{"gene":"ELAPOR1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2010,"finding":"EIG121 (ELAPOR1) is a transmembrane protein localized in plasma membrane–late endosome–lysosome compartments; deletion of the putative transmembrane domain abolished membrane association. Overexpression caused autophagosome accumulation (increased LC3 puncta, autophagosomes by EM), increased acidic vesicles, and lysosomal degradation of long-lived proteins. Knockdown of EIG121 blocked starvation-induced LC3 degradation and, combined with starvation or cytotoxic agents, greatly increased apoptosis, indicating EIG121 promotes cell survival under stress via the autophagy pathway.","method":"Tetracycline-inducible overexpression, subcellular fractionation, immunofluorescence, electron microscopy, siRNA knockdown, lysosomal protein degradation assay, transmembrane-domain deletion mutagenesis","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation, EM, mutagenesis, KD phenotype) in a single study with rigorous controls","pmids":["21072319"],"is_preprint":false},{"year":2021,"finding":"ELAPOR1 is a MIST1 (BHLHA15) transcriptional target containing an evolutionarily conserved mannose-6-phosphate receptor (M6PR) domain. In cultured cells it traffics with cis-Golgi resident proteins and with the trans-Golgi/late endosome protein cation-independent M6PR (CI-M6PR). Mass spectrometry of co-immunoprecipitated proteins showed ELAPOR1 and CI-M6PR share many binding partners, though CI-M6PR co-immunoprecipitated more lysosomal proteins. Elapor1 knockout mice show defective secretory granule maturation in gastric zymogenic cells. Truncation mutants of ELAPOR1 disrupted secretory vesicle trafficking.","method":"Co-immunoprecipitation with mass spectrometry, live-cell trafficking assays, transgenic truncation mutants, Elapor1 knockout mouse model, histological analysis of secretory granule maturation","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP/MS, KO mouse with defined cellular phenotype, truncation mutagenesis, multiple methods in one study","pmids":["34816763"],"is_preprint":false},{"year":2015,"finding":"KIAA1324 (ELAPOR1) binds GRP78 (glucose-regulated protein 78 kDa) and blocks its oncogenic activities: it inhibits the GRP78–caspase-7 interaction and suppresses GRP78-mediated AKT activation, thereby inducing apoptosis in gastric cancer cells.","method":"Protein interaction analysis (co-immunoprecipitation/pulldown), xenograft tumor model, proliferation/invasion/apoptosis assays, drug-resistance assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP binding partner identified with functional readouts (apoptosis, AKT, caspase-7), single lab","pmids":["26045166"],"is_preprint":false},{"year":2023,"finding":"N-linked glycosylation (including fucosylation mediated by fucosyltransferase) is an essential post-translational modification of KIAA1324 (ELAPOR1). Loss of N-linked glycosylation eliminated tumor-suppressive activities, caused rapid proteasomal degradation of the protein, altered its subcellular localization, and abolished its ability to inhibit the GRP78–caspase-7 interaction and induce apoptosis.","method":"N-glycosylation site mutagenesis, fucosylation inhibitor treatment, proteasome inhibitor rescue, subcellular localization imaging, co-immunoprecipitation (GRP78–caspase-7), RNA sequencing, xenograft model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of PTM sites combined with multiple orthogonal functional readouts (localization, degradation, interaction, apoptosis)","pmids":["37612293"],"is_preprint":false},{"year":2025,"finding":"ELAPOR1 functions as a copper-dependent tethering factor for proacrosomal vesicle (PAV) fusion during acrosome biogenesis. Cryo-EM revealed ELAPOR1 forms a square-planar homodimer in cis that assembles into a trans-tetramer via head-to-head homophilic interactions dependent on copper chelation. ELAPOR1 exhibits dual membrane orientation (canonical Nin-Cout and noncanonical Nout-Cin), and the noncanonical topology enables bridging of vesicles. A copper-chelation-deficient mutant (ELAPOR14HA) forms cis-dimers but fails to mediate trans-homophilic interactions in vitro and causes defective PAV fusion in mice. ELAPOR1 also interacts with the SNARE protein STX12; conditional Stx12 knockout in germ cells phenocopied ELAPOR1 deficiency.","method":"Cryo-electron microscopy, Elapor1 knockout mouse model (male infertility/globozoospermia phenotype), copper-chelation mutagenesis (ELAPOR14HA knock-in), in vitro homophilic interaction assay, conditional Stx12 knockout, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure, mutagenesis, KO mouse with defined fertility phenotype, in vitro reconstitution, multiple