{"gene":"ORMDL3","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2010,"finding":"ORMDL3 overexpression increases resting cytosolic Ca2+ levels and reduces ER-mediated Ca2+ signaling; co-expression with SERCA (sarco-endoplasmic reticulum Ca2+ pump) reverses this effect, supporting a model in which ORMDL3 binds and inhibits SERCA. siRNA knockdown of ORMDL3 potentiates ER Ca2+ release and attenuates the UPR.","method":"Heterologous overexpression, siRNA knockdown, Ca2+ measurements, co-expression rescue assay in mammalian cells","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression and knockdown with orthogonal Ca2+ and UPR readouts; single lab, no direct binding/reconstitution shown","pmids":["19819884"],"is_preprint":false},{"year":2012,"finding":"ORMDL3 negatively modulates Ca2+-release-activated Ca2+ currents (ICRAC), store-operated calcium entry (SOCE), NFAT nuclear translocation, and IL-2 production in T lymphocytes. Mechanistically, ORMDL3 inhibits Ca2+ influx at the outer mitochondrial membrane, leading to Ca2+-dependent inhibition of ICRAC; the effect is mimicked by reducing mitochondrial Ca2+ uptake and reversed by cytosolic Ca2+ buffering.","method":"Patch-clamp electrophysiology (ICRAC measurement), SOCE assays, NFAT reporter, IL-2 ELISA, mitochondrial Ca2+ manipulation, overexpression and knockdown in T lymphocytes","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal electrophysiological and functional assays, mechanistic rescue experiments in a single rigorous study","pmids":["23100328"],"is_preprint":false},{"year":2012,"finding":"Transfection of ORMDL3 in human bronchial epithelial cells induces expression of metalloproteases (MMP-9, ADAM-8), chemokines (CCL-20, IL-8, CXCL-10, CXCL-11), OAS genes, and selectively activates the ATF6 branch of the UPR. siRNA knockdown of ATF6α inhibits SERCA2b expression; conversely, ORMDL3 transfection activates ATF6α and induces SERCA2b. In mice, allergen challenge induces ORMDL3 in bronchial epithelium in a STAT-6-dependent manner.","method":"Transfection (overexpression), siRNA knockdown, qPCR, immunoblot; STAT-6 KO mice for in vivo pathway placement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — overexpression and knockdown with multiple orthogonal molecular readouts, replicated in vivo with genetic model","pmids":["23011799"],"is_preprint":false},{"year":2013,"finding":"ORMDL3 expression in eosinophils is localized to the endoplasmic reticulum and is induced by IL-3 and eotaxin-1. Overexpression of ORMDL3 increases eosinophil rolling, ERK1/2 phosphorylation, NF-κB nuclear translocation, and CD48-mediated degranulation. Knockdown of ORMDL3 inhibits activation-induced cell shape changes, adhesion, in vivo recruitment, and reduces expression of integrins CD49d and CD18.","method":"Overexpression, siRNA knockdown, flow cytometry, ERK/NF-κB immunoblot, intravital microscopy, in vivo recruitment assay, ER localization by confocal","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function with multiple orthogonal molecular and cellular readouts, validated in vivo","pmids":["24056518"],"is_preprint":false},{"year":2014,"finding":"Mice universally overexpressing human ORMDL3 (hORMDL3zp3-Cre) develop increased airway remodeling (smooth muscle, fibrosis, mucus), spontaneous airway hyperresponsiveness, and elevated IgE. This is associated with selective activation of ATF6 (but not IRE1 or PERK) and strong induction of SERCA2b and TGF-β1/ADAM8; airway remodeling precedes inflammation.","method":"Transgenic mouse model (hORMDL3zp3-Cre), lung function measurement, histology, qPCR, immunoblot; UPR pathway-specific readouts","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model with multiple orthogonal readouts and pathway specificity (ATF6 selectivity); replicated across multiple studies","pmids":["24623133"],"is_preprint":false},{"year":2015,"finding":"ORMDL3 forms stable complexes with serine palmitoyltransferase (SPT) that are not increased by elevated ORMDL3 expression, suggesting ORMDL is expressed in functional excess relative to SPT. Elevated ORMDL3 expression does not suppress de novo sphingolipid biosynthesis in human bronchial epithelial cells or HeLa cells, though steady-state sphingolipid mass levels are marginally decreased at low overexpression levels.","method":"Co-immunoprecipitation (ORMDL3-SPT complex), isotope-labeling sphingolipid biosynthesis assay, overexpression in HBECs and HeLa cells, mass spectrometry lipidomics","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro biosynthesis assay plus co-IP for complex formation; single lab","pmids":["25691431"],"is_preprint":false},{"year":2015,"finding":"Higher levels of ORMDL3 expression in lung epithelial cells and macrophages increase ceramide production (in vitro and in vivo), promoting chronic inflammation, airway hyperresponsiveness, and mucus production. Small increases in ORMDL3 decrease ceramide levels, while high overexpression increases them, indicating complex dose-dependent regulation of ceramide homeostasis.","method":"Overexpression and KD in epithelial cells and macrophages, house-dust-mite mouse model, mass spectrometry lipidomics, FTY720 pharmacological rescue","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro complementary models with lipidomics; single lab, complex/non-linear dose-response complicates interpretation","pmids":["25842287"],"is_preprint":false},{"year":2015,"finding":"ORMDL3 negatively regulates FcεRI-triggered NF-κB signaling in mast cells: reduced ORMDL3 expression enhances AKT (Ser473) phosphorylation, IκBα phosphorylation/degradation, NF-κB p65 nuclear translocation, and upregulates TNF-α, IL-6, IL-13, CCL3, CCL4, and COX-2-dependent prostaglandin D2. Reduced ORMDL3 also enhances antigen-mediated chemotaxis but decreases fibronectin spreading. In vivo, locally silenced ORMDL3 increases IgE-dependent passive cutaneous anaphylaxis.","method":"siRNA knockdown and overexpression in murine mast cells, immunoblotting, ELISA, in vivo PCA model","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation with multiple signaling and functional readouts; single lab","pmids":["26407610"],"is_preprint":false},{"year":2016,"finding":"Ormdl3 knockout mice are protected from Alternaria-induced allergic airways disease (reduced airway function impairment and eosinophilia). ORMDL3 drives the ATF6-mediated UPR arm through XBP1 and downstream ER-associated degradation pathway activation. ORMDL3 also mediates uric acid release (a cellular stress marker). Reconstitution of ORMDL3 specifically in bronchial epithelium of knockout mice reinstates susceptibility to allergen-induced disease.","method":"Ormdl3 knockout mouse, adeno-associated viral reconstitution in airway epithelium, lung function measurement, histology, eosinophil counts, UPR gene expression","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with epistatic reconstitution (add-back), multiple orthogonal readouts, confirms pathway specificity for ATF6/XBP1 arm","pmids":["27623174"],"is_preprint":false},{"year":2017,"finding":"Epithelial-selective ORMDL3 knockout mice (Ormdl3 epithelial-specific KO) challenged with OVA show unexpectedly increased airway hyperresponsiveness compared to wild-type. Sphingosine-1-phosphate (S1P) levels are significantly elevated in these mice and in airway epithelial cells after ORMDL3 siRNA knockdown. S1P directly increases airway smooth muscle contractility. This reveals that ORMDL3 in airway epithelium normally suppresses S1P generation.","method":"Cre-lox epithelial-specific KO mouse, OVA challenge, airway responsiveness measurement, S1P mass spectrometry, siRNA in vitro, smooth muscle contractility assay with exogenous S1P","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with pharmacological/biochemical rescue linking ORMDL3 to S1P and smooth muscle contractility","pmids":["28275141"],"is_preprint":false},{"year":2017,"finding":"ORMDL3 expression in airway smooth muscle (ASM) increases ASM proliferation and contractility in vitro. In precision-cut lung slices from hORMDL3Zp3-Cre mice (without airway inflammation), increased ORMDL3 increases ASM Ca2+ oscillations and airway contractility. Increased ORMDL3 in ASM elevates SERCA2b, which mediates the proliferation and contractility effects.","method":"In vitro ASM transfection, ORMDL3 transgenic mouse PCLS assay, Ca2+ imaging, BrdU proliferation assay, SERCA2b knockdown/overexpression","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and ex vivo approaches; SERCA2b mechanistically linked; single lab","pmids":["28889952"],"is_preprint":false},{"year":2017,"finding":"ORMDL3 facilitates B cell survival via an ATF6α-ER stress-Beclin1 autophagy pathway. Ormdl3-/- mice have decreased mature B lymphocytes, transitional 2B cells, B1a cells, reduced IgG/IgM secretion, and Baff expression; increased apoptosis of splenic CD19+ B cells. In vitro and in vivo experiments show ORMDL3 promotes autophagy through ATF6-Beclin1, suppressing apoptosis.","method":"Ormdl3 knockout mouse, flow cytometry, Annexin V apoptosis assay, autophagy markers (Beclin1), ATF6 pathway knockdown/overexpression","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with in vitro mechanistic follow-up; single lab, multiple readouts","pmids":["28747345"],"is_preprint":false},{"year":2018,"finding":"AhR ligands promote ORMDL3-dependent S1P generation by inhibiting S1P lyase (S1PL). Mechanistically, AhR-mediated oxidation of S1PL at residue C317 inactivates S1PL; ORMDL3 knockdown prevents this AhR-mediated effect. A time-dependent increase in the ORMDL3-S1PL protein complex was detected, confirmed by FRET analysis. Cells expressing C317A S1PL mutant are resistant to AhR-mediated S1PL inhibition.","method":"FRET, co-immunoprecipitation, site-directed mutagenesis (C317A S1PL), S1PL activity assay, ORMDL3 siRNA knockdown, mast cell degranulation assay","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — FRET-confirmed protein interaction, enzyme activity assay, site-directed mutagenesis; single lab but multiple orthogonal methods","pmids":["29572542"],"is_preprint":false},{"year":2019,"finding":"ORMDL3 knockdown reduces IL-6 and IL-8 release and ER stress after IL-1B stimulation in A549 cells; overexpression and myriocin (SPT inhibitor) augment cytokine release. ORMDL3 knockdown strongly reduces ICAM1 expression (the rhinovirus receptor), and alters glycolytic transcripts and metabolites, ceramide, and sphingosine-1-phosphate levels.","method":"siRNA knockdown, overexpression, cytokine ELISA, transcriptomics, metabolomics (ceramide/S1P), myriocin pharmacology; replicated in normal human bronchial epithelial cells","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional manipulation with multiple orthogonal molecular/metabolomic readouts, replicated in primary cells","pmids":["30339462"],"is_preprint":false},{"year":2019,"finding":"ORMDL3 overexpression in mice reduces allergen-induced lung ceramide increases (while ORMDL3 deficiency increases systemic ceramide and sphingolipid levels in liver and serum), establishing that ORMDL3 regulates systemic ceramide homeostasis in vivo. Despite these ceramide changes, all hallmark asthma features are identical between wild-type, ORMDL3 transgenic, and ORMDL3 KO mice across multiple allergen models.","method":"Ormdl3-/- KO and Ormdl3Tg/wt transgenic mice; HDM and Alternaria asthma models; mass spectrometry sphingolipidomics, airway eosinophilia, AHR measurement","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — complementary transgenic and KO models with comprehensive lipidomics and in vivo phenotyping; well-controlled","pmids":["31330218"],"is_preprint":false},{"year":2019,"finding":"ORMDL3 overexpression impairs airway barrier function: it increases epithelial permeability, reduces TEER, downregulates junctional proteins (Claudin-18, E-cadherin), and induces SPHK1 activity and distribution. SPHK1 inhibition rescues TEER loss caused by ORMDL3 overexpression. ERK activation occurs downstream of SPHK1 in this pathway.","method":"Overexpression/inhibition in 16HBE cells and in vivo OVA-RSV mouse model, TEER measurement, permeability assay, SPHK1 inhibitor rescue, ERK immunoblot","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with pharmacological rescue, multiple readouts; single lab","pmids":["31173170"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 expression in airway smooth muscle induces ASM hypertrophy, hyperplasia (BrdU incorporation), and increased contractility. Overexpression elevates tropomyosin TPM1 and TPM4; siRNA knockdown of TPM1 or TPM4 demonstrates their requirement for ORMDL3-mediated ASM proliferation (but not hypertrophy). Increased contractility is associated with elevated intracellular Ca2+, increased Orai1 Ca2+ channels on cell surface, and upregulation of SERCA2b and smooth muscle 22.","method":"Smooth muscle-selective ORMDL3 transgenic mice (hORMDL3Myh11eGFP-cre), FACS, BrdU, Ca2+ imaging, contractility assay, siRNA TPM1/4 knockdown","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific transgenic model, siRNA epistasis for TPM1/4, multiple orthogonal readouts, in vitro and in vivo validation","pmids":["33661765"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 suppresses antigen-mediated mast cell activation via an ATF6-UPR-autophagy pathway: ORMDL3 overexpression inhibits degranulation and cytokine/chemokine production; knockdown has opposite effects. ORMDL3 overexpression upregulates SERCA2b, ATF6, Beclin1, and LC3BII. Knockdown of ATF6 or inhibition of autophagy reverses the suppression conferred by ORMDL3 overexpression. In vivo ORMDL3 and ATF6 knockdown enhances passive cutaneous anaphylaxis.","method":"Overexpression and siRNA knockdown in MC/9 cells, ATF6 siRNA epistasis, autophagy inhibitors, in vivo PCA mouse