE expression established a negative-feedback loop coupling insulin signaling to its own degradation, with implications for insulin resistance in Alzheimer's disease.\",\n      \"evidence\": \"PI3K inhibitor treatment in primary hippocampal neurons and correlation with reduced IDE in AD brain tissue\",\n      \"pmids\": [\"15590928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional versus post-translational mechanism of PI3K-dependent IDE upregulation not defined\", \"Causal direction of IDE reduction in AD brain not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Crystal structures of IDE bound to insulin B chain, Aβ, amylin, and glucagon revealed the enclosed degradation chamber architecture and explained substrate selectivity through size/charge complementarity and β-sheet-mediated capture.\",\n      \"evidence\": \"X-ray crystallography of four substrate-bound complexes with mutagenesis of IDE-N/IDE-C interface\",\n      \"pmids\": [\"17051221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length insulin-bound structure not obtained\", \"Structural basis for chamber opening/closing dynamics not captured\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Localization of IDE to detergent-resistant membrane microdomains (lipid rafts) and the demonstration that raft displacement impairs Aβ and insulin degradation revealed that IDE's proteolytic function is spatially regulated by membrane cholesterol.\",\n      \"evidence\": \"Immunogold EM, sucrose gradient fractionation, MβCD treatment, and seladin-1 KO mouse validation\",\n      \"pmids\": [\"19117523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism by which IDE associates with lipid rafts (lipid modification, adaptor protein) unknown\", \"Whether raft-associated IDE represents a distinct post-translationally modified pool not determined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Engineering a monomeric IDE variant demonstrated that dimerization is required for allosteric activation and efficient degradation of large substrates, establishing oligomerization as a critical regulatory mechanism.\",\n      \"evidence\": \"Dimer-interface deletion mutant with kinetic analysis across multiple substrates and activators\",\n      \"pmids\": [\"20300529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether physiological regulators modulate IDE oligomerization state in vivo not tested\", \"Structural basis of allosteric communication between subunits unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"IDE-knockout and haploinsufficient β-cells revealed that IDE maintains glucose-stimulated insulin secretion by sustaining autophagic flux and clearing α-synuclein, linking IDE to β-cell proteostasis beyond its known catabolic role.\",\n      \"evidence\": \"IDE KO and haplo-insufficient mice, α-synuclein gain/loss-of-function in vivo, autophagy and microtubule quantification\",\n      \"pmids\": [\"23349488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IDE degrades α-synuclein directly or acts indirectly through autophagy modulation not resolved\", \"Mechanism linking IDE to microtubule maintenance unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of SNX5 as a positive regulator of IDE expression and activity in renal proximal tubules extended IDE regulation beyond neurons, showing that insulin-stimulated SNX5–IDE co-localization controls renal insulin clearance.\",\n      \"evidence\": \"Reciprocal Co-IP, confocal co-localization, renal-selective siRNA knockdown in mice with metabolic phenotyping\",\n      \"pmids\": [\"29080975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SNX5 stabilizes or promotes IDE expression not defined\", \"Whether SNX5–IDE interaction is direct or mediated by a trafficking complex unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The finding that SIRT4 bridges PTEN to IDE for lysosomal degradation under starvation stress revealed a non-canonical IDE function in which the protease participates in targeted protein disposal through the lysosomal pathway, coupling nutrient sensing to PI3K–AKT–mTOR signaling.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown, lysosome inhibitor rescue of PTEN under starvation\",\n      \"pmids\": [\"30649986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IDE directly cleaves PTEN or acts as a scaffold/adaptor for lysosomal targeting not distinguished\", \"Single-lab finding; independent replication needed\", \"Whether this pathway operates in neurons or β-cells unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"IDE knockout induces hippocampal microgliosis and impairs microglial phenotypic switching through a mechanism independent of its enzymatic activity, establishing a non-catalytic scaffolding or signaling role in neuroinflammation.\",\n      \"evidence\": \"IDE-null and haploinsufficient mice, primary microglial cultures, immunohistochemistry, and functional phenotyping\",\n      \"pmids\": [\"37817156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of IDE's non-enzymatic microglial function completely uncharacterized\", \"Whether non-enzymatic role involves protein–protein interactions or structural scaffolding unknown\", \"Relevance to human AD microglia not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural dynamics of IDE chamber gating in vivo, the molecular basis of its non-enzymatic functions in microglia and protein quality control, whether IDE oligomerization state is physiologically regulated, and the direct mechanism linking IDE to autophagic flux in β-cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vivo structure of IDE captured in open/closed transition states\", \"Non-enzymatic interactome of IDE undefined\", \"Relative tissue-specific contributions to systemic insulin clearance not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 10, 11]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 4, 6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 9, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SNX5\",\n      \"SIRT4\",\n      \"ANT2\",\n      \"ANT3\",\n      \"PTEN\",\n      \"ITM2B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}