{"gene":"ESYT3","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2007,"finding":"E-Syt3 (ESYT3) is an ER-resident protein containing three C-terminal C2 domains; its C2A domain binds Ca2+ and phospholipids at micromolar Ca2+ concentrations, and the C2C domain acts as a targeting motif that directs E-Syt3 to the plasma membrane independently of its transmembrane region.","method":"Recombinant protein fragments for Ca2+-dependent phospholipid binding assays; myc-tagged expression constructs with deletion/domain-swap structure–function analysis in transfected cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro biochemical binding assay plus domain mutagenesis/truncation in cells, multiple orthogonal methods in one study","pmids":["17360437"],"is_preprint":false},{"year":2013,"finding":"E-Syt3 is an ER protein that tethers the ER to the plasma membrane via PI(4,5)P2-dependent C2-domain interactions with the PM; E-Syt3 (together with E-Syt1 and E-Syt2) forms heteromeric complexes, conferring cytosolic Ca2+ regulation to ER-PM contact formation. These E-Syt-dependent contacts are not required for store-operated Ca2+ entry (SOCE).","method":"Live-cell fluorescence imaging of ER-PM contacts, co-immunoprecipitation for heteromeric complex formation, PI(4,5)P2 manipulation experiments, SOCE measurements","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, live imaging, lipid manipulation, and functional SOCE assay in a single study; independently replicated in subsequent papers","pmids":["23791178"],"is_preprint":false},{"year":2015,"finding":"E-Syt3 is directed to the ER by its transmembrane domain; E-Syt2 and E-Syt3 (but not E-Syt1) selectively interact in vivo with activated FGFR1 via a TM-adjacent sequence in E-Syt2, independently of receptor autophosphorylation but dependent on receptor conformation; the ESyts hetero- and homodimerize via sequences adjacent to the TM domain.","method":"Co-immunoprecipitation in transfected and embryo cells; domain deletion/mutation constructs; kinase-dead and conformation-specific receptor mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP with multiple mutant constructs in one lab, two orthogonal approaches (deletion analysis + conformation-dependent receptor mutants)","pmids":["25922075"],"is_preprint":false},{"year":2014,"finding":"Loss of both ESyt2 and ESyt3 in mouse embryonic fibroblasts reduces cell migration in standard in vitro assays and decreases resistance to stringent culture conditions and oxidative stress, establishing a functional role for the Esyt2/Esyt3 pair in cell migration and stress survival.","method":"Homozygous esyt2/esyt3 double-knockout mouse generation; in vitro migration assays; oxidative stress survival assays on MEFs","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotypes (migration, stress resistance), single lab","pmids":["25486202"],"is_preprint":false},{"year":2017,"finding":"E-Syt3 negatively modulates HSV-1 viral release, cell-to-cell spread, viral entry, and virus-induced syncytia formation; E-Syt3 (along with E-Syt1) acts as a negative regulator of viral membrane fusion events during the HSV-1 life cycle.","method":"Knockdown/overexpression of E-Syt proteins in HSV-1-infected cells; measurement of viral titers, plaque formation, syncytia induction, and viral entry","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple functional readouts (release, spread, entry, syncytia) for E-Syt3 in infected cells, single lab","pmids":["29046455"],"is_preprint":false},{"year":2017,"finding":"RASSF4 regulates the ER-PM tethering function of E-Syt2 and E-Syt3 by controlling plasma-membrane PI(4,5)P2 levels via ARF6-dependent regulation of PIP5Ks; knockdown of RASSF4 reduces PM PI(4,5)P2 and diminishes E-Syt3 localization at ER-PM junctions.","method":"RASSF4 siRNA knockdown; live-cell imaging of E-Syt3 at ER-PM contacts; PM PI(4,5)P2 measurements; ARF6 interaction and activity assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis placed E-Syt3 downstream of RASSF4/ARF6/PI(4,5)P2 axis with multiple supporting assays, single lab","pmids":["28600435"],"is_preprint":false},{"year":2017,"finding":"Knockdown of ESYT3 (and family members ESYT1/ESYT2) significantly decreased ANO1 (anoctamin 1) current density in epithelial cells, implicating E-Syt3's ER-PM coupling function in supporting plasma membrane localization and function of this Ca2+-activated chloride channel.","method":"siRNA knockdown of ESYT3 in cells expressing inducible 3HA-ANO1-eGFP; ANO1 traffic assay by microscopy; electrophysiological measurement of ANO1 current density","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD phenotype confirmed by two readouts (trafficking assay and electrophysiology), single lab","pmids":["29154949"],"is_preprint":false},{"year":2020,"finding":"Hypothalamic E-Syt3 promotes diet-induced obesity; its ablation in whole body or POMC neurons increases POMC processing to α-MSH, elevates PKC and AP-1 activities, and upregulates prohormone convertases, thereby enhancing energy expenditure and reducing food intake.","method":"Whole-body and POMC neuron-specific conditional knockout mice; measurement of POMC processing products (α-MSH); PKC activity assays; AP-1 reporter assays; qRT-PCR of prohormone convertases; metabolic phenotyping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO mice with multiple orthogonal mechanistic readouts (biochemical, signaling, molecular), single lab but