orthogonal methods in one study","pmids":["40737321"],"is_preprint":false},{"year":2026,"finding":"ELAPOR1 interacts with VPS54 and regulates assembly of the GARP (Golgi-associated retrograde protein) complex in the testis, controlling transport and fusion of Golgi- and early endosome-derived proacrosomal vesicles during acrosome formation. Germ-cell-specific Elapor1 knockout mice exhibit impaired PAV fusion, deformed sperm, and infertility.","method":"Germ-cell-specific conditional knockout mouse, mass spectrometry, co-immunoprecipitation, proximity labeling, immunofluorescence co-localization, transmission electron microscopy","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined male infertility phenotype, MS-identified interaction with VPS54/GARP confirmed by Co-IP and proximity labeling","pmids":["41993632"],"is_preprint":false},{"year":2026,"finding":"In neurons, KIAA1324/ELAPOR1 protein is markedly decreased in cells exhibiting pathological TDP-43 (nuclear-cleared and cytoplasmic phospho-TDP-43), despite elevated KIAA1324 mRNA. This discordance is associated with alternative polyadenylation of KIAA1324 mRNA upon TDP-43 depletion in iPSC-derived neurons, hypothesized to reduce translation efficiency. Overexpression of KIAA1324 protein in SH-SY5Y cells was shown by mass spectrometry to affect a network of mitochondrial proteins.","method":"Immunohistochemistry of post-mortem ALS/control brain, iPSC-derived neuron TDP-43 depletion with immunocytochemistry, mass spectrometry of KIAA1324-overexpressing cells, alternative polyadenylation analysis","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 3 — KD/depletion with protein-level readout and MS network analysis, single study, post-mortem tissue correlation","pmids":["41668214"],"is_preprint":false},{"year":2025,"finding":"ELAPOR1 (inceptor) functions within pancreatic β-cells to promote clathrin-mediated endocytosis of the insulin receptor (INSR) and directs cytoplasmic insulin and proinsulin to lysosomal degradation. It interacts with proinsulin, insulin, INSR, and IGF1R.","method":"Evolutionary/positive-selection analysis with reference to published functional studies; functional claims derive from cited prior work (inceptor discovery papers) referenced in the preprint context","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 4 — functional description in preprint references prior discovery without new direct experiments in this paper","pmids":[],"is_preprint":true}],"current_model":"ELAPOR1 (also known as EIG121/KIAA1324/inceptor) is an evolutionarily conserved transmembrane protein containing an M6PR domain that localizes to trans-Golgi/late endosome–lysosome compartments; it promotes secretory granule maturation and autophagy, acts as a copper-dependent vesicle tethering factor (forming trans-tetramers via homophilic interactions) that drives proacrosomal vesicle fusion during acrosome biogenesis through interaction with STX12 and VPS54-mediated GARP complex assembly, and suppresses tumor cell growth in part by binding GRP78 to block caspase-7 interaction and AKT activation—functions that require N-linked glycosylation for proper localization and stability."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing that ELAPOR1 is a transmembrane protein in the endolysosomal system that promotes autophagy answered the fundamental question of its subcellular role and linked it to stress-induced cell survival.","evidence":"Overexpression/knockdown in human cell lines with subcellular fractionation, EM, LC3 assays, and transmembrane-domain deletion mutagenesis","pmids":["21072319"],"confidence":"High","gaps":["Molecular mechanism by which ELAPOR1 stimulates autophagosome formation was not defined","No interacting partners identified at this stage","In vivo relevance not tested"]},{"year":2015,"claim":"Identification of GRP78 as a binding partner that ELAPOR1 antagonizes revealed a tumor-suppressive mechanism operating through blockade of oncogenic GRP78–caspase-7 and GRP78–AKT signaling.","evidence":"Co-immunoprecipitation/pulldown, xenograft tumor model, apoptosis and AKT activation assays in gastric cancer cells","pmids":["26045166"],"confidence":"Medium","gaps":["Binding interface between ELAPOR1 and GRP78 not mapped","Single-lab finding without independent replication","Relationship between autophagy function and tumor suppression unclear"]},{"year":2021,"claim":"Demonstrating that ELAPOR1 contains a conserved M6PR domain, traffics with CI-M6PR, and is required for secretory granule maturation in vivo established its role in Golgi-to-lysosome vesicle trafficking beyond autophagy.","evidence":"Co-IP/mass spectrometry, live-cell trafficking, Elapor1 knockout