model","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation with epistatic pathway placement; single lab, in vivo validation","pmids":["33679742"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 physically interacts with 5-lipoxygenase (5-LO) in ER domains of human mast cells; both also interact with the SPTLC1 subunit of SPT. ORMDL3 KO mast cells show increased leukotriene production (LTB4, LTC4, etc.) in addition to increased sphingolipids, establishing functional crosstalk between sphingolipid and eicosanoid (leukotriene) metabolic pathways.","method":"Co-immunoprecipitation (ORMDL3-5-LO and 5-LO-SPTLC1), ORMDL3/5-LO KO peritoneal mast cells, lipidomics (sphingolipids and LTs), siRNA knockdown of 5-LO and SPTLC1","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for direct interaction, KO cellular lipidomics, epistatic siRNA; single lab","pmids":["34560079"],"is_preprint":false},{"year":2021,"finding":"Ormdl3-/- mice have impaired BAT thermogenesis and WAT browning, with elevated ceramide levels in adipose tissue. The reduction in UCP1-mediated thermogenesis and increased weight caused by Ormdl3 deficiency is rescued by pharmacological inhibition of ceramide production, placing ORMDL3 upstream of ceramide in regulating adipose thermogenesis.","method":"Ormdl3-/- knockout mice, cold exposure, β3 adrenergic agonist challenge, primary adipocyte cultures, mass spectrometry lipidomics, ceramide synthesis inhibitor rescue","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with pharmacological rescue establishing ceramide pathway; single lab, multiple readouts","pmids":["34954108"],"is_preprint":false},{"year":2022,"finding":"ORMDL3 overexpression in bronchial epithelial cells promotes autophagy (increased autophagosomes, elevated LC3B, ATG3, ATG7, ATG16L1) and subsequent cell death by impairing intracellular calcium mobilization through interaction with SERCA2. Immunoprecipitation confirms the ORMDL3-SERCA2 interaction.","method":"ORMDL3 overexpression in 16HBE and primary HBECs, electron microscopy (autophagosome detection), RFP-GFP-LC3B autophagic flux assay, immunoprecipitation (ORMDL3-SERCA2), intracellular Ca2+ assay, cell viability, coexpression analysis in 44 donors","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — IP-confirmed protein interaction, multiple orthogonal autophagy assays, functional consequence (cell death) established; single lab","pmids":["35353673"],"is_preprint":false},{"year":2024,"finding":"ORMDL3 regulates NLRP3 inflammasome activation in human macrophages by modulating mitochondrial morphology and ER-mitochondria contacts. ORMDL3 overexpression increases mitochondrial fragmentation and ER-mitochondria contacts, enabling efficient NLRP3 inflammasome activation and IL-1β release; knockdown reduces IL-1β. Under inflammatory conditions, ORMDL3 localizes to mitochondria-associated membranes and mitochondria (in addition to ER) and interacts with the mitochondrial fission protein Fis-1.","method":"ORMDL3 knockdown in human monocyte-derived macrophages, co-immunoprecipitation (ORMDL3-Fis-1), subcellular fractionation/localization, mitochondrial morphology imaging, NLRP3 inflammasome activity assay (IL-1β release), DSS colitis mouse model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — co-IP interaction with Fis-1, novel mitochondrial localization confirmed by fractionation, NLRP3 pathway mechanistic link, in vivo validation; single lab","pmids":["38417794"],"is_preprint":false},{"year":2025,"finding":"ORMDL3 negatively regulates type I IFN signaling by interacting with MAVS and promoting proteasome-mediated degradation of RIG-I. IP-MS reveals ORMDL3 binds USP10, a deubiquitinase that stabilizes RIG-I by reducing K48-linked ubiquitination; ORMDL3 disrupts the USP10-RIG-I interaction, leading to RIG-I degradation. In vivo, ORMDL3 inhibition in syngeneic tumor models augments CD8+ T cells and IFN production in the tumor microenvironment.","method":"Co-immunoprecipitation, IP coupled with mass spectrometry (IP-MS), ubiquitination assays (K48-linked), proteasome inhibitor rescue, overexpression/knockdown, syngeneic subcutaneous tumor model in C57BL/6 mice","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — IP-MS identifying interactors, ubiquitination mechanistic dissection with multiple orthogonal methods, in vivo validation; single lab","pmids":["40126553"],"is_preprint":false},{"year":2012,"finding":"The ORMDL3 gene promoter is cooperatively regulated by transcription factors Ets-1, p300, and CREB, which bind the proximal minimal promoter (-84/+58). Chromatin immunoprecipitation and sequential ChIP confirm co-occupancy; siRNA knockdown of each factor reduces ORMDL3 expression.","method":"5'-RACE, 5' deletion luciferase reporter assays, mutagenesis, EMSA, ChIP/Re-ChIP, RNA interference","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple promoter dissection methods, ChIP confirmation; single lab","pmids":["22546552"],"is_preprint":false},{"year":2013,"finding":"STAT6 directly regulates ORMDL3 transcription by binding a -64 to -56 bp motif in the minimal promoter. EMSA and ChIP confirm STAT6 binding; IL-4 and IL-13 treatment increase ORMDL3 promoter activity and endogenous expression. STAT6 and p300 co-occupy the ORMDL3 promoter as a complex (confirmed by IP and ChIP/Re-ChIP).","method":"Luciferase reporter (deletion/mutation analysis), EMSA, ChIP, co-immunoprecipitation (STAT6-p300 complex), siRNA knockdown and overexpression, cytokine stimulation","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by EMSA and ChIP, protein complex by co-IP; single lab","pmids":["23461825"],"is_preprint":false},{"year":2013,"finding":"The cAMP/PKA/CREB pathway regulates basal ORMDL3 transcription through a CRE element (-27/-20) in the core promoter. CREB binding is confirmed by EMSA and ChIP; CREB knockdown reduces ORMDL3 expression, overexpression increases it. Forskolin (PKA activator) increases CREB phosphorylation and ORMDL3 expression; H-89 (PKA inhibitor) reduces it.","method":"Luciferase reporter (deletion/mutation), EMSA, ChIP, siRNA and overexpression, forskolin/H-89 pharmacology in NIH3T3 cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed, pharmacological validation; single lab","pmids":["23577138"],"is_preprint":false},{"year":2015,"finding":"Cbl-b (E3 ubiquitin ligase) suppresses ORMDL3 expression by reducing STAT6 phosphorylation, thereby decreasing STAT6 binding to the ORMDL3 promoter. ChIP and promoter assays confirm that IL-4-induced STAT6 phosphorylation drives ORMDL3 transcription, and Cbl-b counteracts this.","method":"Luciferase reporter, ChIP, immunoblot (STAT6 phosphorylation), Cbl-b siRNA and overexpression","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms mechanism, pharmacological and genetic validation; single lab","pmids":["26112603"],"is_preprint":false},{"year":2017,"finding":"IRF-3 directly binds the ORMDL3 promoter at a proximal IRF-3 binding site following RSV infection, driving ORMDL3 transcription. Mutational analysis of the binding site, overexpression, siRNA knockdown of IRF-3, EMSA, and ChIP confirm IRF-3 as a direct transcriptional regulator of ORMDL3 after RSV infection.","method":"Luciferase reporter (mutation analysis), EMSA, ChIP, IRF-3 siRNA and overexpression in bronchial epithelial cells and lung fibroblasts, clinical sample correlation","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by EMSA and ChIP, bidirectional genetic manipulation; single lab","pmids":["28336364"],"is_preprint":false},{"year":2018,"finding":"STING positively regulates ORMDL3 expression through a TBK1-IRF3-STAT6 complex: STING activation enhances TBK1-mediated phosphorylation of both IRF3 and STAT6, which then bind the ORMDL3 promoter cooperatively to upregulate expression.","method":"Luciferase reporter, immunoprecipitation (STING-TBK1-IRF3-STAT6 complex), ChIP, siRNA knockdown, STING overexpression","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP establish complex at promoter; single lab","pmids":["30009792"],"is_preprint":false},{"year":2019,"finding":"p300-mediated histone acetylation of the ORMDL3 promoter (H3 acetylation) activates ORMDL3 transcription in asthma. In asthmatic mice, p300 and acetylated H3 are enriched at the ORMDL3 promoter (by ChIP). HAT-dead p300 mutant fails to activate ORMDL3. C646 (p300 inhibitor) reduces ORMDL3 expression and airway remodeling.","method":"ChIP (p300, aceH3 at ORMDL3 promoter), luciferase reporter with WT and HAT-deletion p300 mutants, C646 pharmacology in OVA-asthma mouse model, immunohistochemistry, qPCR/Western blot","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms epigenetic mark at promoter, HAT-dead mutant specificity, in vivo validation; single lab","pmids":["31536903"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 overexpression facilitates FcεRI-mediated transcription of IL-4, TNF-α, and MCP-1 in RBL-2H3 mast cells (without affecting degranulation or MAPK phosphorylation), and this enhancement is suppressed by the S1P agonist FTY720. ORMDL3 overexpression also accelerates TG (thapsigargin)-induced PERK phosphorylation, selectively affecting the PERK branch of the UPR.","method":"Stable ORMDL3 overexpressing RBL-2H3 cells, FcεRI crosslinking, cytokine qPCR, degranulation assay, MAPK and PERK phosphorylation immunoblot, FTY720 pharmacology","journal":"Immunity, inflammation and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable cell line model with multiple functional and signaling readouts, pharmacological rescue; single lab","pmids":["34288557"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 knockdown in human airway smooth muscle cells reduces CSM (cigarette smoke medium)-induced ER stress (inhibiting ATF6 and PERK UPR pathways), and attenuates CSM-induced inflammation, cell proliferation, and apoptosis. ORMDL3 is also involved in CSM-induced mitochondrial dysfunction via the mitochondrial fission process.","method":"siRNA knockdown of ORMDL3 in primary HASMCs, CSM treatment, UPR pathway immunoblot (ATF6, PERK), inflammation/proliferation/apoptosis assays, mitochondrial morphology assessment","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal cellular readouts; single lab","pmids":["34624393"],"is_preprint":false},{"year":2023,"finding":"ORMDL3 overexpression activates NLRP3 inflammasome expression in bronchial epithelial cells; RSV infection induces ORMDL3 overexpression through histone hyperacetylation (p300-mediated), which in turn drives NLRP3 inflammasome upregulation. p300 and acetylated H3 bind the ORMDL3 promoter (ChIP). C646 (p300 inhibitor) reduces ORMDL3 and NLRP3 expression and alleviates lung inflammation in rRSV+OVA asthma mice.","method":"BEAS-2B cells, RSV infection, ORMDL3 siRNA and overexpression, NLRP3 immunoblot/qPCR, ChIP (p300, aceH3 at ORMDL3 promoter), C646 pharmacology, in vivo rRSV+OVA mouse model","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms epigenetic regulation, epistatic link ORMDL3→NLRP3; single lab, in vivo confirmation","pmids":["37877592"],"is_preprint":false}],"current_model":"ORMDL3 is an ER-resident transmembrane protein that acts as a negative homeostatic regulator of serine palmitoyltransferase (SPT), inhibiting de novo sphingolipid biosynthesis, while also binding and inhibiting SERCA to reduce ER Ca2+ stores, thereby promoting the ATF6-selective branch of the unfolded protein response; beyond lipid and calcium regulation, ORMDL3 interacts with MAVS to promote proteasome-mediated RIG-I degradation (dampening type I IFN signaling), interacts with Fis-1 at mitochondria-associated membranes to modulate mitochondrial fission and NLRP3 inflammasome activation, suppresses S1P lyase activity in complex with AhR signaling to elevate S1P, physically associates with 5-lipoxygenase to coordinate leukotriene and sphingolipid synthesis, and regulates autophagy via an ATF6-Beclin1 pathway, collectively placing ORMDL3 at a hub connecting ER stress, sphingolipid/eicosanoid metabolism, innate immune signaling, and calcium homeostasis relevant to asthma and inflammatory disease."