comprehensive","pmids":["32747560"],"is_preprint":false},{"year":2021,"finding":"In differentiating adipocytes, the C2C domain of E-Syt3 is proteolytically cleaved by a proteasome-dependent multi-step mechanism; the resulting truncated E-Syt3ΔC2C localizes to a specialized single giant ER cisterna (the 'primordial cisterna') that serves as the birth and nurturing site of lipid droplets; knockdown of E-Syt3 inhibits lipid droplet biogenesis in this context.","method":"Confocal microscopy and live-cell time-lapse imaging; proteasome inhibitor treatment; E-Syt3ΔC2C expression constructs; electron microscopy and 3D electron tomography; siRNA knockdown of E-Syt3 with LD biogenesis readout","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple imaging modalities plus functional knockdown with defined phenotype, single lab","pmids":["34693607"],"is_preprint":false},{"year":2025,"finding":"E-Syt3 transfers phosphatidylserine (PtdSer) at ER/PM junctions and its C2C domain restricts its plasma membrane localization; removal of PtdSer from junctions by E-Syt3 dissociates the cAMP signaling complex, preventing CFTR activation and inhibiting NBCe1-B activation by IRBIT; E-Syt3 depletion in mice improved chloride flux and fluid secretion in salivary glands and pancreatic ducts.","method":"Lipid transfer assays; C2C domain deletion constructs; co-immunoprecipitation of signaling complexes; PtdSer sensor domain assays; electrophysiology (CFTR, NBCe1-B); in vivo salivary gland and pancreatic duct secretion measurements in E-Syt3-depleted mice","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution of lipid transfer function, domain mutagenesis, multiple ion transport functional assays, and in vivo mouse model with defined phenotype, single lab but highly orthogonal","pmids":["40425857"],"is_preprint":false},{"year":2024,"finding":"ESYT3 directly interacts with STING (by co-immunoprecipitation and co-immunofluorescence) and activates the cGAS-STING signaling pathway, leading to increased type I IFN production and upregulation of CCL5 and CXCL10; overexpression of ESYT3 sensitizes lung adenocarcinoma cells to DNA damage from irradiation.","method":"Co-immunoprecipitation and immunofluorescence co-staining of ESYT3 and STING; measurement of cGAS-STING pathway activation, type I IFN, CCL5, and CXCL10; overexpression and KD in cell lines; in vivo mouse tumor models with combination radiotherapy","journal":"Experimental hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP interaction plus downstream pathway activation assays and in vivo functional data, single lab","pmids":["39103908"],"is_preprint":false}],"current_model":"ESYT3 (E-Syt3) is an ER-resident transmembrane protein with three C2 domains that tethers the ER to the plasma membrane via PI(4,5)P2-dependent C2 domain interactions; it forms heteromeric complexes with E-Syt1/2 to confer Ca2+-regulated ER-PM contact formation, transfers phosphatidylserine at ER/PM junctions to modulate cAMP-dependent ion transport (CFTR, NBCe1-B), interacts with activated FGFR1 to participate in receptor signaling, activates the cGAS-STING innate immune pathway by direct interaction with STING, plays a role in hypothalamic POMC neuron energy balance by regulating POMC processing and PKC/AP-1 signaling, and undergoes proteasome-dependent C2C domain cleavage in adipocytes to facilitate lipid droplet biogenesis from a specialized ER cisterna."},"narrative":{"mechanistic_narrative":"ESYT3 (E-Syt3) is an ER-resident transmembrane protein that uses three C-terminal C2 domains to build and regulate ER–plasma membrane (ER-PM) contact sites and to transfer lipids across them [PMID:17360437, PMID:23791178, PMID:40425857]. Its C2A domain binds Ca2+ and phospholipids at micromolar Ca2+, while the C2C domain functions as a targeting motif that directs the protein toward the plasma membrane independently of the ER-anchoring transmembrane region [PMID:17360437]. E-Syt3 tethers the ER to the PM through PI(4,5)P2-dependent C2-domain interactions and forms heteromeric complexes with E-Syt1 and E-Syt2 to confer cytosolic Ca2+ regulation onto contact formation, a process placed downstream of a RASSF4–ARF6–PIP5K axis that controls PM PI(4,5)P2 levels [PMID:23791178, PMID:28600435]. At these junctions E-Syt3 transfers phosphatidylserine, and its removal of PtdSer dissociates a cAMP-signaling complex to restrain CFTR and IRBIT-dependent NBCe1-B activation, with E-Syt3 depletion enhancing chloride flux and fluid secretion in salivary glands and pancreatic ducts in mice [PMID:40425857]. Through its ER-PM coupling role E-Syt3 supports plasma-membrane channel function, including ANO1 chloride current density [PMID:29154949]. Beyond contact-site lipid handling, E-Syt3 has tissue- and pathway-specific roles: it promotes diet-induced obesity by limiting POMC processing to α-MSH and modulating PKC/AP-1 signaling in hypothalamic POMC neurons [PMID:32747560], undergoes proteasome-dependent C2C cleavage during adipocyte differentiation to seed a specialized ER cisterna for lipid-droplet biogenesis [PMID:34693607], and directly interacts with STING to activate cGAS-STING type I interferon signaling [PMID:39103908].","teleology":[{"year":2007,"claim":"Established the domain logic of E-Syt3 — how an ER protein engages membranes and lipids — by defining a Ca2+/phospholipid-binding C2A domain and a C2C domain that targets the protein toward the plasma membrane.","evidence":"In vitro Ca2+-dependent phospholipid