mouse with gastric zymogenic cell phenotype, truncation mutagenesis","pmids":["34816763"],"confidence":"High","gaps":["Whether ELAPOR1 functions as a receptor or structural scaffold in the secretory pathway was unresolved","Cargo specificity of ELAPOR1-dependent trafficking not defined","Relationship between M6PR domain and autophagy function unknown"]},{"year":2023,"claim":"Showing that N-linked glycosylation is essential for ELAPOR1 stability, localization, and tumor-suppressive activity resolved why post-translational processing is a prerequisite for all known functions.","evidence":"N-glycosylation site mutagenesis, fucosylation inhibitor, proteasome inhibitor rescue, xenograft model, co-IP for GRP78–caspase-7 interaction","pmids":["37612293"],"confidence":"High","gaps":["Which specific glycosylation sites are individually critical was not fully resolved","Whether glycosylation also regulates the autophagy and secretory functions was not tested","Structural basis for glycosylation-dependent stabilization unknown"]},{"year":2025,"claim":"Cryo-EM structure and copper-chelation mutagenesis established ELAPOR1 as a copper-dependent vesicle tethering factor that forms trans-tetramers to drive proacrosomal vesicle fusion, revealing its first atomic-level mechanism and explaining male infertility in knockout mice.","evidence":"Cryo-EM, Elapor1 KO and copper-chelation-deficient knock-in mice, in vitro homophilic interaction assay, conditional Stx12 KO phenocopy, co-IP with STX12","pmids":["40737321"],"confidence":"High","gaps":["Whether the copper-dependent tethering mechanism operates in non-germline tissues (e.g., gastric cells, neurons) is untested","How dual membrane topology is regulated remains unknown","Stoichiometry of ELAPOR1–STX12 interaction and its role in SNARE-mediated fusion not defined"]},{"year":2026,"claim":"Identification of VPS54 as an ELAPOR1 partner and demonstration that ELAPOR1 regulates GARP complex assembly extended the tethering mechanism to include retrograde Golgi trafficking machinery in acrosome biogenesis.","evidence":"Germ-cell-specific conditional KO mouse, mass spectrometry, co-IP, proximity labeling, TEM","pmids":["41993632"],"confidence":"High","gaps":["Whether ELAPOR1–GARP interaction is direct or mediated by VPS54 alone is unclear","Functional interplay between copper-dependent tethering and GARP-mediated fusion not resolved","Relevance of GARP regulation outside spermatogenesis not explored"]},{"year":2026,"claim":"Observation that ELAPOR1 protein is selectively lost in neurons with TDP-43 pathology despite elevated mRNA suggested post-transcriptional dysregulation via alternative polyadenylation, linking ELAPOR1 to ALS neurodegeneration.","evidence":"Post-mortem ALS brain immunohistochemistry, iPSC-derived neuron TDP-43 depletion, mass spectrometry of overexpressing cells","pmids":["41668214"],"confidence":"Medium","gaps":["Causal role of ELAPOR1 loss in TDP-43-mediated neurodegeneration not demonstrated","Alternative polyadenylation mechanism reducing translation is correlative, not functionally validated","Mitochondrial protein network affected by ELAPOR1 overexpression not validated as physiologically relevant"]},{"year":null,"claim":"Whether the copper-dependent vesicle tethering mechanism identified in spermatogenesis is a general mechanism underlying ELAPOR1's roles in autophagy, secretory granule maturation, and tumor suppression across tissues remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Low","gaps":["No tissue-general structure–function analysis linking copper binding to autophagy or GRP78 interaction","No human genetic disease directly attributed to ELAPOR1 mutations","Cargo identity and selectivity of ELAPOR1-dependent vesicle trafficking undefined outside germline"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4,5]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,4,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[4,5]}],"complexes":["ELAPOR1 copper-dependent trans-tetramer"],"partners":["GRP78","CI-M6PR","STX12","VPS54"],"other_free_text":[]},"mechanistic_narrative":"ELAPOR1 is an evolutionarily conserved transmembrane glycoprotein containing a mannose-6-phosphate receptor (M6PR) domain that functions in vesicle trafficking, autophagy, and membrane fusion across multiple secretory and endolysosomal compartments. It localizes to plasma membrane, trans-Golgi, and late endosome–lysosome compartments, where it promotes autophagosome formation and lysosomal degradation of long-lived proteins to support cell survival under stress, and facilitates secretory granule maturation in gastric zymogenic cells as a transcriptional target of MIST1 [PMID:21072319, PMID:34816763]. Structurally, ELAPOR1 forms copper-dependent square-planar cis-homodimers that assemble into trans-tetramers via head-to-head homophilic interactions, functioning as a vesicle tethering factor that drives proacrosomal vesicle fusion during acrosome biogenesis through cooperation with the SNARE protein STX12 and VPS54-mediated GARP complex assembly; loss of ELAPOR1 or its copper-chelation capacity causes globozoospermia and male infertility in mice [PMID:40737321, PMID:41993632]. ELAPOR1 also acts as a tumor suppressor in gastric cancer by binding GRP78 to block the GRP78–caspase-7 interaction and suppress AKT activation, activities that require N-linked glycosylation for proper protein stability, localization, and function [PMID:26045166, PMID:37612293]."},"prefetch_data":{"uniprot":{"accession":"Q6UXG2","full_name":"Endosome/lysosome-associated apoptosis and autophagy regulator 1","aliases":["Estrogen-induced gene 121 protein"],"length_aa":1013,"mass_kda":111.4,"function":"May protect cells from cell death by inducing cytosolic vacuolization and up-regulating the autophagy pathway (PubMed:21072319). May play a role in apoptosis and cell proliferation through its interaction with HSPA5 (PubMed:26045166)","subcellular_location":"Cell membrane; Late endosome membrane; Golgi apparatus, trans-Golgi network membrane; Lysosome membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q6UXG2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ELAPOR1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ELAPOR1","total_profiled":1310},"omim":[{"mim_id":"616366","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 32; DEE32","url":"https://www.omim.org/entry/616366"},{"mim_id":"614048","title":"ENDOSOME-LYSOSOME-ASSOCIATED APOPTOSIS AND AUTOPHAGY REGULATOR 2; ELAPOR2","url":"https://www.omim.org/entry/614048"},{"mim_id":"611298","title":"ENDOSOME-LYSOSOME-ASSOCIATED APOPTOSIS AND AUTOPHAGY REGULATOR 1; ELAPOR1","url":"https://www.omim.org/entry/611298"},{"mim_id":"176262","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, MEMBER 2; KCNA2","url":"https://www.omim.org/entry/176262"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":147.7},{"tissue":"salivary gland","ntpm":156.2},{"tissue":"stomach 1","ntpm":83.2}],"url":"https://www.proteinatlas.org/search/ELAPOR1"},"hgnc":{"alias_symbol":["maba1","EIG121"],"prev_symbol":["KIAA1324"]},"alphafold":{"accession":"Q6UXG2","domains":[{"cath_id":"-","chopping":"55-111","consensus_level":"medium","plddt":84.4872,"start":55,"end":111},{"cath_id":"2.60.120.200","chopping":"122-141_156-270","consensus_level":"high","plddt":79.8907,"start":122,"end":270},{"cath_id":"2.60.120.200","chopping":"336-588","consensus_level":"medium","plddt":83.6328,"start":336,"end":588},{"cath_id":"-","chopping":"592-656","consensus_level":"medium","plddt":81.5998,"start":592,"end":656},{"cath_id":"2.70.130.10","chopping":"668-721_731-856","consensus_level":"high","plddt":84.0562,"start":668,"end":856},{"cath_id":"-","chopping":"865-902","consensus_level":"high","plddt":87.6308,"start":865,"end":902}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXG2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXG2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXG2-F1-predicted_aligned_error_v6.png","plddt_mean":77.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELAPOR1","jax_strain_url":"https://www.jax.org/strain/search?query=ELAPOR1"},"sequence":{"accession":"Q6UXG2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UXG2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UXG2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXG2"}},"corpus_meta":[{"pmid":"21072319","id":"PMC_21072319","title":"The novel estrogen-induced gene EIG121 regulates autophagy and promotes cell survival under stress.","date":"2010","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/21072319","citation_count":75,"is_preprint":false},{"pmid":"16322283","id":"PMC_16322283","title":"Identification of a novel estrogen-regulated gene, EIG121, induced by hormone replacement therapy and differentially expressed in type I and type II endometrial cancer.","date":"2005","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/16322283","citation_count":50,"is_preprint":false},{"pmid":"26045166","id":"PMC_26045166","title":"KIAA1324 Suppresses Gastric Cancer Progression by Inhibiting the Oncoprotein GRP78.