},"narrative":{"mechanistic_narrative":"ORMDL3 is an endoplasmic reticulum-resident transmembrane protein that acts as a homeostatic hub coupling ER calcium handling, sphingolipid/eicosanoid metabolism, and the unfolded protein response to inflammatory and airway phenotypes [PMID:19819884, PMID:24623133, PMID:34560079]. It restrains ER Ca2+ stores by physically interacting with the SERCA pump (SERCA2), elevating resting cytosolic Ca2+, dampening ER-mediated Ca2+ signaling, and selectively engaging the ATF6 branch of the UPR with downstream induction of SERCA2b [PMID:19819884, PMID:35353673, PMID:23011799, PMID:24623133]. ORMDL3 forms stable complexes with serine palmitoyltransferase (SPT/SPTLC1) and regulates ceramide and sphingosine-1-phosphate levels in a dose-dependent manner, and its loss elevates S1P that directly increases airway smooth muscle contractility [PMID:25691431, PMID:25842287, PMID:28275141, PMID:34560079]. Through ATF6-driven, Beclin1-dependent autophagy it controls cell survival and degranulation in B cells and mast cells [PMID:28747345, PMID:33679742, PMID:35353673]. Beyond lipid and calcium control, ORMDL3 interacts with the mitochondrial fission protein Fis-1 at ER-mitochondria contacts to promote NLRP3 inflammasome activation, associates with 5-lipoxygenase to coordinate leukotriene and sphingolipid synthesis, suppresses S1P lyase in concert with AhR signaling, and binds MAVS/USP10 to drive proteasomal RIG-I degradation and dampen type I interferon signaling [PMID:38417794, PMID:34560079, PMID:29572542, PMID:40126553]. Its expression is induced by Th2 cytokines via STAT6 and by viral/innate signals via IRF-3 and p300-dependent histone acetylation, integrating ORMDL3 into asthma and inflammatory airway disease [PMID:23461825, PMID:28336364, PMID:31536903].","teleology":[{"year":2010,"claim":"Established the first molecular activity for ORMDL3 by showing it controls ER calcium homeostasis and UPR rather than being a passive ER protein.","evidence":"Heterologous overexpression/knockdown with Ca2+ measurement and SERCA co-expression rescue in mammalian cells","pmids":["19819884"],"confidence":"Medium","gaps":["No direct ORMDL3-SERCA binding shown at this stage","Single overexpression system, physiological relevance unaddressed"]},{"year":2012,"claim":"Defined how ORMDL3-mediated calcium control feeds immune signaling, showing it suppresses store-operated calcium entry, NFAT activation, and IL-2 in T cells via mitochondrial Ca2+ handling.","evidence":"Patch-clamp ICRAC, SOCE assays, NFAT reporter, IL-2 ELISA with mitochondrial Ca2+ manipulation in T lymphocytes","pmids":["23100328"],"confidence":"High","gaps":["Molecular target at the mitochondrial membrane not identified","Link to direct SERCA interaction not made"]},{"year":2012,"claim":"Tied ORMDL3 to a specific UPR branch and airway inflammation, showing selective ATF6 activation, SERCA2b induction, and STAT6-dependent in vivo induction.","evidence":"Transfection, siRNA, qPCR/immunoblot in bronchial epithelium plus STAT6-KO allergen challenge","pmids":["23011799"],"confidence":"High","gaps":["Why ORMDL3 selects ATF6 over IRE1/PERK not resolved","Causal chain from Ca2+ to ATF6 incomplete"]},{"year":2012,"claim":"Began mapping how ORMDL3 itself is transcriptionally controlled, identifying cooperative Ets-1/p300/CREB promoter occupancy.","evidence":"5'-RACE, deletion luciferase, EMSA, ChIP/Re-ChIP, RNAi","pmids":["22546552"],"confidence":"Medium","gaps":["Stimulus-specific regulation of these factors not defined"]},{"year":2013,"claim":"Identified ORMDL3 as a direct Th2-cytokine target gene, placing it downstream of STAT6/p300 and explaining IL-4/IL-13 inducibility in allergic disease.","evidence":"Reporter assays, EMSA, ChIP, STAT6-p300 co-IP, cytokine stimulation","pmids":["23461825","23577138","26112603"],"confidence":"Medium","gaps":["Quantitative contribution of each promoter element in vivo unclear"]},{"year":2013,"claim":"Extended ORMDL3 function to granulocyte effector biology, showing it localizes to the ER in eosinophils and promotes adhesion, recruitment, and degranulation.","evidence":"Gain/loss-of-function, flow cytometry, ERK/NF-kB immunoblot, intravital microscopy","pmids":["24056518"],"confidence":"High","gaps":["Mechanistic link between ER ORMDL3 and surface integrin expression not defined"]},{"year":2014,"claim":"Demonstrated that constitutive ORMDL3 overexpression is sufficient to drive airway remodeling and hyperresponsiveness in vivo via selective ATF6 activation.","evidence":"hORMDL3 transgenic mice, lung function, histology, UPR pathway-specific readouts","pmids":["24623133"],"confidence":"High","gaps":["Whether remodeling depends on lipid versus calcium arm not dissected"]},{"year":2015,"claim":"Tested the canonical SPT-inhibitory model in mammalian cells, showing ORMDL3-SPT complexes exist but ORMDL3 is in functional excess and overexpression does not strongly suppress sphingolipid synthesis.","evidence":"Co-IP, isotope-labeling biosynthesis assay, lipidomics in HBECs/HeLa","pmids":["25691431"],"confidence":"Medium","gaps":["Reconciliation with yeast SPT-inhibition model unresolved","Conditions where ORMDL3 limits SPT not defined"]},{"year":2015,"claim":"Resolved the lipid-regulatory role as non-linear, showing small ORMDL3 increases lower ceramide while high overexpression raises it, promoting inflammation.","evidence":"Overexpression/KD in epithelia and macrophages, HDM model, lipidomics, FTY720 rescue","pmids":["25842287"],"confidence":"Medium","gaps":["Mechanistic basis of dose-dependent reversal unknown"]},{"year":2015,"claim":"Revealed context-dependent immunoregulation, showing ORMDL3 negatively regulates FcεRI-NF-kB signaling in mast cells and restrains anaphylaxis.","evidence":"Bidirectional manipulation in mast cells, immunoblot, ELISA, in vivo PCA","pmids":["26407610"],"confidence":"Medium","gaps":["Connection to ER calcium/lipid arms not established"]},{"year":2016,"claim":"Provided loss-of-function and add-back proof that epithelial ORMDL3 is required for allergic airways disease via the ATF6/XBP1-ERAD arm.","evidence":"Ormdl3 KO mice with AAV epithelial reconstitution, lung function, UPR gene expression","pmids":["27623174"],"confidence":"High","gaps":["How ATF6 selectively couples to XBP1/ERAD here not detailed"]},{"year":2017,"claim":"Exposed a protective epithelial function, showing epithelial ORMDL3 normally suppresses S1P generation and that its loss elevates S1P to increase smooth muscle contractility.","evidence":"Epithelial-specific KO, OVA challenge, S1P mass spec, smooth muscle contractility assay","pmids":["28275141"],"confidence":"High","gaps":["Enzymatic step by which ORMDL3 limits S1P not identified here"]},{"year":2017,"claim":"Showed cell-type-specific pro-contractile actions in smooth muscle, linking ORMDL3 to SERCA2b-dependent Ca2+ oscillations, proliferation, and contractility.","evidence":"ASM transfection, transgenic PCLS Ca2+ imaging, BrdU, SERCA2b manipulation","pmids":["28889952"],"confidence":"Medium","gaps":["Direct SERCA2b regulation versus induction not separated"]},{"year":2017,"claim":"Connected ORMDL3 to cell survival through an ATF6-ER stress-Beclin1 autophagy axis controlling B lymphocyte homeostasis.","evidence":"Ormdl3 KO mice, flow cytometry, apoptosis assays, ATF6/Beclin1 pathway manipulation","pmids":["28747345"],"confidence":"Medium","gaps":["Direct ORMDL3 contribution to Beclin1 induction mechanism unclear"]},{"year":2018,"claim":"Identified a direct enzymatic crosstalk, showing AhR-driven S1P lyase oxidation/inactivation requires ORMDL3, which forms a complex with S1PL to elevate S1P.","evidence":"FRET, co-IP, C317A S1PL mutant, S1PL activity assay, mast cell degranulation","pmids":["29572542"],"confidence":"High","gaps":["How ORMDL3 promotes C317 oxidation mechanistically unknown"]},{"year":2018,"claim":"Added an innate-immune transcriptional input, showing STING-TBK1 drives IRF3/STAT6 cooperative ORMDL3 promoter activation.","evidence":"Reporter, STING-TBK1-IRF3-STAT6 co-IP, ChIP, siRNA","pmids":["30009792","28336364"],"confidence":"Medium","gaps":["Integration of innate and Th2 promoter inputs in vivo not tested"]},{"year":2019,"claim":"Tied ORMDL3 directly to inflammatory cytokine output and rhinovirus receptor expression, linking its function to lipid/glycolytic metabolic reprogramming.","evidence":"Bidirectional manipulation, ELISA, transcriptomics/metabolomics, myriocin in primary HBECs","pmids":["30339462"],"confidence":"High","gaps":["Causal hierarchy between metabolic, lipid, and cytokine changes unresolved"]},{"year":2019,"claim":"Showed in vivo that ORMDL3 governs systemic ceramide homeostasis yet asthma hallmarks are dissociable from these lipid changes.","evidence":"KO and transgenic mice, multiple allergen models, sphingolipidomics","pmids":["31330218"],"confidence":"High","gaps":["Which ORMDL3 function actually drives asthma phenotypes left open"]},{"year":2019,"claim":"Linked ORMDL3 to epithelial barrier integrity via SPHK1/ERK and junctional protein downregulation.","evidence":"Overexpression/inhibition in 16HBE, TEER, permeability, SPHK1 inhibitor rescue","pmids":["31173170"],"confidence":"Medium","gaps":["Relation to S1P-lyase axis not integrated"]},{"year":2019,"claim":"Established p300-mediated histone acetylation as an epigenetic activator of ORMDL3 in asthma.","evidence":"ChIP, HAT-dead p300 mutant, C646 in OVA model","pmids":["31536903"],"confidence":"Medium","gaps":["Upstream signals recruiting p300 to the locus not defined"]},{"year":2021,"claim":"Mapped a physical sphingolipid-eicosanoid interface, showing ORMDL3 interacts with 5-LO and SPTLC1 and its loss elevates leukotrienes.","evidence":"Co-IP, KO mast cell lipidomics, siRNA of 5-LO/SPTLC1","pmids":["34560079"],"confidence":"Medium","gaps":["Whether the interaction directly regulates 5-LO catalysis untested"]},{"year":2021,"claim":"Demonstrated SERCA2b- and tropomyosin-dependent smooth muscle remodeling, identifying TPM1/TPM4 as required for ORMDL3-driven proliferation.","evidence":"Smooth muscle-specific transgenic mice, TPM1/4 siRNA epistasis, Ca2+ imaging, contractility","pmids":["33661765"],"confidence":"High","gaps":["How ORMDL3 induces TPM1/4 mechanistically unclear"]},{"year":2021,"claim":"Reinforced the ATF6-UPR-autophagy axis as the mechanism by which ORMDL3 suppresses mast cell activation.","evidence":"Bidirectional manipulation in MC/9, ATF6 siRNA epistasis, autophagy inhibitors, PCA","pmids":["33679742","34288557"],"confidence":"Medium","gaps":["Apparent opposite directionality across mast cell studies unreconciled"]},{"year":2021,"claim":"Extended ORMDL3 to systemic metabolism, placing it upstream of ceramide in adipose thermogenesis.","evidence":"Ormdl3 KO mice, cold/β3-agonist challenge, lipidomics, ceramide-synthesis inhibitor rescue","pmids":["34954108"],"confidence":"Medium","gaps":["Tissue-autonomous versus systemic ceramide source not separated"]},{"year":2021,"claim":"Linked ORMDL3 to smoke-induced airway pathology through ER stress and mitochondrial fission.","evidence":"siRNA in primary HASMCs, CSM treatment, UPR immunoblot, mitochondrial morphology","pmids":["34624393"],"confidence":"Medium","gaps":["Direct mitochondrial localization not yet shown here"]},{"year":2022,"claim":"Provided direct biochemical confirmation of the ORMDL3-SERCA2 interaction and tied it to autophagy and cell death via impaired Ca2+ mobilization.","evidence":"Overexpression in HBECs, EM, RFP-GFP-LC3B flux, IP of ORMDL3-SERCA2, Ca2+ assays","pmids":["35353673"],"confidence":"High","gaps":["Stoichiometry and binding interface of ORMDL3-SERCA2 unknown"]},{"year":2023,"claim":"Connected viral-induced ORMDL3 to NLRP3 inflammasome activation in epithelium via p300 acetylation.","evidence":"BEAS-2B RSV infection, ORMDL3 manipulation, ChIP, C646 in rRSV+OVA model","pmids":["37877592"],"confidence":"Medium","gaps":["How ORMDL3 mechanistically activates NLRP3 in epithelia not defined here"]},{"year":2024,"claim":"Revealed a non-ER localization and mechanism, showing inflammatory ORMDL3 relocates to mitochondria-associated membranes, binds Fis-1, and promotes NLRP3 activation via mitochondrial fragmentation.","evidence":"Macrophage knockdown, ORMDL3-Fis-1 co-IP, fractionation, mitochondrial imaging, IL-1β assay, DSS colitis","pmids":["38417794"],"confidence":"High","gaps":["Trigger for ORMDL3 relocalization to MAMs unknown"]},{"year":2025,"claim":"Defined an antiviral/antitumor immune-regulatory function, showing ORMDL3 binds MAVS and disrupts USP10-RIG-I to drive RIG-I degradation and limit type I IFN.","evidence":"Co-IP, IP-MS, K48 ubiquitination assays, proteasome rescue, syngeneic tumor model","pmids":["40126553"],"confidence":"High","gaps":["How ORMDL3 displaces USP10 from RIG-I mechanistically unclear","Relation to ER/lipid functions not integrated"]},{"year":null,"claim":"Which single biochemical activity (SPT regulation, SERCA inhibition, S1PL/5-LO complexing, Fis-1/MAVS binding) is the primary driver of ORMDL3's disease-relevant phenotypes, and how these functions are mechanistically interconnected, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of ORMDL3 with any partner","Dissociation of lipid changes from asthma phenotypes unexplained","Conditions selecting ER versus mitochondrial localization undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,20,12,18]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[22,12]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,18,20,21]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,4,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,9,14,18,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21,22,32]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,17,20]}],"complexes":["ORMDL3-SPT (SPTLC1)","ORMDL3-SERCA2","ORMDL3-S1P lyase","ORMDL3-5-lipoxygenase"],"partners":["SPTLC1","SERCA2","ATP2A2","FIS1","MAVS","USP10","ALOX5","SGPL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N138","full_name":"ORM1-like protein 3","aliases":[],"length_aa":153,"mass_kda":17.5,"function":"Plays an essential role in the homeostatic regulation of sphingolipid de novo biosynthesis by modulating the activity of the serine palmitoyltransferase (SPT) in response to ceramide levels (PubMed:20182505, PubMed:30700557, PubMed:37308477). When complexed to SPT, the binding of ceramides to its N-terminus stabilizes a conformation that block SPT substrate entry, hence preventing SPT catalytic activity. Through this mechanism, maintains ceramide levels at sufficient concentrations for the production of complex sphingolipids, but which prevents the accumulation of ceramides to levels that trigger apoptosis (PubMed:37308477)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q8N138/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ORMDL3","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ORMDL3","total_profiled":1310},"omim":[{"mim_id":"620417","title":"SPASTIC PARAPLEGIA 90B, AUTOSOMAL RECESSIVE; SPG90B","url":"https://www.omim.org/entry/620417"},{"mim_id":"620416","title":"SPASTIC PARAPLEGIA 90A, AUTOSOMAL DOMINANT; SPG90A","url":"https://www.omim.org/entry/620416"},{"mim_id":"613540","title":"SERINE PALMITOYLTRANSFERASE, SMALL SUBUNIT, A; SPTSSA","url":"https://www.omim.org/entry/613540"},{"mim_id":"612380","title":"INFLAMMATORY BOWEL DISEASE 22; IBD22","url":"https://www.omim.org/entry/612380"},{"mim_id":"611403","title":"ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO, 6","url":"https://www.omim.org/entry/611403"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":225.6}],"url":"https://www.proteinatlas.org/search/ORMDL3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q8N138","domains":[{"cath_id":"-","chopping":"12-143","consensus_level":"high","plddt":96.9152,"start":12,"end":143}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N138","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N138-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N138-F1-predicted_aligned_error_v6.png","plddt_mean":94.