binding with recombinant fragments plus domain-swap/deletion analysis in transfected cells","pmids":["17360437"],"confidence":"High","gaps":["Did not establish a physiological ligand or contact partner at the PM","C2C targeting mechanism (the PM lipid recognized) left undefined"]},{"year":2013,"claim":"Resolved how E-Syt3 functions in cells by showing it tethers ER to PM via PI(4,5)P2-dependent C2 interactions and forms Ca2+-regulated heteromers with E-Syt1/2, while excluding a requirement for these contacts in SOCE.","evidence":"Live-cell imaging of ER-PM contacts, reciprocal co-IP, PI(4,5)P2 manipulation, and SOCE measurements","pmids":["23791178"],"confidence":"High","gaps":["Did not identify what is transported or signaled at the contacts","Stoichiometry of E-Syt1/2/3 heteromers not defined"]},{"year":2014,"claim":"Provided the first organismal phenotype for the E-Syt2/E-Syt3 pair, linking them to cell migration and survival under oxidative/stringent stress.","evidence":"esyt2/esyt3 double-knockout mice and MEF migration and oxidative-stress survival assays","pmids":["25486202"],"confidence":"Medium","gaps":["Did not separate E-Syt3-specific from E-Syt2-specific contributions","Molecular basis connecting contact sites to migration/stress unresolved"]},{"year":2015,"claim":"Connected E-Syt3 to receptor signaling by showing it (with E-Syt2) selectively interacts with activated FGFR1 in a conformation-dependent, autophosphorylation-independent manner via TM-adjacent sequences that also mediate E-Syt dimerization.","evidence":"Co-IP in transfected and embryo cells with kinase-dead and conformation-specific receptor mutants and deletion constructs","pmids":["25922075"],"confidence":"Medium","gaps":["Functional consequence of the E-Syt3–FGFR1 interaction for signaling not established","Single-lab Co-IP without orthogonal interaction method"]},{"year":2017,"claim":"Placed E-Syt3 within an upstream regulatory circuit, showing RASSF4 controls its ER-PM localization through ARF6/PIP5K-dependent PM PI(4,5)P2 levels.","evidence":"RASSF4 siRNA, live imaging of E-Syt3 at contacts, PM PI(4,5)P2 measurement, and ARF6 activity assays","pmids":["28600435"],"confidence":"Medium","gaps":["Whether RASSF4 acts directly on E-Syt3 versus only on lipid environment unresolved","Single lab"]},{"year":2017,"claim":"Demonstrated a downstream output of E-Syt3 contact function — supporting plasma-membrane localization and current of the Ca2+-activated chloride channel ANO1.","evidence":"siRNA knockdown with ANO1 trafficking microscopy and electrophysiology","pmids":["29154949"],"confidence":"Medium","gaps":["Mechanism coupling ER-PM contacts to ANO1 surface delivery not defined","Redundancy with E-Syt1/2 not dissected"]},{"year":2017,"claim":"Implicated E-Syt3 in host defense as a negative regulator of HSV-1 membrane fusion, release, entry, spread, and syncytia formation.","evidence":"Knockdown/overexpression in HSV-1-infected cells with viral titer, plaque, entry, and syncytia readouts","pmids":["29046455"],"confidence":"Medium","gaps":["Molecular target through which E-Syt3 restrains fusion unidentified","Contribution of contact-site lipids versus protein interactions unclear"]},{"year":2020,"claim":"Revealed a neuroendocrine role: hypothalamic E-Syt3 promotes diet-induced obesity by limiting POMC processing to α-MSH and modulating PKC/AP-1 signaling.","evidence":"Whole-body and POMC-neuron conditional knockout mice with α-MSH, PKC, AP-1 reporter, prohormone convertase, and metabolic readouts","pmids":["32747560"],"confidence":"High","gaps":["How an ER-PM contact protein controls prohormone convertase expression mechanistically unresolved","Link between contact-site lipid function and PKC/AP-1 activity not defined"]},{"year":2021,"claim":"Showed E-Syt3 undergoes proteasome-dependent C2C cleavage in differentiating adipocytes, generating a truncated form that localizes to a specialized ER cisterna nucleating lipid-droplet biogenesis.","evidence":"Confocal and live time-lapse imaging, proteasome inhibitors, ΔC2C constructs, electron tomography, and siRNA with LD biogenesis readout","pmids":["34693607"],"confidence":"Medium","gaps":["Identity of the protease/E3 ligase driving C2C cleavage unknown","How E-Syt3ΔC2C shapes the primordial cisterna mechanistically unresolved"]},{"year":2024,"claim":"Linked E-Syt3 to innate immune signaling, showing it directly interacts with STING and activates cGAS-STING type I IFN/chemokine output and radiosensitizes lung adenocarcinoma.","evidence":"Co-IP and co-immunofluorescence with STING, pathway and cytokine assays, overexpression/KD, and in vivo tumor radiotherapy models","pmids":["39103908"],"confidence":"Medium","gaps":["Whether the interaction is direct versus contact-site-mediated not confirmed by reciprocal/structural methods","How an ER-PM tether activates STING mechanistically unresolved"]},{"year":2025,"claim":"Defined E-Syt3 as a phosphatidylserine transfer protein at ER/PM junctions whose PtdSer removal dissociates a cAMP complex to restrain CFTR and NBCe1-B, with depletion improving epithelial chloride and fluid secretion in vivo.","evidence":"Lipid transfer assays, C2C deletion, signaling-complex co-IP, PtdSer sensors, CFTR/NBCe1-B electrophysiology, and salivary/pancreatic secretion in E-Syt3-depleted mice","pmids":["40425857"],"confidence":"High","gaps":["Directionality and net flux of PtdSer transfer in vivo not quantified","How PtdSer levels mechanistically assemble/disassemble the cAMP complex unresolved"]},{"year":null,"claim":"It remains unresolved how a single ER-PM tethering and lipid-transfer protein produces such divergent outputs — channel trafficking, prohormone processing, lipid-droplet biogenesis, antiviral restriction, and STING activation — and whether these reflect distinct lipid cargoes, tissue-specific partners, or proteolytic isoforms.