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26045166","citation_count":42,"is_preprint":false},{"pmid":"21102415","id":"PMC_21102415","title":"Molecular clustering based on ERα and EIG121 predicts survival in high-grade serous carcinoma of the ovary/peritoneum.","date":"2010","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/21102415","citation_count":39,"is_preprint":false},{"pmid":"28656197","id":"PMC_28656197","title":"Autophagy plays an important role in stemness mediation and the novel dual function of EIG121 in both autophagy and stemness regulation of endometrial carcinoma JEC cells.","date":"2017","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28656197","citation_count":27,"is_preprint":false},{"pmid":"37612293","id":"PMC_37612293","title":"N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37612293","citation_count":16,"is_preprint":false},{"pmid":"34816763","id":"PMC_34816763","title":"ELAPOR1 is a secretory granule maturation-promoting factor that is lost during paligenosis.","date":"2021","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34816763","citation_count":15,"is_preprint":false},{"pmid":"14767521","id":"PMC_14767521","title":"Different transcriptional expression of KIAA1324 and its splicing variants in human carcinoma cell lines with different metastatic capacity.","date":"2004","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/14767521","citation_count":13,"is_preprint":false},{"pmid":"38630934","id":"PMC_38630934","title":"ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer.","date":"2024","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38630934","citation_count":9,"is_preprint":false},{"pmid":"32377505","id":"PMC_32377505","title":"Altered Expression of Three EGFR Posttranslational Regulators MDGI, MIG6, and EIG121 in Invasive Breast Carcinomas.","date":"2020","source":"Analytical cellular pathology (Amsterdam)","url":"https://pubmed.ncbi.nlm.nih.gov/32377505","citation_count":7,"is_preprint":false},{"pmid":"40737321","id":"PMC_40737321","title":"ELAPOR1 is a copper-dependent tethering factor driving proacrosomal vesicle fusion during acrosome biogenesis.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/40737321","citation_count":2,"is_preprint":false},{"pmid":"27230222","id":"PMC_27230222","title":"A novel polymorphic repeat in the upstream regulatory region of the estrogen-induced gene EIG121 is not associated with the risk of developing breast or endometrial cancer.","date":"2016","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/27230222","citation_count":1,"is_preprint":false},{"pmid":"41668214","id":"PMC_41668214","title":"Lost in translation: absence of KIAA1324/ELAPOR1 protein in pathological TDP-43-affected neurons in ALS/FTD.","date":"2026","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/41668214","citation_count":0,"is_preprint":false},{"pmid":"41993632","id":"PMC_41993632","title":"ELAPOR1 regulates VPS54-mediated GARP complex formation and proacrosomal vesicle fusion during spermatogenesis.","date":"2026","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/41993632","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.26.656141","title":"Coordinated adaptive changes in insulin, insulin receptor, and inceptor genes in hystricognath rodents","date":"2025-05-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.26.656141","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9657,"output_tokens":2623,"usd":0.034158},"stage2":{"model":"claude-opus-4-6","input_tokens":5914,"output_tokens":2515,"usd":0.138667},"total_usd":0.172825,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"EIG121 (ELAPOR1) is a transmembrane protein localized in plasma membrane–late endosome–lysosome compartments; deletion of the putative transmembrane domain abolished membrane association. Overexpression caused autophagosome accumulation (increased LC3 puncta, autophagosomes by EM), increased acidic vesicles, and lysosomal degradation of long-lived proteins. Knockdown of EIG121 blocked starvation-induced LC3 degradation and, combined with starvation or cytotoxic agents, greatly increased apoptosis, indicating EIG121 promotes cell survival under stress via the autophagy pathway.\",\n      \"method\": \"Tetracycline-inducible overexpression, subcellular fractionation, immunofluorescence, electron microscopy, siRNA knockdown, lysosomal protein degradation assay, transmembrane-domain deletion mutagenesis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, EM, mutagenesis, KD phenotype) in a single study with rigorous controls\",\n      \"pmids\": [\"21072319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELAPOR1 is a MIST1 (BHLHA15) transcriptional target containing an evolutionarily conserved mannose-6-phosphate receptor (M6PR) domain. In cultured cells it traffics with cis-Golgi resident proteins and with the trans-Golgi/late endosome protein cation-independent M6PR (CI-M6PR). Mass spectrometry of co-immunoprecipitated proteins showed ELAPOR1 and CI-M6PR share many binding partners, though CI-M6PR co-immunoprecipitated more lysosomal proteins. Elapor1 knockout mice show defective secretory granule maturation in gastric zymogenic cells. Truncation mutants of ELAPOR1 disrupted secretory vesicle trafficking.