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ORMDL3","jax_strain_url":"https://www.jax.org/strain/search?query=ORMDL3"},"sequence":{"accession":"Q8N138","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N138.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N138/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N138"}},"corpus_meta":[{"pmid":"17611496","id":"PMC_17611496","title":"Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.","date":"2007","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/17611496","citation_count":1224,"is_preprint":false},{"pmid":"19732864","id":"PMC_19732864","title":"Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19732864","citation_count":245,"is_preprint":false},{"pmid":"19819884","id":"PMC_19819884","title":"The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19819884","citation_count":219,"is_preprint":false},{"pmid":"18310477","id":"PMC_18310477","title":"ORMDL3 gene is associated with asthma in three ethnically diverse populations.","date":"2008","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18310477","citation_count":206,"is_preprint":false},{"pmid":"23011799","id":"PMC_23011799","title":"ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23011799","citation_count":169,"is_preprint":false},{"pmid":"24623133","id":"PMC_24623133","title":"ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24623133","citation_count":148,"is_preprint":false},{"pmid":"18395550","id":"PMC_18395550","title":"A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications.","date":"2008","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18395550","citation_count":125,"is_preprint":false},{"pmid":"25842287","id":"PMC_25842287","title":"Aberrant ORM (yeast)-like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice.","date":"2015","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25842287","citation_count":109,"is_preprint":false},{"pmid":"19133921","id":"PMC_19133921","title":"Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma.","date":"2008","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/19133921","citation_count":104,"is_preprint":false},{"pmid":"28826527","id":"PMC_28826527","title":"Chromosome 17q21 Genes ORMDL3 and GSDMB in Asthma and Immune Diseases.","date":"2017","source":"Advances in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28826527","citation_count":98,"is_preprint":false},{"pmid":"24056518","id":"PMC_24056518","title":"ORMDL3 promotes eosinophil trafficking and activation via regulation of integrins and CD48.","date":"2013","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24056518","citation_count":98,"is_preprint":false},{"pmid":"21150878","id":"PMC_21150878","title":"Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.","date":"2010","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/21150878","citation_count":98,"is_preprint":false},{"pmid":"28333149","id":"PMC_28333149","title":"Upregulation of miR-665 promotes apoptosis and colitis in inflammatory bowel disease by repressing the endoplasmic reticulum stress components XBP1 and ORMDL3.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28333149","citation_count":82,"is_preprint":false},{"pmid":"23100328","id":"PMC_23100328","title":"ORMDL3 modulates store-operated calcium entry and lymphocyte activation.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23100328","citation_count":76,"is_preprint":false},{"pmid":"30339462","id":"PMC_30339462","title":"The ORMDL3 Asthma Gene Regulates ICAM1 and Has Multiple Effects on Cellular Inflammation.","date":"2019","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30339462","citation_count":72,"is_preprint":false},{"pmid":"27623174","id":"PMC_27623174","title":"Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease.","date":"2016","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27623174","citation_count":72,"is_preprint":false},{"pmid":"31376405","id":"PMC_31376405","title":"ORMDL3 and allergic asthma: From physiology to pathology.","date":"2019","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31376405","citation_count":70,"is_preprint":false},{"pmid":"25256354","id":"PMC_25256354","title":"Risk of childhood asthma is associated with CpG-site polymorphisms, regional DNA methylation and mRNA levels at the GSDMB/ORMDL3 locus.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25256354","citation_count":67,"is_preprint":false},{"pmid":"28889952","id":"PMC_28889952","title":"Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma.","date":"2017","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28889952","citation_count":65,"is_preprint":false},{"pmid":"25930191","id":"PMC_25930191","title":"Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels.","date":"2015","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25930191","citation_count":63,"is_preprint":false},{"pmid":"25691431","id":"PMC_25691431","title":"ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis.","date":"2015","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/25691431","citation_count":59,"is_preprint":false},{"pmid":"25729625","id":"PMC_25729625","title":"The Association of GSDMB and ORMDL3 Gene Polymorphisms With Asthma: A Meta-Analysis.","date":"2014","source":"Allergy, asthma & immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/25729625","citation_count":46,"is_preprint":false},{"pmid":"28275141","id":"PMC_28275141","title":"Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28275141","citation_count":46,"is_preprint":false},{"pmid":"22732088","id":"PMC_22732088","title":"GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness.","date":"2012","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22732088","citation_count":44,"is_preprint":false},{"pmid":"23369242","id":"PMC_23369242","title":"Functional analysis of the impact of ORMDL3 expression on inflammation and activation of the unfolded protein response in human airway epithelial cells.","date":"2013","source":"Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23369242","citation_count":42,"is_preprint":false},{"pmid":"24165737","id":"PMC_24165737","title":"17q21 locus and ORMDL3: an increased risk for childhood asthma.","date":"2013","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/24165737","citation_count":37,"is_preprint":false},{"pmid":"31330218","id":"PMC_31330218","title":"The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice.","date":"2019","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31330218","citation_count":35,"is_preprint":false},{"pmid":"33424845","id":"PMC_33424845","title":"ORMDL3 and Asthma: Linking Sphingolipid Regulation to Altered T Cell Function.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33424845","citation_count":34,"is_preprint":false},{"pmid":"28747345","id":"PMC_28747345","title":"ORMDL3 Facilitates the Survival of Splenic B Cells via an ATF6α-Endoplasmic Reticulum Stress-Beclin1 Autophagy Regulatory Pathway.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28747345","citation_count":31,"is_preprint":false},{"pmid":"28588209","id":"PMC_28588209","title":"Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28588209","citation_count":29,"is_preprint":false},{"pmid":"22546552","id":"PMC_22546552","title":"Mechanisms elevating ORMDL3 expression in recurrent wheeze patients: role of Ets-1, p300 and CREB.","date":"2012","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22546552","citation_count":28,"is_preprint":false},{"pmid":"26603569","id":"PMC_26603569","title":"ORMDL3 contributes to the risk of atherosclerosis in Chinese Han population and mediates oxidized low-density lipoprotein-induced autophagy in endothelial cells.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26603569","citation_count":28,"is_preprint":false},{"pmid":"32277517","id":"PMC_32277517","title":"Long noncoding RNA SOX21-AS1 regulates the progression of triple-negative breast cancer through regulation of miR-520a-5p/ORMDL3 axis.","date":"2020","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32277517","citation_count":28,"is_preprint":false},{"pmid":"28358425","id":"PMC_28358425","title":"ORMDL3 is associated with airway remodeling in asthma via the ERK/MMP-9 pathway.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28358425","citation_count":27,"is_preprint":false},{"pmid":"26407610","id":"PMC_26407610","title":"Negative regulatory roles of ORMDL3 in the FcεRI-triggered expression of proinflammatory mediators and chemotactic response in murine mast cells.","date":"2015","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/26407610","citation_count":26,"is_preprint":false},{"pmid":"23461825","id":"PMC_23461825","title":"Signal transducer and activator of transcription 6 directly regulates human ORMDL3 expression.","date":"2013","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/23461825","citation_count":24,"is_preprint":false},{"pmid":"33679742","id":"PMC_33679742","title":"ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation via an ATF6-UPR-Autophagy-Dependent Pathway.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33679742","citation_count":24,"is_preprint":false},{"pmid":"29572542","id":"PMC_29572542","title":"Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase.","date":"2018","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29572542","citation_count":24,"is_preprint":false},{"pmid":"22017802","id":"PMC_22017802","title":"Association of ORMDL3, STAT6 and TBXA2R gene polymorphisms with asthma.","date":"2011","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/22017802","citation_count":23,"is_preprint":false},{"pmid":"28030368","id":"PMC_28030368","title":"Sphingolipids, ORMDL3 and asthma: what is the evidence?","date":"2017","source":"Current opinion in clinical nutrition and metabolic care","url":"https://pubmed.ncbi.nlm.nih.gov/28030368","citation_count":22,"is_preprint":false},{"pmid":"34872583","id":"PMC_34872583","title":"Single cell sequencing analysis identifies genetics-modulated ORMDL3+ cholangiocytes having higher metabolic effects on primary biliary cholangitis.","date":"2021","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/34872583","citation_count":22,"is_preprint":false},{"pmid":"28192616","id":"PMC_28192616","title":"Association of ORMDL3 with rhinovirus-induced endoplasmic reticulum stress and type I Interferon responses in human leucocytes.","date":"2017","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28192616","citation_count":22,"is_preprint":false},{"pmid":"34624393","id":"PMC_34624393","title":"ORMDL3 regulates cigarette smoke-induced endoplasmic reticulum stress in airway smooth muscle cells.","date":"2021","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34624393","citation_count":19,"is_preprint":false},{"pmid":"35353673","id":"PMC_35353673","title":"Asthma Susceptibility Gene ORMDL3 Promotes Autophagy in Human Bronchial Epithelium.","date":"2022","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35353673","citation_count":18,"is_preprint":false},{"pmid":"34954108","id":"PMC_34954108","title":"Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation.","date":"2021","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34954108","citation_count":18,"is_preprint":false},{"pmid":"32820688","id":"PMC_32820688","title":"MiR-200a and miR-200b restrain inflammation by targeting ORMDL3 to regulate the ERK/MMP-9 pathway in asthma.","date":"2020","source":"Experimental lung research","url":"https://pubmed.ncbi.nlm.nih.gov/32820688","citation_count":18,"is_preprint":false},{"pmid":"31255288","id":"PMC_31255288","title":"ORMDL3 knockdown in the lungs alleviates airway inflammation and airway remodeling in asthmatic mice via JNK1/2-MMP-9 pathway.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31255288","citation_count":18,"is_preprint":false},{"pmid":"32444308","id":"PMC_32444308","title":"ORMDL3/GSDMB genotype as a risk factor for early-onset adult asthma is linked to total serum IgE levels but not to allergic sensitization.","date":"2020","source":"Allergology international : official journal of the Japanese Society of Allergology","url":"https://pubmed.ncbi.nlm.nih.gov/32444308","citation_count":18,"is_preprint":false},{"pmid":"23964555","id":"PMC_23964555","title":"A polymorphism in ORMDL3 is associated not only with asthma without rhinitis but also with chronic obstructive pulmonary disease.","date":"2013","source":"Journal of investigational allergology & clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23964555","citation_count":18,"is_preprint":false},{"pmid":"31173170","id":"PMC_31173170","title":"Investigating the regulatory role of ORMDL3 in airway barrier dysfunction using in vivo and in vitro models.","date":"2019","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31173170","citation_count":17,"is_preprint":false},{"pmid":"23577138","id":"PMC_23577138","title":"Promoter characterization and role of cAMP/PKA/CREB in the basal transcription of the mouse ORMDL3 gene.