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying mechanism connecting contact-site lipid transfer to the tissue-specific signaling phenotypes","Structural basis of C2-domain lipid selectivity not determined","E-Syt1/2/3 redundancy across these functions not systematically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,9]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,9,10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,10]}],"complexes":[],"partners":["ESYT1","ESYT2","FGFR1","STING1","RASSF4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A0FGR9","full_name":"Extended synaptotagmin-3","aliases":["Chr3Syt"],"length_aa":886,"mass_kda":100.0,"function":"Binds glycerophospholipids in a barrel-like domain and may play a role in cellular lipid transport (By similarity). Tethers the endoplasmic reticulum to the cell membrane and promotes the formation of appositions between the endoplasmic reticulum and the cell membrane","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/A0FGR9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ESYT3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ESYT3","total_profiled":1310},"omim":[{"mim_id":"616692","title":"EXTENDED SYNAPTOTAGMIN-LIKE PROTEIN 3; ESYT3","url":"https://www.omim.org/entry/616692"},{"mim_id":"616691","title":"EXTENDED SYNAPTOTAGMIN-LIKE PROTEIN 2; ESYT2","url":"https://www.omim.org/entry/616691"},{"mim_id":"616670","title":"EXTENDED SYNAPTOTAGMIN-LIKE PROTEIN 1; ESYT1","url":"https://www.omim.org/entry/616670"},{"mim_id":"610841","title":"STROMAL INTERACTION MOLECULE 2; STIM2","url":"https://www.omim.org/entry/610841"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":4.2},{"tissue":"lung","ntpm":4.4},{"tissue":"skin 1","ntpm":6.1}],"url":"https://www.proteinatlas.org/search/ESYT3"},"hgnc":{"alias_symbol":["CHR3SYT"],"prev_symbol":["FAM62C"]},"alphafold":{"accession":"A0FGR9","domains":[{"cath_id":"2.60.40.150","chopping":"307-429","consensus_level":"high","plddt":87.1282,"start":307,"end":429},{"cath_id":"2.60.40.150","chopping":"445-462_485-585","consensus_level":"high","plddt":87.1669,"start":445,"end":585},{"cath_id":"2.60.40.150","chopping":"754-879","consensus_level":"high","plddt":84.9913,"start":754,"end":879},{"cath_id":"3.15.10","chopping":"120-301","consensus_level":"high","plddt":83.0314,"start":120,"end":301}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A0FGR9","model_url":"https://alphafold.ebi.ac.uk/files/AF-A0FGR9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A0FGR9-F1-predicted_aligned_error_v6.png","plddt_mean":71.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ESYT3","jax_strain_url":"https://www.jax.org/strain/search?query=ESYT3"},"sequence":{"accession":"A0FGR9","fasta_url":"https://rest.uniprot.org/uniprotkb/A0FGR9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A0FGR9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A0FGR9"}},"corpus_meta":[{"pmid":"23791178","id":"PMC_23791178","title":"PI(4,5)P(2)-dependent and Ca(2+)-regulated ER-PM interactions mediated by the extended synaptotagmins.","date":"2013","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/23791178","citation_count":481,"is_preprint":false},{"pmid":"17360437","id":"PMC_17360437","title":"E-Syts, a family of membranous Ca2+-sensor proteins with multiple C2 domains.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17360437","citation_count":156,"is_preprint":false},{"pmid":"16778180","id":"PMC_16778180","title":"Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16778180","citation_count":150,"is_preprint":false},{"pmid":"20484983","id":"PMC_20484983","title":"Genome-wide DNA methylation profiling of chronic lymphocytic leukemia allows identification of epigenetically repressed molecular pathways with clinical impact.","date":"2010","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/20484983","citation_count":89,"is_preprint":false},{"pmid":"28600435","id":"PMC_28600435","title":"RASSF4 controls SOCE and ER-PM junctions through regulation of PI(4,5)P2.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28600435","citation_count":59,"is_preprint":false},{"pmid":"27348751","id":"PMC_27348751","title":"Extended Synaptotagmin (ESyt) Triple Knock-Out Mice Are Viable and Fertile without Obvious Endoplasmic Reticulum Dysfunction.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27348751","citation_count":52,"is_preprint":false},{"pmid":"27399837","id":"PMC_27399837","title":"Loss of all 3 Extended Synaptotagmins does not affect normal mouse development, viability or fertility.","date":"2016","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/27399837","citation_count":35,"is_preprint":false},{"pmid":"29154949","id":"PMC_29154949","title":"A novel microscopy-based assay identifies extended synaptotagmin-1 (ESYT1) as a positive regulator of anoctamin 1 traffic.","date":"2017","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29154949","citation_count":23,"is_preprint":false},{"pmid":"29046455","id":"PMC_29046455","title":"Extended Synaptotagmin 1 Interacts with Herpes Simplex Virus 1 Glycoprotein M and Negatively Modulates Virus-Induced Membrane Fusion.","date":"2017","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/29046455","citation_count":22,"is_preprint":false},{"pmid":"25486202","id":"PMC_25486202","title":"Loss of Extended Synaptotagmins ESyt2 and ESyt3 does not affect mouse development or viability, but in vitro cell migration and survival under stress are affected.","date":"2014","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/25486202","citation_count":21,"is_preprint":false},{"pmid":"32747560","id":"PMC_32747560","title":"Hypothalamic extended synaptotagmin-3 contributes to the development of dietary obesity and related metabolic disorders.