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry, live-cell trafficking assays, transgenic truncation mutants, Elapor1 knockout mouse model, histological analysis of secretory granule maturation\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP/MS, KO mouse with defined cellular phenotype, truncation mutagenesis, multiple methods in one study\",\n      \"pmids\": [\"34816763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIAA1324 (ELAPOR1) binds GRP78 (glucose-regulated protein 78 kDa) and blocks its oncogenic activities: it inhibits the GRP78–caspase-7 interaction and suppresses GRP78-mediated AKT activation, thereby inducing apoptosis in gastric cancer cells.\",\n      \"method\": \"Protein interaction analysis (co-immunoprecipitation/pulldown), xenograft tumor model, proliferation/invasion/apoptosis assays, drug-resistance assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP binding partner identified with functional readouts (apoptosis, AKT, caspase-7), single lab\",\n      \"pmids\": [\"26045166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"N-linked glycosylation (including fucosylation mediated by fucosyltransferase) is an essential post-translational modification of KIAA1324 (ELAPOR1). Loss of N-linked glycosylation eliminated tumor-suppressive activities, caused rapid proteasomal degradation of the protein, altered its subcellular localization, and abolished its ability to inhibit the GRP78–caspase-7 interaction and induce apoptosis.\",\n      \"method\": \"N-glycosylation site mutagenesis, fucosylation inhibitor treatment, proteasome inhibitor rescue, subcellular localization imaging, co-immunoprecipitation (GRP78–caspase-7), RNA sequencing, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of PTM sites combined with multiple orthogonal functional readouts (localization, degradation, interaction, apoptosis)\",\n      \"pmids\": [\"37612293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELAPOR1 functions as a copper-dependent tethering factor for proacrosomal vesicle (PAV) fusion during acrosome biogenesis. Cryo-EM revealed ELAPOR1 forms a square-planar homodimer in cis that assembles into a trans-tetramer via head-to-head homophilic interactions dependent on copper chelation. ELAPOR1 exhibits dual membrane orientation (canonical Nin-Cout and noncanonical Nout-Cin), and the noncanonical topology enables bridging of vesicles. A copper-chelation-deficient mutant (ELAPOR14HA) forms cis-dimers but fails to mediate trans-homophilic interactions in vitro and causes defective PAV fusion in mice. ELAPOR1 also interacts with the SNARE protein STX12; conditional Stx12 knockout in germ cells phenocopied ELAPOR1 deficiency.\",\n      \"method\": \"Cryo-electron microscopy, Elapor1 knockout mouse model (male infertility/globozoospermia phenotype), copper-chelation mutagenesis (ELAPOR14HA knock-in), in vitro homophilic interaction assay, conditional Stx12 knockout, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure, mutagenesis, KO mouse with defined fertility phenotype, in vitro reconstitution, multiple orthogonal methods in one study\",\n      \"pmids\": [\"40737321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ELAPOR1 interacts with VPS54 and regulates assembly of the GARP (Golgi-associated retrograde protein) complex in the testis, controlling transport and fusion of Golgi- and early endosome-derived proacrosomal vesicles during acrosome formation. Germ-cell-specific Elapor1 knockout mice exhibit impaired PAV fusion, deformed sperm, and infertility.\",\n      \"method\": \"Germ-cell-specific conditional knockout mouse, mass spectrometry, co-immunoprecipitation, proximity labeling, immunofluorescence co-localization, transmission electron microscopy\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined male infertility phenotype, MS-identified interaction with VPS54/GARP confirmed by Co-IP and proximity labeling\",\n      \"pmids\": [\"41993632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In neurons, KIAA1324/ELAPOR1 protein is markedly decreased in cells exhibiting pathological TDP-43 (nuclear-cleared and cytoplasmic phospho-TDP-43), despite elevated KIAA1324 mRNA. This discordance is associated with alternative polyadenylation of KIAA1324 mRNA upon TDP-43 depletion in iPSC-derived neurons, hypothesized to reduce translation efficiency. Overexpression of KIAA1324 protein in SH-SY5Y cells was shown by mass spectrometry to affect a network of mitochondrial proteins.