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23577138","citation_count":16,"is_preprint":false},{"pmid":"31536903","id":"PMC_31536903","title":"p300 mediates the histone acetylation of ORMDL3 to affect airway inflammation and remodeling in asthma.","date":"2019","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31536903","citation_count":16,"is_preprint":false},{"pmid":"29879314","id":"PMC_29879314","title":"ORMDL3 and its implication in inflammatory disorders.","date":"2018","source":"International journal of rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29879314","citation_count":15,"is_preprint":false},{"pmid":"28336364","id":"PMC_28336364","title":"Mechanisms and roles by which IRF-3 mediates the regulation of ORMDL3 transcription in respiratory syncytial virus infection.","date":"2017","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28336364","citation_count":15,"is_preprint":false},{"pmid":"33661765","id":"PMC_33661765","title":"ORMDL3 expression in ASM regulates hypertrophy, hyperplasia via TPM1 and TPM4, and contractility.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/33661765","citation_count":14,"is_preprint":false},{"pmid":"31061237","id":"PMC_31061237","title":"The role of ORMDL3/ATF6 in compensated beta cell proliferation during early diabetes.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31061237","citation_count":14,"is_preprint":false},{"pmid":"29115563","id":"PMC_29115563","title":"ORMDL3 may participate in the pathogenesis of bronchial epithelial‑mesenchymal transition in asthmatic mice with airway remodeling.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29115563","citation_count":14,"is_preprint":false},{"pmid":"36753412","id":"PMC_36753412","title":"Neutrophilia in severe asthma is reduced in Ormdl3 overexpressing mice.","date":"2023","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36753412","citation_count":13,"is_preprint":false},{"pmid":"33643282","id":"PMC_33643282","title":"ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33643282","citation_count":13,"is_preprint":false},{"pmid":"30897694","id":"PMC_30897694","title":"Ceramide Imbalance and Impaired TLR4-Mediated Autophagy in BMDM of an ORMDL3-Overexpressing Mouse Model.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30897694","citation_count":13,"is_preprint":false},{"pmid":"29588858","id":"PMC_29588858","title":"Single nucleotide polymorphisms in asthma candidate genes TBXA2R, ADAM33 FCER1B and ORMDL3 in Pakistani asthmatics a case control study.","date":"2018","source":"Asthma research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/29588858","citation_count":13,"is_preprint":false},{"pmid":"38417794","id":"PMC_38417794","title":"ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38417794","citation_count":12,"is_preprint":false},{"pmid":"28827284","id":"PMC_28827284","title":"Rhinovirus Infection of ORMDL3 Transgenic Mice Is Associated with Reduced Rhinovirus Viral Load and Airway Inflammation.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28827284","citation_count":12,"is_preprint":false},{"pmid":"37877592","id":"PMC_37877592","title":"Histone acetylation regulates ORMDL3 expression-mediated NLRP3 inflammasome overexpression during RSV-allergic exacerbation mice.","date":"2023","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37877592","citation_count":11,"is_preprint":false},{"pmid":"30217493","id":"PMC_30217493","title":"Methylation status of ORMDL3 regulates cytokine production and p-ERK/MMP9 pathway expression.","date":"2018","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30217493","citation_count":11,"is_preprint":false},{"pmid":"36680386","id":"PMC_36680386","title":"The inhibition of ORMDL3 prevents Alzheimer's disease through ferroptosis by PERK/ATF4/HSPA5 pathway.","date":"2023","source":"IET nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36680386","citation_count":11,"is_preprint":false},{"pmid":"35252072","id":"PMC_35252072","title":"ORMDL3 Promotes Angiogenesis in Chronic Asthma Through the ERK1/2/VEGF/MMP-9 Pathway.","date":"2022","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/35252072","citation_count":10,"is_preprint":false},{"pmid":"31929192","id":"PMC_31929192","title":"At last - linking ORMDL3 polymorphisms, decreased sphingolipid synthesis, and asthma susceptibility.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31929192","citation_count":10,"is_preprint":false},{"pmid":"26125920","id":"PMC_26125920","title":"Correlation between the genetic polymorphism of ORMDL3 gene and asthma risk: a meta-analysis.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26125920","citation_count":9,"is_preprint":false},{"pmid":"26112603","id":"PMC_26112603","title":"E3 ubiquitin ligase Cbl-b suppresses human ORMDL3 expression through STAT6 mediation.","date":"2015","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/26112603","citation_count":9,"is_preprint":false},{"pmid":"39171126","id":"PMC_39171126","title":"From gene identifications to therapeutic targets for asthma: Focus on great potentials of TSLP, ORMDL3, and GSDMB.","date":"2023","source":"Chinese medical journal pulmonary and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39171126","citation_count":8,"is_preprint":false},{"pmid":"25167772","id":"PMC_25167772","title":"Genetic variation in ORMDL3 gene may contribute to the risk of asthma: a meta-analysis.","date":"2014","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25167772","citation_count":8,"is_preprint":false},{"pmid":"34560079","id":"PMC_34560079","title":"Crosstalk between ORMDL3, serine palmitoyltransferase, and 5-lipoxygenase in the sphingolipid and eicosanoid metabolic pathways.","date":"2021","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/34560079","citation_count":8,"is_preprint":false},{"pmid":"37499392","id":"PMC_37499392","title":"Evaluation of the association between clinical parameters and ADAM33 and ORMDL3 asthma gene single-nucleotide polymorphisms with the severity of COVID-19.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37499392","citation_count":8,"is_preprint":false},{"pmid":"24204796","id":"PMC_24204796","title":"All-trans retinoic acid modulates ORMDL3 expression via transcriptional regulation.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24204796","citation_count":8,"is_preprint":false},{"pmid":"27932194","id":"PMC_27932194","title":"Associations between NOD2, IRGM and ORMDL3 polymorphisms and pediatric-onset inflammatory bowel disease in the Lithuanian population.","date":"2016","source":"Medicina (Kaunas, Lithuania)","url":"https://pubmed.ncbi.nlm.nih.gov/27932194","citation_count":8,"is_preprint":false},{"pmid":"34288557","id":"PMC_34288557","title":"ORMDL3 overexpression facilitates FcεRI-mediated transcription of proinflammatory cytokines and thapsigargin-mediated PERK phosphorylation in RBL-2H3 cells.","date":"2021","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/34288557","citation_count":7,"is_preprint":false},{"pmid":"34525218","id":"PMC_34525218","title":"Single-base editing of rs12603332 on chromosome 17q21 with a cytosine base editor regulates ORMDL3 and ATF6α expression.","date":"2021","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/34525218","citation_count":7,"is_preprint":false},{"pmid":"37594074","id":"PMC_37594074","title":"ORMDL3‑mediated bronchial epithelial pyroptosis leads to lung inflammation in obese mice with asthma.","date":"2023","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/37594074","citation_count":7,"is_preprint":false},{"pmid":"33031402","id":"PMC_33031402","title":"Increased expression of serine palmitoyl transferase and ORMDL3 polymorphism are associated with eosinophilic inflammation and airflow limitation in aspirin-exacerbated respiratory disease.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33031402","citation_count":7,"is_preprint":false},{"pmid":"18754760","id":"PMC_18754760","title":"ORMDL3--guilt by association?","date":"2008","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18754760","citation_count":7,"is_preprint":false},{"pmid":"38715613","id":"PMC_38715613","title":"Simultaneous deletion of ORMDL1 and ORMDL3 proteins disrupts immune cell homeostasis.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38715613","citation_count":6,"is_preprint":false},{"pmid":"22015541","id":"PMC_22015541","title":"Characterization of a novel isoform of the human ORMDL3 gene.","date":"2011","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/22015541","citation_count":6,"is_preprint":false},{"pmid":"30009792","id":"PMC_30009792","title":"STING positively regulates human ORMDL3 expression through TBK1-IRF3-STAT6 complex mediation.","date":"2018","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30009792","citation_count":6,"is_preprint":false},{"pmid":"34001091","id":"PMC_34001091","title":"ORMDL3 regulates poly I:C induced inflammatory responses in airway epithelial cells.","date":"2021","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34001091","citation_count":6,"is_preprint":false},{"pmid":"37881318","id":"PMC_37881318","title":"A Common Functional Variant at the Enhancer of the Rheumatoid Arthritis Risk Gene ORMDL3 Regulates its Expression Through Allele-Specific JunD Binding.","date":"2023","source":"Phenomics (Cham, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37881318","citation_count":6,"is_preprint":false},{"pmid":"32273303","id":"PMC_32273303","title":"Treatment of Allergic Asthma with Fenretinide Formulation (LAU-7b) Downregulates ORMDL Sphingolipid Biosynthesis Regulator 3 (Ormdl3) Expression and Normalizes Ceramide Imbalance.","date":"2020","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/32273303","citation_count":6,"is_preprint":false},{"pmid":"29769657","id":"PMC_29769657","title":"Correction to: Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase.","date":"2018","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29769657","citation_count":6,"is_preprint":false},{"pmid":"35321632","id":"PMC_35321632","title":"Increased expression of ORMDL3 in allergic asthma: a case control and in vitro study.","date":"2022","source":"The Journal of asthma : official journal of the Association for the Care of Asthma","url":"https://pubmed.ncbi.nlm.nih.gov/35321632","citation_count":5,"is_preprint":false},{"pmid":"31560728","id":"PMC_31560728","title":"Regulatory interaction between the ZPBP2-ORMDL3/Zpbp2-Ormdl3 region and the circadian clock.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31560728","citation_count":5,"is_preprint":false},{"pmid":"26064206","id":"PMC_26064206","title":"Association between ORMDL3 polymorphism and susceptibility to asthma: a meta-analysis.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26064206","citation_count":5,"is_preprint":false},{"pmid":"27784618","id":"PMC_27784618","title":"Benomyl-induced effects of ORMDL3 overexpression via oxidative stress in human bronchial epithelial cells.","date":"2016","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/27784618","citation_count":5,"is_preprint":false},{"pmid":"40126553","id":"PMC_40126553","title":"ORMDL3 restrains type I interferon signaling and anti-tumor immunity by promoting RIG-I degradation.","date":"2025","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/40126553","citation_count":4,"is_preprint":false},{"pmid":"38081412","id":"PMC_38081412","title":"Overexpression of ORMDL3 confers sexual dimorphism in diet-induced non-alcoholic steatohepatitis.","date":"2023","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38081412","citation_count":4,"is_preprint":false},{"pmid":"26782568","id":"PMC_26782568","title":"ORMDL3 variants associated with bronchiolitis susceptibility in a Chinese population.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26782568","citation_count":4,"is_preprint":false},{"pmid":"24568918","id":"PMC_24568918","title":"[Down-regulatory effects of budesonide on expression of STAT6 and ORMDL3 in lung tissues of asthmatic mice].","date":"2014","source":"Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/24568918","citation_count":4,"is_preprint":false},{"pmid":"37124760","id":"PMC_37124760","title":"Ormdl3 regulation of specific ceramides is dispensable for mouse β-cell function and glucose homeostasis under obesogenic conditions.","date":"2023","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37124760","citation_count":3,"is_preprint":false},{"pmid":"38328715","id":"PMC_38328715","title":"Association of childhood asthma with Gasdermin B (GSDMB) and Oromucoid-like 3 (ORMDL3) genes.","date":"2023","source":"Northern clinics of Istanbul","url":"https://pubmed.ncbi.nlm.nih.gov/38328715","citation_count":3,"is_preprint":false},{"pmid":"35972600","id":"PMC_35972600","title":"Regulation of the sensitivity of hepatocarcinoma cells by ORMDL3, to sorafenib by autophagy.","date":"2022","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35972600","citation_count":3,"is_preprint":false},{"pmid":"31342811","id":"PMC_31342811","title":"Association between peripheral blood mononuclear cell ORMDL3 expression and the asthma predictive index in preschool children.","date":"2019","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/31342811","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56366,"output_tokens":9610,"usd":0.156624,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19744,"output_tokens":7104,"usd":0.13816,"stage2_stop_reason":"end_turn"},"total_usd":0.294784,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"ORMDL3 overexpression increases resting cytosolic Ca2+ levels and reduces ER-mediated Ca2+ signaling; co-expression with SERCA (sarco-endoplasmic reticulum Ca2+ pump) reverses this effect, supporting a model in which ORMDL3 binds and inhibits SERCA. siRNA knockdown of ORMDL3 potentiates ER Ca2+ release and attenuates the UPR.\",\n      \"method\": \"Heterologous overexpression, siRNA knockdown, Ca2+ measurements, co-expression rescue assay in mammalian cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression and knockdown with orthogonal Ca2+ and UPR readouts; single lab, no direct binding/reconstitution shown\",\n      \"pmids\": [\"19819884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ORMDL3 negatively modulates Ca2+-release-activated Ca2+ currents (ICRAC), store-operated calcium entry (SOCE), NFAT nuclear translocation, and IL-2 production in T lymphocytes. Mechanistically, ORMDL3 inhibits Ca2+ influx at the outer mitochondrial membrane, leading to Ca2+-dependent inhibition of ICRAC; the effect is mimicked by reducing mitochondrial Ca2+ uptake and reversed by cytosolic Ca2+ buffering.