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32747560","citation_count":17,"is_preprint":false},{"pmid":"21733517","id":"PMC_21733517","title":"Fine mapping of chromosome 3q22.3 identifies two haplotype blocks in ESYT3 associated with coronary artery disease in female Han Chinese.","date":"2011","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/21733517","citation_count":14,"is_preprint":false},{"pmid":"39103908","id":"PMC_39103908","title":"Overexpression of ESYT3 improves radioimmune responses through activating cGAS-STING pathway in lung adenocarcinoma.","date":"2024","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39103908","citation_count":12,"is_preprint":false},{"pmid":"25922075","id":"PMC_25922075","title":"Extended Synaptotagmin Interaction with the Fibroblast Growth Factor Receptor Depends on Receptor Conformation, Not Catalytic Activity.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25922075","citation_count":12,"is_preprint":false},{"pmid":"34197731","id":"PMC_34197731","title":"Whole-exome sequencing reveals common and rare variants in immunologic and neurological genes implicated in achalasia.","date":"2021","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34197731","citation_count":12,"is_preprint":false},{"pmid":"34693607","id":"PMC_34693607","title":"The E-Syt3 cleavage and traffic uncovers the primordial cisterna, a new organelle that mothers the lipid droplets in the adipocyte.","date":"2021","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/34693607","citation_count":4,"is_preprint":false},{"pmid":"38111060","id":"PMC_38111060","title":"Risk factors analysis and survival prediction model establishment of patients with lung adenocarcinoma based on different pyroptosis-related gene subtypes.","date":"2023","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/38111060","citation_count":4,"is_preprint":false},{"pmid":"39325237","id":"PMC_39325237","title":"Single-cell RNA sequencing reveals surface markers of primordial germ cells in chicken and zebra finch.","date":"2024","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/39325237","citation_count":3,"is_preprint":false},{"pmid":"40425857","id":"PMC_40425857","title":"Lipid transporters E-Syt3 and ORP5 regulate epithelial ion transport by controlling phosphatidylserine enrichment at ER/PM junctions.","date":"2025","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/40425857","citation_count":2,"is_preprint":false},{"pmid":"40923693","id":"PMC_40923693","title":"Genome-Wide Insights Into the Genes and Pathways Shaping Human Foveal Development: Redefining the Genetic Landscape of Foveal Hypoplasia.","date":"2025","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/40923693","citation_count":1,"is_preprint":false},{"pmid":"40585125","id":"PMC_40585125","title":"Genome-Wide Insights into the Genes and Pathways Shaping Human Foveal Development.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40585125","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13051,"output_tokens":3202,"usd":0.043591,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10599,"output_tokens":4068,"usd":0.077347,"stage2_stop_reason":"end_turn"},"total_usd":0.120938,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"E-Syt3 (ESYT3) is an ER-resident protein containing three C-terminal C2 domains; its C2A domain binds Ca2+ and phospholipids at micromolar Ca2+ concentrations, and the C2C domain acts as a targeting motif that directs E-Syt3 to the plasma membrane independently of its transmembrane region.\",\n      \"method\": \"Recombinant protein fragments for Ca2+-dependent phospholipid binding assays; myc-tagged expression constructs with deletion/domain-swap structure–function analysis in transfected cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro biochemical binding assay plus domain mutagenesis/truncation in cells, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17360437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"E-Syt3 is an ER protein that tethers the ER to the plasma membrane via PI(4,5)P2-dependent C2-domain interactions with the PM; E-Syt3 (together with E-Syt1 and E-Syt2) forms heteromeric complexes, conferring cytosolic Ca2+ regulation to ER-PM contact formation. These E-Syt-dependent contacts are not required for store-operated Ca2+ entry (SOCE).\",\n      \"method\": \"Live-cell fluorescence imaging of ER-PM contacts, co-immunoprecipitation for heteromeric complex formation, PI(4,5)P2 manipulation experiments, SOCE measurements\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, live imaging, lipid manipulation, and functional SOCE assay in a single study; independently replicated in subsequent papers\",\n      \"pmids\": [\"23791178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"E-Syt3 is directed to the ER by its transmembrane domain; E-Syt2 and E-Syt3 (but not E-Syt1) selectively interact in vivo with activated FGFR1 via a TM-adjacent sequence in E-Syt2, independently of receptor autophosphorylation but dependent on receptor conformation; the ESyts hetero- and homodimerize via sequences adjacent to the TM domain.