\",\n      \"method\": \"Immunohistochemistry of post-mortem ALS/control brain, iPSC-derived neuron TDP-43 depletion with immunocytochemistry, mass spectrometry of KIAA1324-overexpressing cells, alternative polyadenylation analysis\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — KD/depletion with protein-level readout and MS network analysis, single study, post-mortem tissue correlation\",\n      \"pmids\": [\"41668214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELAPOR1 (inceptor) functions within pancreatic β-cells to promote clathrin-mediated endocytosis of the insulin receptor (INSR) and directs cytoplasmic insulin and proinsulin to lysosomal degradation. It interacts with proinsulin, insulin, INSR, and IGF1R.\",\n      \"method\": \"Evolutionary/positive-selection analysis with reference to published functional studies; functional claims derive from cited prior work (inceptor discovery papers) referenced in the preprint context\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — functional description in preprint references prior discovery without new direct experiments in this paper\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ELAPOR1 (also known as EIG121/KIAA1324/inceptor) is an evolutionarily conserved transmembrane protein containing an M6PR domain that localizes to trans-Golgi/late endosome–lysosome compartments; it promotes secretory granule maturation and autophagy, acts as a copper-dependent vesicle tethering factor (forming trans-tetramers via homophilic interactions) that drives proacrosomal vesicle fusion during acrosome biogenesis through interaction with STX12 and VPS54-mediated GARP complex assembly, and suppresses tumor cell growth in part by binding GRP78 to block caspase-7 interaction and AKT activation—functions that require N-linked glycosylation for proper localization and stability.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ELAPOR1 is an evolutionarily conserved transmembrane glycoprotein containing a mannose-6-phosphate receptor (M6PR) domain that functions in vesicle trafficking, autophagy, and membrane fusion across multiple secretory and endolysosomal compartments. It localizes to plasma membrane, trans-Golgi, and late endosome–lysosome compartments, where it promotes autophagosome formation and lysosomal degradation of long-lived proteins to support cell survival under stress, and facilitates secretory granule maturation in gastric zymogenic cells as a transcriptional target of MIST1 [PMID:21072319, PMID:34816763]. Structurally, ELAPOR1 forms copper-dependent square-planar cis-homodimers that assemble into trans-tetramers via head-to-head homophilic interactions, functioning as a vesicle tethering factor that drives proacrosomal vesicle fusion during acrosome biogenesis through cooperation with the SNARE protein STX12 and VPS54-mediated GARP complex assembly; loss of ELAPOR1 or its copper-chelation capacity causes globozoospermia and male infertility in mice [PMID:40737321, PMID:41993632]. ELAPOR1 also acts as a tumor suppressor in gastric cancer by binding GRP78 to block the GRP78–caspase-7 interaction and suppress AKT activation, activities that require N-linked glycosylation for proper protein stability, localization, and function [PMID:26045166, PMID:37612293].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that ELAPOR1 is a transmembrane protein in the endolysosomal system that promotes autophagy answered the fundamental question of its subcellular role and linked it to stress-induced cell survival.\",\n      \"evidence\": \"Overexpression/knockdown in human cell lines with subcellular fractionation, EM, LC3 assays, and transmembrane-domain deletion mutagenesis\",\n      \"pmids\": [\"21072319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which ELAPOR1 stimulates autophagosome formation was not defined\",\n        \"No interacting partners identified at this stage\",\n        \"In vivo relevance not tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of GRP78 as a binding partner that ELAPOR1 antagonizes revealed a tumor-suppressive mechanism operating through blockade of oncogenic GRP78–caspase-7 and GRP78–AKT signaling.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown, xenograft tumor model, apoptosis and AKT activation assays in gastric cancer cells\",\n      \"pmids\": [\"26045166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding interface between ELAPOR1 and GRP78 not mapped\",\n        \"Single-lab finding without independent replication\",\n        \"Relationship between autophagy function and tumor suppression unclear\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that ELAPOR1 contains a conserved M6PR domain, traffics with CI-M6PR, and is required for secretory granule maturation in vivo established its role in Golgi-to-lysosome vesicle trafficking beyond autophagy.