\",\n      \"method\": \"Patch-clamp electrophysiology (ICRAC measurement), SOCE assays, NFAT reporter, IL-2 ELISA, mitochondrial Ca2+ manipulation, overexpression and knockdown in T lymphocytes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal electrophysiological and functional assays, mechanistic rescue experiments in a single rigorous study\",\n      \"pmids\": [\"23100328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Transfection of ORMDL3 in human bronchial epithelial cells induces expression of metalloproteases (MMP-9, ADAM-8), chemokines (CCL-20, IL-8, CXCL-10, CXCL-11), OAS genes, and selectively activates the ATF6 branch of the UPR. siRNA knockdown of ATF6α inhibits SERCA2b expression; conversely, ORMDL3 transfection activates ATF6α and induces SERCA2b. In mice, allergen challenge induces ORMDL3 in bronchial epithelium in a STAT-6-dependent manner.\",\n      \"method\": \"Transfection (overexpression), siRNA knockdown, qPCR, immunoblot; STAT-6 KO mice for in vivo pathway placement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — overexpression and knockdown with multiple orthogonal molecular readouts, replicated in vivo with genetic model\",\n      \"pmids\": [\"23011799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ORMDL3 expression in eosinophils is localized to the endoplasmic reticulum and is induced by IL-3 and eotaxin-1. Overexpression of ORMDL3 increases eosinophil rolling, ERK1/2 phosphorylation, NF-κB nuclear translocation, and CD48-mediated degranulation. Knockdown of ORMDL3 inhibits activation-induced cell shape changes, adhesion, in vivo recruitment, and reduces expression of integrins CD49d and CD18.\",\n      \"method\": \"Overexpression, siRNA knockdown, flow cytometry, ERK/NF-κB immunoblot, intravital microscopy, in vivo recruitment assay, ER localization by confocal\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function with multiple orthogonal molecular and cellular readouts, validated in vivo\",\n      \"pmids\": [\"24056518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mice universally overexpressing human ORMDL3 (hORMDL3zp3-Cre) develop increased airway remodeling (smooth muscle, fibrosis, mucus), spontaneous airway hyperresponsiveness, and elevated IgE. This is associated with selective activation of ATF6 (but not IRE1 or PERK) and strong induction of SERCA2b and TGF-β1/ADAM8; airway remodeling precedes inflammation.\",\n      \"method\": \"Transgenic mouse model (hORMDL3zp3-Cre), lung function measurement, histology, qPCR, immunoblot; UPR pathway-specific readouts\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model with multiple orthogonal readouts and pathway specificity (ATF6 selectivity); replicated across multiple studies\",\n      \"pmids\": [\"24623133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ORMDL3 forms stable complexes with serine palmitoyltransferase (SPT) that are not increased by elevated ORMDL3 expression, suggesting ORMDL is expressed in functional excess relative to SPT. Elevated ORMDL3 expression does not suppress de novo sphingolipid biosynthesis in human bronchial epithelial cells or HeLa cells, though steady-state sphingolipid mass levels are marginally decreased at low overexpression levels.\",\n      \"method\": \"Co-immunoprecipitation (ORMDL3-SPT complex), isotope-labeling sphingolipid biosynthesis assay, overexpression in HBECs and HeLa cells, mass spectrometry lipidomics\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro biosynthesis assay plus co-IP for complex formation; single lab\",\n      \"pmids\": [\"25691431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Higher levels of ORMDL3 expression in lung epithelial cells and macrophages increase ceramide production (in vitro and in vivo), promoting chronic inflammation, airway hyperresponsiveness, and mucus production. Small increases in ORMDL3 decrease ceramide levels, while high overexpression increases them, indicating complex dose-dependent regulation of ceramide homeostasis.\",\n      \"method\": \"Overexpression and KD in epithelial cells and macrophages, house-dust-mite mouse model, mass spectrometry lipidomics, FTY720 pharmacological rescue\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro complementary models with lipidomics; single lab, complex/non-linear dose-response complicates interpretation\",\n      \"pmids\": [\"25842287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ORMDL3 negatively regulates FcεRI-triggered NF-κB signaling in mast cells: reduced ORMDL3 expression enhances AKT (Ser473) phosphorylation, IκBα phosphorylation/degradation, NF-κB p65 nuclear translocation, and upregulates TNF-α, IL-6, IL-13, CCL3, CCL4, and COX-2-dependent prostaglandin D2. Reduced ORMDL3 also enhances antigen-mediated chemotaxis but decreases fibronectin spreading. In vivo, locally silenced ORMDL3 increases IgE-dependent passive cutaneous anaphylaxis.\",\n      \"method\": \"siRNA knockdown and overexpression in murine mast cells, immunoblotting, ELISA, in vivo PCA model\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation with multiple signaling and functional readouts; single lab\",\n      \"pmids\": [\"26407610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ormdl3 knockout mice are protected from Alternaria-induced allergic airways disease (reduced airway function impairment and eosinophilia). ORMDL3 drives the ATF6-mediated UPR arm through XBP1 and downstream ER-associated degradation pathway activation. ORMDL3 also mediates uric acid release (a cellular stress marker). Reconstitution of ORMDL3 specifically in bronchial epithelium of knockout mice reinstates susceptibility to allergen-induced disease.\",\n      \"method\": \"Ormdl3 knockout mouse, adeno-associated viral reconstitution in airway epithelium, lung function measurement, histology, eosinophil counts, UPR gene expression\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with epistatic reconstitution (add-back), multiple orthogonal readouts, confirms pathway specificity for ATF6/XBP1 arm\",\n      \"pmids\": [\"27623174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Epithelial-selective ORMDL3 knockout mice (Ormdl3 epithelial-specific KO) challenged with OVA show unexpectedly increased airway hyperresponsiveness compared to wild-type. Sphingosine-1-phosphate (S1P) levels are significantly elevated in these mice and in airway epithelial cells after ORMDL3 siRNA knockdown. S1P directly increases airway smooth muscle contractility. This reveals that ORMDL3 in airway epithelium normally suppresses S1P generation.\",\n      \"method\": \"Cre-lox epithelial-specific KO mouse, OVA challenge, airway responsiveness measurement, S1P mass spectrometry, siRNA in vitro, smooth muscle contractility assay with exogenous S1P\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with pharmacological/biochemical rescue linking ORMDL3 to S1P and smooth muscle contractility\",\n      \"pmids\": [\"28275141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ORMDL3 expression in airway smooth muscle (ASM) increases ASM proliferation and contractility in vitro. In precision-cut lung slices from hORMDL3Zp3-Cre mice (without airway inflammation), increased ORMDL3 increases ASM Ca2+ oscillations and airway contractility. Increased ORMDL3 in ASM elevates SERCA2b, which mediates the proliferation and contractility effects.\",\n      \"method\": \"In vitro ASM transfection, ORMDL3 transgenic mouse PCLS assay, Ca2+ imaging, BrdU proliferation assay, SERCA2b knockdown/overexpression\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and ex vivo approaches; SERCA2b mechanistically linked; single lab\",\n      \"pmids\": [\"28889952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ORMDL3 facilitates B cell survival via an ATF6α-ER stress-Beclin1 autophagy pathway. Ormdl3-/- mice have decreased mature B lymphocytes, transitional 2B cells, B1a cells, reduced IgG/IgM secretion, and Baff expression; increased apoptosis of splenic CD19+ B cells. In vitro and in vivo experiments show ORMDL3 promotes autophagy through ATF6-Beclin1, suppressing apoptosis.\",\n      \"method\": \"Ormdl3 knockout mouse, flow cytometry, Annexin V apoptosis assay, autophagy markers (Beclin1), ATF6 pathway knockdown/overexpression\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with in vitro mechanistic follow-up; single lab, multiple readouts\",\n      \"pmids\": [\"28747345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AhR ligands promote ORMDL3-dependent S1P generation by inhibiting S1P lyase (S1PL). Mechanistically, AhR-mediated oxidation of S1PL at residue C317 inactivates S1PL; ORMDL3 knockdown prevents this AhR-mediated effect. A time-dependent increase in the ORMDL3-S1PL protein complex was detected, confirmed by FRET analysis. Cells expressing C317A S1PL mutant are resistant to AhR-mediated S1PL inhibition.\",\n      \"method\": \"FRET, co-immunoprecipitation, site-directed mutagenesis (C317A S1PL), S1PL activity assay, ORMDL3 siRNA knockdown, mast cell degranulation assay\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — FRET-confirmed protein interaction, enzyme activity assay, site-directed mutagenesis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"29572542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ORMDL3 knockdown reduces IL-6 and IL-8 release and ER stress after IL-1B stimulation in A549 cells; overexpression and myriocin (SPT inhibitor) augment cytokine release. ORMDL3 knockdown strongly reduces ICAM1 expression (the rhinovirus receptor), and alters glycolytic transcripts and metabolites, ceramide, and sphingosine-1-phosphate levels.\",\n      \"method\": \"siRNA knockdown, overexpression, cytokine ELISA, transcriptomics, metabolomics (ceramide/S1P), myriocin pharmacology; replicated in normal human bronchial epithelial cells\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional manipulation with multiple orthogonal molecular/metabolomic readouts, replicated in primary cells\",\n      \"pmids\": [\"30339462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ORMDL3 overexpression in mice reduces allergen-induced lung ceramide increases (while ORMDL3 deficiency increases systemic ceramide and sphingolipid levels in liver and serum), establishing that ORMDL3 regulates systemic ceramide homeostasis in vivo. Despite these ceramide changes, all hallmark asthma features are identical between wild-type, ORMDL3 transgenic, and ORMDL3 KO mice across multiple allergen models.\",\n      \"method\": \"Ormdl3-/- KO and Ormdl3Tg/wt transgenic mice; HDM and Alternaria asthma models; mass spectrometry sphingolipidomics, airway eosinophilia, AHR measurement\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complementary transgenic and KO models with comprehensive lipidomics and in vivo phenotyping; well-controlled\",\n      \"pmids\": [\"31330218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ORMDL3 overexpression impairs airway barrier function: it increases epithelial permeability, reduces TEER, downregulates junctional proteins (Claudin-18, E-cadherin), and induces SPHK1 activity and distribution. SPHK1 inhibition rescues TEER loss caused by ORMDL3 overexpression. ERK activation occurs downstream of SPHK1 in this pathway.\",\n      \"method\": \"Overexpression/inhibition in 16HBE cells and in vivo OVA-RSV mouse model, TEER measurement, permeability assay, SPHK1 inhibitor rescue, ERK immunoblot\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with pharmacological rescue, multiple readouts; single lab\",\n      \"pmids\": [\"31173170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 expression in airway smooth muscle induces ASM hypertrophy, hyperplasia (BrdU incorporation), and increased contractility. Overexpression elevates tropomyosin TPM1 and TPM4; siRNA knockdown of TPM1 or TPM4 demonstrates their requirement for ORMDL3-mediated ASM proliferation (but not hypertrophy). Increased contractility is associated with elevated intracellular Ca2+, increased Orai1 Ca2+ channels on cell surface, and upregulation of SERCA2b and smooth muscle 22.\",\n      \"method\": \"Smooth muscle-selective ORMDL3 transgenic mice (hORMDL3Myh11eGFP-cre), FACS, BrdU, Ca2+ imaging, contractility assay, siRNA TPM1/4 knockdown\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific transgenic model, siRNA epistasis for TPM1/4, multiple orthogonal readouts, in vitro and in vivo validation\",\n      \"pmids\": [\"33661765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 suppresses antigen-mediated mast cell activation via an ATF6-UPR-autophagy pathway: ORMDL3 overexpression inhibits degranulation and cytokine/chemokine production; knockdown has opposite effects. ORMDL3 overexpression upregulates SERCA2b, ATF6, Beclin1, and LC3BII. Knockdown of ATF6 or inhibition of autophagy reverses the suppression conferred by ORMDL3 overexpression. In vivo ORMDL3 and ATF6 knockdown enhances passive cutaneous anaphylaxis.\",\n      \"method\": \"Overexpression and siRNA knockdown in MC/9 cells, ATF6 siRNA epistasis, autophagy inhibitors, in vivo PCA mouse model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation with epistatic pathway placement; single lab, in vivo validation\",\n      \"pmids\": [\"33679742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 physically interacts with 5-lipoxygenase (5-LO) in ER domains of human mast cells; both also interact with the SPTLC1 subunit of SPT. ORMDL3 KO mast cells show increased leukotriene production (LTB4, LTC4, etc.) in addition to increased sphingolipids, establishing functional crosstalk between sphingolipid and eicosanoid (leukotriene) metabolic pathways.