Affinage

ELAPOR1

Endosome/lysosome-associated apoptosis and autophagy regulator 1 · UniProt Q6UXG2

Length
1013 aa
Mass
111.4 kDa
Annotated
2026-04-28
14 papers in source corpus 7 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2010 High

    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

    PMID:21072319

    Open questions at the time
    • Molecular mechanism by which ELAPOR1 stimulates autophagosome formation was not defined
    • No interacting partners identified at this stage
    • In vivo relevance not tested
  2. 2015 Medium

    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

    PMID:26045166

    Open questions at the time
    • Binding interface between ELAPOR1 and GRP78 not mapped
    • Single-lab finding without independent replication
    • Relationship between autophagy function and tumor suppression unclear
  3. 2021 High

    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

    PMID:34816763

    Open questions at the time
    • 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
  4. 2023 High

    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

    PMID:37612293

    Open questions at the time
    • 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
  5. 2025 High

    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

    PMID:40737321

    Open questions at the time
    • 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
  6. 2026 High

    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

    PMID:41993632

    Open questions at the time
    • 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
  7. 2026 Medium

    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

    PMID:41668214

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005764 lysosome 2 GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2 GO:0031410 cytoplasmic vesicle 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1474165 Reproduction 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 1
Partners
CI-M6PRGRP78STX12VPS54
Complex memberships
ELAPOR1 copper-dependent trans-tetramer

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. Tetracycline-inducible overexpression, subcellular fractionation, immunofluorescence, electron microscopy, siRNA knockdown, lysosomal protein degradation assay, transmembrane-domain deletion mutagenesis Cell death & disease High 21072319
2021 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. Co-immunoprecipitation with mass spectrometry, live-cell trafficking assays, transgenic truncation mutants, Elapor1 knockout mouse model, histological analysis of secretory granule maturation American journal of physiology. Gastrointestinal and liver physiology High 34816763
2015 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. Protein interaction analysis (co-immunoprecipitation/pulldown), xenograft tumor model, proliferation/invasion/apoptosis assays, drug-resistance assays Cancer research Medium 26045166
2023 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-glycosylation site mutagenesis, fucosylation inhibitor treatment, proteasome inhibitor rescue, subcellular localization imaging, co-immunoprecipitation (GRP78–caspase-7), RNA sequencing, xenograft model Cell death & disease High 37612293
2025 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. 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 Proceedings of the National Academy of Sciences of the United States of America High 40737321
2026 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. Germ-cell-specific conditional knockout mouse, mass spectrometry, co-immunoprecipitation, proximity labeling, immunofluorescence co-localization, transmission electron microscopy Theranostics High 41993632
2026 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. Immunohistochemistry of post-mortem ALS/control brain, iPSC-derived neuron TDP-43 depletion with immunocytochemistry, mass spectrometry of KIAA1324-overexpressing cells, alternative polyadenylation analysis Acta neuropathologica communications Medium 41668214
2025 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. 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 bioRxiv (preprint)preprint Low

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The novel estrogen-induced gene EIG121 regulates autophagy and promotes cell survival under stress. Cell death & disease 75 21072319
2005 Identification of a novel estrogen-regulated gene, EIG121, induced by hormone replacement therapy and differentially expressed in type I and type II endometrial cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 50 16322283
2015 KIAA1324 Suppresses Gastric Cancer Progression by Inhibiting the Oncoprotein GRP78. Cancer research 42 26045166
2010 Molecular clustering based on ERα and EIG121 predicts survival in high-grade serous carcinoma of the ovary/peritoneum. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 39 21102415
2017 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. International journal of oncology 27 28656197
2023 N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer. Cell death & disease 16 37612293
2021 ELAPOR1 is a secretory granule maturation-promoting factor that is lost during paligenosis. American journal of physiology. Gastrointestinal and liver physiology 15 34816763
2004 Different transcriptional expression of KIAA1324 and its splicing variants in human carcinoma cell lines with different metastatic capacity. Oncology reports 13 14767521
2024 ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer. International journal of cancer 9 38630934
2020 Altered Expression of Three EGFR Posttranslational Regulators MDGI, MIG6, and EIG121 in Invasive Breast Carcinomas. Analytical cellular pathology (Amsterdam) 7 32377505
2025 ELAPOR1 is a copper-dependent tethering factor driving proacrosomal vesicle fusion during acrosome biogenesis. Proceedings of the National Academy of Sciences of the United States of America 2 40737321
2016 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. BMC research notes 1 27230222
2026 Lost in translation: absence of KIAA1324/ELAPOR1 protein in pathological TDP-43-affected neurons in ALS/FTD. Acta neuropathologica communications 0 41668214
2026 ELAPOR1 regulates VPS54-mediated GARP complex formation and proacrosomal vesicle fusion during spermatogenesis. Theranostics 0 41993632