\",\n      \"method\": \"Co-immunoprecipitation in transfected and embryo cells; domain deletion/mutation constructs; kinase-dead and conformation-specific receptor mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP with multiple mutant constructs in one lab, two orthogonal approaches (deletion analysis + conformation-dependent receptor mutants)\",\n      \"pmids\": [\"25922075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of both ESyt2 and ESyt3 in mouse embryonic fibroblasts reduces cell migration in standard in vitro assays and decreases resistance to stringent culture conditions and oxidative stress, establishing a functional role for the Esyt2/Esyt3 pair in cell migration and stress survival.\",\n      \"method\": \"Homozygous esyt2/esyt3 double-knockout mouse generation; in vitro migration assays; oxidative stress survival assays on MEFs\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotypes (migration, stress resistance), single lab\",\n      \"pmids\": [\"25486202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"E-Syt3 negatively modulates HSV-1 viral release, cell-to-cell spread, viral entry, and virus-induced syncytia formation; E-Syt3 (along with E-Syt1) acts as a negative regulator of viral membrane fusion events during the HSV-1 life cycle.\",\n      \"method\": \"Knockdown/overexpression of E-Syt proteins in HSV-1-infected cells; measurement of viral titers, plaque formation, syncytia induction, and viral entry\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple functional readouts (release, spread, entry, syncytia) for E-Syt3 in infected cells, single lab\",\n      \"pmids\": [\"29046455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RASSF4 regulates the ER-PM tethering function of E-Syt2 and E-Syt3 by controlling plasma-membrane PI(4,5)P2 levels via ARF6-dependent regulation of PIP5Ks; knockdown of RASSF4 reduces PM PI(4,5)P2 and diminishes E-Syt3 localization at ER-PM junctions.\",\n      \"method\": \"RASSF4 siRNA knockdown; live-cell imaging of E-Syt3 at ER-PM contacts; PM PI(4,5)P2 measurements; ARF6 interaction and activity assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis placed E-Syt3 downstream of RASSF4/ARF6/PI(4,5)P2 axis with multiple supporting assays, single lab\",\n      \"pmids\": [\"28600435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of ESYT3 (and family members ESYT1/ESYT2) significantly decreased ANO1 (anoctamin 1) current density in epithelial cells, implicating E-Syt3's ER-PM coupling function in supporting plasma membrane localization and function of this Ca2+-activated chloride channel.\",\n      \"method\": \"siRNA knockdown of ESYT3 in cells expressing inducible 3HA-ANO1-eGFP; ANO1 traffic assay by microscopy; electrophysiological measurement of ANO1 current density\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD phenotype confirmed by two readouts (trafficking assay and electrophysiology), single lab\",\n      \"pmids\": [\"29154949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hypothalamic E-Syt3 promotes diet-induced obesity; its ablation in whole body or POMC neurons increases POMC processing to α-MSH, elevates PKC and AP-1 activities, and upregulates prohormone convertases, thereby enhancing energy expenditure and reducing food intake.\",\n      \"method\": \"Whole-body and POMC neuron-specific conditional knockout mice; measurement of POMC processing products (α-MSH); PKC activity assays; AP-1 reporter assays; qRT-PCR of prohormone convertases; metabolic phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO mice with multiple orthogonal mechanistic readouts (biochemical, signaling, molecular), single lab but comprehensive\",\n      \"pmids\": [\"32747560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In differentiating adipocytes, the C2C domain of E-Syt3 is proteolytically cleaved by a proteasome-dependent multi-step mechanism; the resulting truncated E-Syt3ΔC2C localizes to a specialized single giant ER cisterna (the 'primordial cisterna') that serves as the birth and nurturing site of lipid droplets; knockdown of E-Syt3 inhibits lipid droplet biogenesis in this context.\",\n      \"method\": \"Confocal microscopy and live-cell time-lapse imaging; proteasome inhibitor treatment; E-Syt3ΔC2C expression constructs; electron microscopy and 3D electron tomography; siRNA knockdown of E-Syt3 with LD biogenesis readout\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple imaging modalities plus functional knockdown with defined phenotype, single lab\",\n      \"pmids\": [\"34693607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"E-Syt3 transfers phosphatidylserine (PtdSer) at ER/PM junctions and its C2C domain restricts its plasma membrane localization; removal of PtdSer from junctions by E-Syt3 dissociates the cAMP signaling complex, preventing CFTR activation and inhibiting NBCe1-B activation by IRBIT; E-Syt3 depletion in mice improved chloride flux and fluid secretion in salivary glands and pancreatic ducts.