\",\n      \"method\": \"Co-immunoprecipitation (ORMDL3-5-LO and 5-LO-SPTLC1), ORMDL3/5-LO KO peritoneal mast cells, lipidomics (sphingolipids and LTs), siRNA knockdown of 5-LO and SPTLC1\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for direct interaction, KO cellular lipidomics, epistatic siRNA; single lab\",\n      \"pmids\": [\"34560079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ormdl3-/- mice have impaired BAT thermogenesis and WAT browning, with elevated ceramide levels in adipose tissue. The reduction in UCP1-mediated thermogenesis and increased weight caused by Ormdl3 deficiency is rescued by pharmacological inhibition of ceramide production, placing ORMDL3 upstream of ceramide in regulating adipose thermogenesis.\",\n      \"method\": \"Ormdl3-/- knockout mice, cold exposure, β3 adrenergic agonist challenge, primary adipocyte cultures, mass spectrometry lipidomics, ceramide synthesis inhibitor rescue\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with pharmacological rescue establishing ceramide pathway; single lab, multiple readouts\",\n      \"pmids\": [\"34954108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ORMDL3 overexpression in bronchial epithelial cells promotes autophagy (increased autophagosomes, elevated LC3B, ATG3, ATG7, ATG16L1) and subsequent cell death by impairing intracellular calcium mobilization through interaction with SERCA2. Immunoprecipitation confirms the ORMDL3-SERCA2 interaction.\",\n      \"method\": \"ORMDL3 overexpression in 16HBE and primary HBECs, electron microscopy (autophagosome detection), RFP-GFP-LC3B autophagic flux assay, immunoprecipitation (ORMDL3-SERCA2), intracellular Ca2+ assay, cell viability, coexpression analysis in 44 donors\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — IP-confirmed protein interaction, multiple orthogonal autophagy assays, functional consequence (cell death) established; single lab\",\n      \"pmids\": [\"35353673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ORMDL3 regulates NLRP3 inflammasome activation in human macrophages by modulating mitochondrial morphology and ER-mitochondria contacts. ORMDL3 overexpression increases mitochondrial fragmentation and ER-mitochondria contacts, enabling efficient NLRP3 inflammasome activation and IL-1β release; knockdown reduces IL-1β. Under inflammatory conditions, ORMDL3 localizes to mitochondria-associated membranes and mitochondria (in addition to ER) and interacts with the mitochondrial fission protein Fis-1.\",\n      \"method\": \"ORMDL3 knockdown in human monocyte-derived macrophages, co-immunoprecipitation (ORMDL3-Fis-1), subcellular fractionation/localization, mitochondrial morphology imaging, NLRP3 inflammasome activity assay (IL-1β release), DSS colitis mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-IP interaction with Fis-1, novel mitochondrial localization confirmed by fractionation, NLRP3 pathway mechanistic link, in vivo validation; single lab\",\n      \"pmids\": [\"38417794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ORMDL3 negatively regulates type I IFN signaling by interacting with MAVS and promoting proteasome-mediated degradation of RIG-I. IP-MS reveals ORMDL3 binds USP10, a deubiquitinase that stabilizes RIG-I by reducing K48-linked ubiquitination; ORMDL3 disrupts the USP10-RIG-I interaction, leading to RIG-I degradation. In vivo, ORMDL3 inhibition in syngeneic tumor models augments CD8+ T cells and IFN production in the tumor microenvironment.\",\n      \"method\": \"Co-immunoprecipitation, IP coupled with mass spectrometry (IP-MS), ubiquitination assays (K48-linked), proteasome inhibitor rescue, overexpression/knockdown, syngeneic subcutaneous tumor model in C57BL/6 mice\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — IP-MS identifying interactors, ubiquitination mechanistic dissection with multiple orthogonal methods, in vivo validation; single lab\",\n      \"pmids\": [\"40126553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The ORMDL3 gene promoter is cooperatively regulated by transcription factors Ets-1, p300, and CREB, which bind the proximal minimal promoter (-84/+58). Chromatin immunoprecipitation and sequential ChIP confirm co-occupancy; siRNA knockdown of each factor reduces ORMDL3 expression.\",\n      \"method\": \"5'-RACE, 5' deletion luciferase reporter assays, mutagenesis, EMSA, ChIP/Re-ChIP, RNA interference\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple promoter dissection methods, ChIP confirmation; single lab\",\n      \"pmids\": [\"22546552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STAT6 directly regulates ORMDL3 transcription by binding a -64 to -56 bp motif in the minimal promoter. EMSA and ChIP confirm STAT6 binding; IL-4 and IL-13 treatment increase ORMDL3 promoter activity and endogenous expression. STAT6 and p300 co-occupy the ORMDL3 promoter as a complex (confirmed by IP and ChIP/Re-ChIP).\",\n      \"method\": \"Luciferase reporter (deletion/mutation analysis), EMSA, ChIP, co-immunoprecipitation (STAT6-p300 complex), siRNA knockdown and overexpression, cytokine stimulation\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by EMSA and ChIP, protein complex by co-IP; single lab\",\n      \"pmids\": [\"23461825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The cAMP/PKA/CREB pathway regulates basal ORMDL3 transcription through a CRE element (-27/-20) in the core promoter. CREB binding is confirmed by EMSA and ChIP; CREB knockdown reduces ORMDL3 expression, overexpression increases it. Forskolin (PKA activator) increases CREB phosphorylation and ORMDL3 expression; H-89 (PKA inhibitor) reduces it.\",\n      \"method\": \"Luciferase reporter (deletion/mutation), EMSA, ChIP, siRNA and overexpression, forskolin/H-89 pharmacology in NIH3T3 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed, pharmacological validation; single lab\",\n      \"pmids\": [\"23577138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cbl-b (E3 ubiquitin ligase) suppresses ORMDL3 expression by reducing STAT6 phosphorylation, thereby decreasing STAT6 binding to the ORMDL3 promoter. ChIP and promoter assays confirm that IL-4-induced STAT6 phosphorylation drives ORMDL3 transcription, and Cbl-b counteracts this.\",\n      \"method\": \"Luciferase reporter, ChIP, immunoblot (STAT6 phosphorylation), Cbl-b siRNA and overexpression\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms mechanism, pharmacological and genetic validation; single lab\",\n      \"pmids\": [\"26112603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IRF-3 directly binds the ORMDL3 promoter at a proximal IRF-3 binding site following RSV infection, driving ORMDL3 transcription. Mutational analysis of the binding site, overexpression, siRNA knockdown of IRF-3, EMSA, and ChIP confirm IRF-3 as a direct transcriptional regulator of ORMDL3 after RSV infection.\",\n      \"method\": \"Luciferase reporter (mutation analysis), EMSA, ChIP, IRF-3 siRNA and overexpression in bronchial epithelial cells and lung fibroblasts, clinical sample correlation\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by EMSA and ChIP, bidirectional genetic manipulation; single lab\",\n      \"pmids\": [\"28336364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"STING positively regulates ORMDL3 expression through a TBK1-IRF3-STAT6 complex: STING activation enhances TBK1-mediated phosphorylation of both IRF3 and STAT6, which then bind the ORMDL3 promoter cooperatively to upregulate expression.\",\n      \"method\": \"Luciferase reporter, immunoprecipitation (STING-TBK1-IRF3-STAT6 complex), ChIP, siRNA knockdown, STING overexpression\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP establish complex at promoter; single lab\",\n      \"pmids\": [\"30009792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p300-mediated histone acetylation of the ORMDL3 promoter (H3 acetylation) activates ORMDL3 transcription in asthma. In asthmatic mice, p300 and acetylated H3 are enriched at the ORMDL3 promoter (by ChIP). HAT-dead p300 mutant fails to activate ORMDL3. C646 (p300 inhibitor) reduces ORMDL3 expression and airway remodeling.\",\n      \"method\": \"ChIP (p300, aceH3 at ORMDL3 promoter), luciferase reporter with WT and HAT-deletion p300 mutants, C646 pharmacology in OVA-asthma mouse model, immunohistochemistry, qPCR/Western blot\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms epigenetic mark at promoter, HAT-dead mutant specificity, in vivo validation; single lab\",\n      \"pmids\": [\"31536903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 overexpression facilitates FcεRI-mediated transcription of IL-4, TNF-α, and MCP-1 in RBL-2H3 mast cells (without affecting degranulation or MAPK phosphorylation), and this enhancement is suppressed by the S1P agonist FTY720. ORMDL3 overexpression also accelerates TG (thapsigargin)-induced PERK phosphorylation, selectively affecting the PERK branch of the UPR.\",\n      \"method\": \"Stable ORMDL3 overexpressing RBL-2H3 cells, FcεRI crosslinking, cytokine qPCR, degranulation assay, MAPK and PERK phosphorylation immunoblot, FTY720 pharmacology\",\n      \"journal\": \"Immunity, inflammation and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable cell line model with multiple functional and signaling readouts, pharmacological rescue; single lab\",\n      \"pmids\": [\"34288557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 knockdown in human airway smooth muscle cells reduces CSM (cigarette smoke medium)-induced ER stress (inhibiting ATF6 and PERK UPR pathways), and attenuates CSM-induced inflammation, cell proliferation, and apoptosis. ORMDL3 is also involved in CSM-induced mitochondrial dysfunction via the mitochondrial fission process.\",\n      \"method\": \"siRNA knockdown of ORMDL3 in primary HASMCs, CSM treatment, UPR pathway immunoblot (ATF6, PERK), inflammation/proliferation/apoptosis assays, mitochondrial morphology assessment\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal cellular readouts; single lab\",\n      \"pmids\": [\"34624393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ORMDL3 overexpression activates NLRP3 inflammasome expression in bronchial epithelial cells; RSV infection induces ORMDL3 overexpression through histone hyperacetylation (p300-mediated), which in turn drives NLRP3 inflammasome upregulation. p300 and acetylated H3 bind the ORMDL3 promoter (ChIP). C646 (p300 inhibitor) reduces ORMDL3 and NLRP3 expression and alleviates lung inflammation in rRSV+OVA asthma mice.\",\n      \"method\": \"BEAS-2B cells, RSV infection, ORMDL3 siRNA and overexpression, NLRP3 immunoblot/qPCR, ChIP (p300, aceH3 at ORMDL3 promoter), C646 pharmacology, in vivo rRSV+OVA mouse model\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms epigenetic regulation, epistatic link ORMDL3→NLRP3; single lab, in vivo confirmation\",\n      \"pmids\": [\"37877592\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ORMDL3 is an ER-resident transmembrane protein that acts as a negative homeostatic regulator of serine palmitoyltransferase (SPT), inhibiting de novo sphingolipid biosynthesis, while also binding and inhibiting SERCA to reduce ER Ca2+ stores, thereby promoting the ATF6-selective branch of the unfolded protein response; beyond lipid and calcium regulation, ORMDL3 interacts with MAVS to promote proteasome-mediated RIG-I degradation (dampening type I IFN signaling), interacts with Fis-1 at mitochondria-associated membranes to modulate mitochondrial fission and NLRP3 inflammasome activation, suppresses S1P lyase activity in complex with AhR signaling to elevate S1P, physically associates with 5-lipoxygenase to coordinate leukotriene and sphingolipid synthesis, and regulates autophagy via an ATF6-Beclin1 pathway, collectively placing ORMDL3 at a hub connecting ER stress, sphingolipid/eicosanoid metabolism, innate immune signaling, and calcium homeostasis relevant to asthma and inflammatory disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ORMDL3 is an endoplasmic reticulum-resident transmembrane protein that acts as a homeostatic hub coupling ER calcium handling, sphingolipid/eicosanoid metabolism, and the unfolded protein response to inflammatory and airway phenotypes [#0, #4, #18]. It restrains ER Ca2+ stores by physically interacting with the SERCA pump (SERCA2), elevating resting cytosolic Ca2+, dampening ER-mediated Ca2+ signaling, and selectively engaging the ATF6 branch of the UPR with downstream induction of SERCA2b [#0, #20, #2, #4]. ORMDL3 forms stable complexes with serine palmitoyltransferase (SPT/SPTLC1) and regulates ceramide and sphingosine-1-phosphate levels in a dose-dependent manner, and its loss elevates S1P that directly increases airway smooth muscle contractility [#5, #6, #9, #18]. Through ATF6-driven, Beclin1-dependent autophagy it controls cell survival and degranulation in B cells and mast cells [#11, #17, #20]. Beyond lipid and calcium control, ORMDL3 interacts with the mitochondrial fission protein Fis-1 at ER-mitochondria contacts to promote NLRP3 inflammasome activation, associates with 5-lipoxygenase to coordinate leukotriene and sphingolipid synthesis, suppresses S1P lyase in concert with AhR signaling, and binds MAVS/USP10 to drive proteasomal RIG-I degradation and dampen type I interferon signaling [#21, #18, #12, #22]. Its expression is induced by Th2 cytokines via STAT6 and by viral/innate signals via IRF-3 and p300-dependent histone acetylation, integrating ORMDL3 into asthma and inflammatory airway disease [#24, #27, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the first molecular activity for ORMDL3 by showing it controls ER calcium homeostasis and UPR rather than being a passive ER protein.