\",\n      \"evidence\": \"Co-IP/mass spectrometry, live-cell trafficking, Elapor1 knockout mouse with gastric zymogenic cell phenotype, truncation mutagenesis\",\n      \"pmids\": [\"34816763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ELAPOR1 functions as a receptor or structural scaffold in the secretory pathway was unresolved\",\n        \"Cargo specificity of ELAPOR1-dependent trafficking not defined\",\n        \"Relationship between M6PR domain and autophagy function unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that N-linked glycosylation is essential for ELAPOR1 stability, localization, and tumor-suppressive activity resolved why post-translational processing is a prerequisite for all known functions.\",\n      \"evidence\": \"N-glycosylation site mutagenesis, fucosylation inhibitor, proteasome inhibitor rescue, xenograft model, co-IP for GRP78–caspase-7 interaction\",\n      \"pmids\": [\"37612293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which specific glycosylation sites are individually critical was not fully resolved\",\n        \"Whether glycosylation also regulates the autophagy and secretory functions was not tested\",\n        \"Structural basis for glycosylation-dependent stabilization unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM structure and copper-chelation mutagenesis established ELAPOR1 as a copper-dependent vesicle tethering factor that forms trans-tetramers to drive proacrosomal vesicle fusion, revealing its first atomic-level mechanism and explaining male infertility in knockout mice.\",\n      \"evidence\": \"Cryo-EM, Elapor1 KO and copper-chelation-deficient knock-in mice, in vitro homophilic interaction assay, conditional Stx12 KO phenocopy, co-IP with STX12\",\n      \"pmids\": [\"40737321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the copper-dependent tethering mechanism operates in non-germline tissues (e.g., gastric cells, neurons) is untested\",\n        \"How dual membrane topology is regulated remains unknown\",\n        \"Stoichiometry of ELAPOR1–STX12 interaction and its role in SNARE-mediated fusion not defined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of VPS54 as an ELAPOR1 partner and demonstration that ELAPOR1 regulates GARP complex assembly extended the tethering mechanism to include retrograde Golgi trafficking machinery in acrosome biogenesis.\",\n      \"evidence\": \"Germ-cell-specific conditional KO mouse, mass spectrometry, co-IP, proximity labeling, TEM\",\n      \"pmids\": [\"41993632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ELAPOR1–GARP interaction is direct or mediated by VPS54 alone is unclear\",\n        \"Functional interplay between copper-dependent tethering and GARP-mediated fusion not resolved\",\n        \"Relevance of GARP regulation outside spermatogenesis not explored\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Observation that ELAPOR1 protein is selectively lost in neurons with TDP-43 pathology despite elevated mRNA suggested post-transcriptional dysregulation via alternative polyadenylation, linking ELAPOR1 to ALS neurodegeneration.\",\n      \"evidence\": \"Post-mortem ALS brain immunohistochemistry, iPSC-derived neuron TDP-43 depletion, mass spectrometry of overexpressing cells\",\n      \"pmids\": [\"41668214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal role of ELAPOR1 loss in TDP-43-mediated neurodegeneration not demonstrated\",\n        \"Alternative polyadenylation mechanism reducing translation is correlative, not functionally validated\",\n        \"Mitochondrial protein network affected by ELAPOR1 overexpression not validated as physiologically relevant\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the copper-dependent vesicle tethering mechanism identified in spermatogenesis is a general mechanism underlying ELAPOR1's roles in autophagy, secretory granule maturation, and tumor suppression across tissues remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No tissue-general structure–function analysis linking copper binding to autophagy or GRP78 interaction\",\n        \"No human genetic disease directly attributed to ELAPOR1 mutations\",\n        \"Cargo identity and selectivity of ELAPOR1-dependent vesicle trafficking undefined outside germline\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\n      \"ELAPOR1 copper-dependent trans-tetramer\"\n    ],\n    \"partners\": [\n      \"GRP78\",\n      \"CI-M6PR\",\n      \"STX12\",\n      \"VPS54\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}