\",\n      \"method\": \"Lipid transfer assays; C2C domain deletion constructs; co-immunoprecipitation of signaling complexes; PtdSer sensor domain assays; electrophysiology (CFTR, NBCe1-B); in vivo salivary gland and pancreatic duct secretion measurements in E-Syt3-depleted mice\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution of lipid transfer function, domain mutagenesis, multiple ion transport functional assays, and in vivo mouse model with defined phenotype, single lab but highly orthogonal\",\n      \"pmids\": [\"40425857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ESYT3 directly interacts with STING (by co-immunoprecipitation and co-immunofluorescence) and activates the cGAS-STING signaling pathway, leading to increased type I IFN production and upregulation of CCL5 and CXCL10; overexpression of ESYT3 sensitizes lung adenocarcinoma cells to DNA damage from irradiation.\",\n      \"method\": \"Co-immunoprecipitation and immunofluorescence co-staining of ESYT3 and STING; measurement of cGAS-STING pathway activation, type I IFN, CCL5, and CXCL10; overexpression and KD in cell lines; in vivo mouse tumor models with combination radiotherapy\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP interaction plus downstream pathway activation assays and in vivo functional data, single lab\",\n      \"pmids\": [\"39103908\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ESYT3 (E-Syt3) is an ER-resident transmembrane protein with three C2 domains that tethers the ER to the plasma membrane via PI(4,5)P2-dependent C2 domain interactions; it forms heteromeric complexes with E-Syt1/2 to confer Ca2+-regulated ER-PM contact formation, transfers phosphatidylserine at ER/PM junctions to modulate cAMP-dependent ion transport (CFTR, NBCe1-B), interacts with activated FGFR1 to participate in receptor signaling, activates the cGAS-STING innate immune pathway by direct interaction with STING, plays a role in hypothalamic POMC neuron energy balance by regulating POMC processing and PKC/AP-1 signaling, and undergoes proteasome-dependent C2C domain cleavage in adipocytes to facilitate lipid droplet biogenesis from a specialized ER cisterna.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ESYT3 (E-Syt3) is an ER-resident transmembrane protein that uses three C-terminal C2 domains to build and regulate ER–plasma membrane (ER-PM) contact sites and to transfer lipids across them [#0, #1, #9]. Its C2A domain binds Ca2+ and phospholipids at micromolar Ca2+, while the C2C domain functions as a targeting motif that directs the protein toward the plasma membrane independently of the ER-anchoring transmembrane region [#0]. E-Syt3 tethers the ER to the PM through PI(4,5)P2-dependent C2-domain interactions and forms heteromeric complexes with E-Syt1 and E-Syt2 to confer cytosolic Ca2+ regulation onto contact formation, a process placed downstream of a RASSF4–ARF6–PIP5K axis that controls PM PI(4,5)P2 levels [#1, #5]. At these junctions E-Syt3 transfers phosphatidylserine, and its removal of PtdSer dissociates a cAMP-signaling complex to restrain CFTR and IRBIT-dependent NBCe1-B activation, with E-Syt3 depletion enhancing chloride flux and fluid secretion in salivary glands and pancreatic ducts in mice [#9]. Through its ER-PM coupling role E-Syt3 supports plasma-membrane channel function, including ANO1 chloride current density [#6]. Beyond contact-site lipid handling, E-Syt3 has tissue- and pathway-specific roles: it promotes diet-induced obesity by limiting POMC processing to α-MSH and modulating PKC/AP-1 signaling in hypothalamic POMC neurons [#7], undergoes proteasome-dependent C2C cleavage during adipocyte differentiation to seed a specialized ER cisterna for lipid-droplet biogenesis [#8], and directly interacts with STING to activate cGAS-STING type I interferon signaling [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the domain logic of E-Syt3 — how an ER protein engages membranes and lipids — by defining a Ca2+/phospholipid-binding C2A domain and a C2C domain that targets the protein toward the plasma membrane.\",\n      \"evidence\": \"In vitro Ca2+-dependent phospholipid binding with recombinant fragments plus domain-swap/deletion analysis in transfected cells\",\n      \"pmids\": [\"17360437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish a physiological ligand or contact partner at the PM\", \"C2C targeting mechanism (the PM lipid recognized) left undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how E-Syt3 functions in cells by showing it tethers ER to PM via PI(4,5)P2-dependent C2 interactions and forms Ca2+-regulated heteromers with E-Syt1/2, while excluding a requirement for these contacts in SOCE.\",\n      \"evidence\": \"Live-cell imaging of ER-PM contacts, reciprocal co-IP, PI(4,5)P2 manipulation, and SOCE measurements\",\n      \"pmids\": [\"23791178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify what is transported or signaled at the contacts\", \"Stoichiometry of E-Syt1/2/3 heteromers not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the first organismal phenotype for the E-Syt2/E-Syt3 pair, linking them to cell migration and survival under oxidative/stringent stress.\",\n      \"evidence\": \"esyt2/esyt3 double-knockout mice and MEF migration and oxidative-stress survival assays\",\n      \"pmids\": [\"25486202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not separate E-Syt3-specific from E-Syt2-specific contributions\", \"Molecular basis connecting contact sites to migration/stress unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected E-Syt3 to receptor signaling by showing it (with E-Syt2) selectively interacts with activated FGFR1 in a conformation-dependent, autophosphorylation-independent manner via TM-adjacent sequences that also mediate E-Syt dimerization.