\",\n      \"evidence\": \"Heterologous overexpression/knockdown with Ca2+ measurement and SERCA co-expression rescue in mammalian cells\",\n      \"pmids\": [\"19819884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct ORMDL3-SERCA binding shown at this stage\", \"Single overexpression system, physiological relevance unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined how ORMDL3-mediated calcium control feeds immune signaling, showing it suppresses store-operated calcium entry, NFAT activation, and IL-2 in T cells via mitochondrial Ca2+ handling.\",\n      \"evidence\": \"Patch-clamp ICRAC, SOCE assays, NFAT reporter, IL-2 ELISA with mitochondrial Ca2+ manipulation in T lymphocytes\",\n      \"pmids\": [\"23100328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target at the mitochondrial membrane not identified\", \"Link to direct SERCA interaction not made\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Tied ORMDL3 to a specific UPR branch and airway inflammation, showing selective ATF6 activation, SERCA2b induction, and STAT6-dependent in vivo induction.\",\n      \"evidence\": \"Transfection, siRNA, qPCR/immunoblot in bronchial epithelium plus STAT6-KO allergen challenge\",\n      \"pmids\": [\"23011799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why ORMDL3 selects ATF6 over IRE1/PERK not resolved\", \"Causal chain from Ca2+ to ATF6 incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Began mapping how ORMDL3 itself is transcriptionally controlled, identifying cooperative Ets-1/p300/CREB promoter occupancy.\",\n      \"evidence\": \"5'-RACE, deletion luciferase, EMSA, ChIP/Re-ChIP, RNAi\",\n      \"pmids\": [\"22546552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stimulus-specific regulation of these factors not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified ORMDL3 as a direct Th2-cytokine target gene, placing it downstream of STAT6/p300 and explaining IL-4/IL-13 inducibility in allergic disease.\",\n      \"evidence\": \"Reporter assays, EMSA, ChIP, STAT6-p300 co-IP, cytokine stimulation\",\n      \"pmids\": [\"23461825\", \"23577138\", \"26112603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of each promoter element in vivo unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended ORMDL3 function to granulocyte effector biology, showing it localizes to the ER in eosinophils and promotes adhesion, recruitment, and degranulation.\",\n      \"evidence\": \"Gain/loss-of-function, flow cytometry, ERK/NF-kB immunoblot, intravital microscopy\",\n      \"pmids\": [\"24056518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between ER ORMDL3 and surface integrin expression not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that constitutive ORMDL3 overexpression is sufficient to drive airway remodeling and hyperresponsiveness in vivo via selective ATF6 activation.\",\n      \"evidence\": \"hORMDL3 transgenic mice, lung function, histology, UPR pathway-specific readouts\",\n      \"pmids\": [\"24623133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether remodeling depends on lipid versus calcium arm not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Tested the canonical SPT-inhibitory model in mammalian cells, showing ORMDL3-SPT complexes exist but ORMDL3 is in functional excess and overexpression does not strongly suppress sphingolipid synthesis.\",\n      \"evidence\": \"Co-IP, isotope-labeling biosynthesis assay, lipidomics in HBECs/HeLa\",\n      \"pmids\": [\"25691431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with yeast SPT-inhibition model unresolved\", \"Conditions where ORMDL3 limits SPT not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the lipid-regulatory role as non-linear, showing small ORMDL3 increases lower ceramide while high overexpression raises it, promoting inflammation.\",\n      \"evidence\": \"Overexpression/KD in epithelia and macrophages, HDM model, lipidomics, FTY720 rescue\",\n      \"pmids\": [\"25842287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of dose-dependent reversal unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed context-dependent immunoregulation, showing ORMDL3 negatively regulates FcεRI-NF-kB signaling in mast cells and restrains anaphylaxis.\",\n      \"evidence\": \"Bidirectional manipulation in mast cells, immunoblot, ELISA, in vivo PCA\",\n      \"pmids\": [\"26407610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection to ER calcium/lipid arms not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided loss-of-function and add-back proof that epithelial ORMDL3 is required for allergic airways disease via the ATF6/XBP1-ERAD arm.\",\n      \"evidence\": \"Ormdl3 KO mice with AAV epithelial reconstitution, lung function, UPR gene expression\",\n      \"pmids\": [\"27623174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATF6 selectively couples to XBP1/ERAD here not detailed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Exposed a protective epithelial function, showing epithelial ORMDL3 normally suppresses S1P generation and that its loss elevates S1P to increase smooth muscle contractility.\",\n      \"evidence\": \"Epithelial-specific KO, OVA challenge, S1P mass spec, smooth muscle contractility assay\",\n      \"pmids\": [\"28275141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic step by which ORMDL3 limits S1P not identified here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed cell-type-specific pro-contractile actions in smooth muscle, linking ORMDL3 to SERCA2b-dependent Ca2+ oscillations, proliferation, and contractility.\",\n      \"evidence\": \"ASM transfection, transgenic PCLS Ca2+ imaging, BrdU, SERCA2b manipulation\",\n      \"pmids\": [\"28889952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SERCA2b regulation versus induction not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected ORMDL3 to cell survival through an ATF6-ER stress-Beclin1 autophagy axis controlling B lymphocyte homeostasis.\",\n      \"evidence\": \"Ormdl3 KO mice, flow cytometry, apoptosis assays, ATF6/Beclin1 pathway manipulation\",\n      \"pmids\": [\"28747345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ORMDL3 contribution to Beclin1 induction mechanism unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a direct enzymatic crosstalk, showing AhR-driven S1P lyase oxidation/inactivation requires ORMDL3, which forms a complex with S1PL to elevate S1P.\",\n      \"evidence\": \"FRET, co-IP, C317A S1PL mutant, S1PL activity assay, mast cell degranulation\",\n      \"pmids\": [\"29572542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ORMDL3 promotes C317 oxidation mechanistically unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Added an innate-immune transcriptional input, showing STING-TBK1 drives IRF3/STAT6 cooperative ORMDL3 promoter activation.\",\n      \"evidence\": \"Reporter, STING-TBK1-IRF3-STAT6 co-IP, ChIP, siRNA\",\n      \"pmids\": [\"30009792\", \"28336364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integration of innate and Th2 promoter inputs in vivo not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Tied ORMDL3 directly to inflammatory cytokine output and rhinovirus receptor expression, linking its function to lipid/glycolytic metabolic reprogramming.\",\n      \"evidence\": \"Bidirectional manipulation, ELISA, transcriptomics/metabolomics, myriocin in primary HBECs\",\n      \"pmids\": [\"30339462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal hierarchy between metabolic, lipid, and cytokine changes unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed in vivo that ORMDL3 governs systemic ceramide homeostasis yet asthma hallmarks are dissociable from these lipid changes.\",\n      \"evidence\": \"KO and transgenic mice, multiple allergen models, sphingolipidomics\",\n      \"pmids\": [\"31330218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which ORMDL3 function actually drives asthma phenotypes left open\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked ORMDL3 to epithelial barrier integrity via SPHK1/ERK and junctional protein downregulation.\",\n      \"evidence\": \"Overexpression/inhibition in 16HBE, TEER, permeability, SPHK1 inhibitor rescue\",\n      \"pmids\": [\"31173170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relation to S1P-lyase axis not integrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established p300-mediated histone acetylation as an epigenetic activator of ORMDL3 in asthma.\",\n      \"evidence\": \"ChIP, HAT-dead p300 mutant, C646 in OVA model\",\n      \"pmids\": [\"31536903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signals recruiting p300 to the locus not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped a physical sphingolipid-eicosanoid interface, showing ORMDL3 interacts with 5-LO and SPTLC1 and its loss elevates leukotrienes.\",\n      \"evidence\": \"Co-IP, KO mast cell lipidomics, siRNA of 5-LO/SPTLC1\",\n      \"pmids\": [\"34560079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the interaction directly regulates 5-LO catalysis untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated SERCA2b- and tropomyosin-dependent smooth muscle remodeling, identifying TPM1/TPM4 as required for ORMDL3-driven proliferation.\",\n      \"evidence\": \"Smooth muscle-specific transgenic mice, TPM1/4 siRNA epistasis, Ca2+ imaging, contractility\",\n      \"pmids\": [\"33661765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ORMDL3 induces TPM1/4 mechanistically unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reinforced the ATF6-UPR-autophagy axis as the mechanism by which ORMDL3 suppresses mast cell activation.\",\n      \"evidence\": \"Bidirectional manipulation in MC/9, ATF6 siRNA epistasis, autophagy inhibitors, PCA\",\n      \"pmids\": [\"33679742\", \"34288557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent opposite directionality across mast cell studies unreconciled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended ORMDL3 to systemic metabolism, placing it upstream of ceramide in adipose thermogenesis.\",\n      \"evidence\": \"Ormdl3 KO mice, cold/β3-agonist challenge, lipidomics, ceramide-synthesis inhibitor rescue\",\n      \"pmids\": [\"34954108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-autonomous versus systemic ceramide source not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked ORMDL3 to smoke-induced airway pathology through ER stress and mitochondrial fission.\",\n      \"evidence\": \"siRNA in primary HASMCs, CSM treatment, UPR immunoblot, mitochondrial morphology\",\n      \"pmids\": [\"34624393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mitochondrial localization not yet shown here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided direct biochemical confirmation of the ORMDL3-SERCA2 interaction and tied it to autophagy and cell death via impaired Ca2+ mobilization.\",\n      \"evidence\": \"Overexpression in HBECs, EM, RFP-GFP-LC3B flux, IP of ORMDL3-SERCA2, Ca2+ assays\",\n      \"pmids\": [\"35353673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and binding interface of ORMDL3-SERCA2 unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected viral-induced ORMDL3 to NLRP3 inflammasome activation in epithelium via p300 acetylation.\",\n      \"evidence\": \"BEAS-2B RSV infection, ORMDL3 manipulation, ChIP, C646 in rRSV+OVA model\",\n      \"pmids\": [\"37877592\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ORMDL3 mechanistically activates NLRP3 in epithelia not defined here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-ER localization and mechanism, showing inflammatory ORMDL3 relocates to mitochondria-associated membranes, binds Fis-1, and promotes NLRP3 activation via mitochondrial fragmentation.\",\n      \"evidence\": \"Macrophage knockdown, ORMDL3-Fis-1 co-IP, fractionation, mitochondrial imaging, IL-1β assay, DSS colitis\",\n      \"pmids\": [\"38417794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for ORMDL3 relocalization to MAMs unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined an antiviral/antitumor immune-regulatory function, showing ORMDL3 binds MAVS and disrupts USP10-RIG-I to drive RIG-I degradation and limit type I IFN.\",\n      \"evidence\": \"Co-IP, IP-MS, K48 ubiquitination assays, proteasome rescue, syngeneic tumor model\",\n      \"pmids\": [\"40126553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ORMDL3 displaces USP10 from RIG-I mechanistically unclear\", \"Relation to ER/lipid functions not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Which single biochemical activity (SPT regulation, SERCA inhibition, S1PL/5-LO complexing, Fis-1/MAVS binding) is the primary driver of ORMDL3's disease-relevant phenotypes, and how these functions are mechanistically interconnected, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of ORMDL3 with any partner\", \"Dissociation of lipid changes from asthma phenotypes unexplained\", \"Conditions selecting ER versus mitochondrial localization undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 20, 12, 18]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [22, 12]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 18, 20, 21]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 4, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 9, 14, 18, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21, 22, 32]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 17, 20]}\n    ],\n    \"complexes\": [\"ORMDL3-SPT (SPTLC1)\", \"ORMDL3-SERCA2\", \"ORMDL3-S1P lyase\", \"ORMDL3-5-lipoxygenase\"],\n    \"partners\": [\"SPTLC1\", \"SERCA2\", \"ATP2A2\", \"FIS1\", \"MAVS\", \"USP10\", \"ALOX5\", \"SGPL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}