\",\n      \"evidence\": \"Co-IP in transfected and embryo cells with kinase-dead and conformation-specific receptor mutants and deletion constructs\",\n      \"pmids\": [\"25922075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the E-Syt3–FGFR1 interaction for signaling not established\", \"Single-lab Co-IP without orthogonal interaction method\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed E-Syt3 within an upstream regulatory circuit, showing RASSF4 controls its ER-PM localization through ARF6/PIP5K-dependent PM PI(4,5)P2 levels.\",\n      \"evidence\": \"RASSF4 siRNA, live imaging of E-Syt3 at contacts, PM PI(4,5)P2 measurement, and ARF6 activity assays\",\n      \"pmids\": [\"28600435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RASSF4 acts directly on E-Syt3 versus only on lipid environment unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a downstream output of E-Syt3 contact function — supporting plasma-membrane localization and current of the Ca2+-activated chloride channel ANO1.\",\n      \"evidence\": \"siRNA knockdown with ANO1 trafficking microscopy and electrophysiology\",\n      \"pmids\": [\"29154949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling ER-PM contacts to ANO1 surface delivery not defined\", \"Redundancy with E-Syt1/2 not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Implicated E-Syt3 in host defense as a negative regulator of HSV-1 membrane fusion, release, entry, spread, and syncytia formation.\",\n      \"evidence\": \"Knockdown/overexpression in HSV-1-infected cells with viral titer, plaque, entry, and syncytia readouts\",\n      \"pmids\": [\"29046455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target through which E-Syt3 restrains fusion unidentified\", \"Contribution of contact-site lipids versus protein interactions unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a neuroendocrine role: hypothalamic E-Syt3 promotes diet-induced obesity by limiting POMC processing to α-MSH and modulating PKC/AP-1 signaling.\",\n      \"evidence\": \"Whole-body and POMC-neuron conditional knockout mice with α-MSH, PKC, AP-1 reporter, prohormone convertase, and metabolic readouts\",\n      \"pmids\": [\"32747560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an ER-PM contact protein controls prohormone convertase expression mechanistically unresolved\", \"Link between contact-site lipid function and PKC/AP-1 activity not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed E-Syt3 undergoes proteasome-dependent C2C cleavage in differentiating adipocytes, generating a truncated form that localizes to a specialized ER cisterna nucleating lipid-droplet biogenesis.\",\n      \"evidence\": \"Confocal and live time-lapse imaging, proteasome inhibitors, ΔC2C constructs, electron tomography, and siRNA with LD biogenesis readout\",\n      \"pmids\": [\"34693607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the protease/E3 ligase driving C2C cleavage unknown\", \"How E-Syt3ΔC2C shapes the primordial cisterna mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked E-Syt3 to innate immune signaling, showing it directly interacts with STING and activates cGAS-STING type I IFN/chemokine output and radiosensitizes lung adenocarcinoma.\",\n      \"evidence\": \"Co-IP and co-immunofluorescence with STING, pathway and cytokine assays, overexpression/KD, and in vivo tumor radiotherapy models\",\n      \"pmids\": [\"39103908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the interaction is direct versus contact-site-mediated not confirmed by reciprocal/structural methods\", \"How an ER-PM tether activates STING mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined E-Syt3 as a phosphatidylserine transfer protein at ER/PM junctions whose PtdSer removal dissociates a cAMP complex to restrain CFTR and NBCe1-B, with depletion improving epithelial chloride and fluid secretion in vivo.\",\n      \"evidence\": \"Lipid transfer assays, C2C deletion, signaling-complex co-IP, PtdSer sensors, CFTR/NBCe1-B electrophysiology, and salivary/pancreatic secretion in E-Syt3-depleted mice\",\n      \"pmids\": [\"40425857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Directionality and net flux of PtdSer transfer in vivo not quantified\", \"How PtdSer levels mechanistically assemble/disassemble the cAMP complex unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single ER-PM tethering and lipid-transfer protein produces such divergent outputs — channel trafficking, prohormone processing, lipid-droplet biogenesis, antiviral restriction, and STING activation — and whether these reflect distinct lipid cargoes, tissue-specific partners, or proteolytic isoforms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying mechanism connecting contact-site lipid transfer to the tissue-specific signaling phenotypes\", \"Structural basis of C2-domain lipid selectivity not determined\", \"E-Syt1/2/3 redundancy across these functions not systematically dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 9, 10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ESYT1\", \"ESYT2\", \"FGFR1\", \"STING1\", \"RASSF4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}