{"gene":"ORMDL3","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2007,"finding":"ORMDL3 encodes a transmembrane protein anchored in the endoplasmic reticulum, and its expression level is regulated in cis by SNPs on chromosome 17q21 associated with childhood asthma.","method":"Genome-wide association study with systematic eQTL mapping in lymphoblastoid cell lines","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — large-scale eQTL mapping replicated across multiple cohorts; foundational paper with >1200 citations","pmids":["17611496"],"is_preprint":false},{"year":2010,"finding":"ORMDL3 overexpression increases resting cytosolic Ca²⁺, reduces ER Ca²⁺ release, and promotes activation of the unfolded protein response (UPR); co-expression of SERCA reverses these effects, consistent with a model in which ORMDL3 binds to and inhibits SERCA.","method":"Heterologous overexpression and siRNA knockdown in cell lines with Ca²⁺ imaging; co-expression rescue experiments","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional methods (Ca²⁺ imaging, UPR reporter assays, siRNA KD, rescue by SERCA co-expression) in single well-controlled study","pmids":["19819884"],"is_preprint":false},{"year":2012,"finding":"ORMDL3 negatively modulates Ca²⁺ release-activated Ca²⁺ current (I_CRAC) and store-operated calcium entry (SOCE) in T lymphocytes by inhibiting mitochondrial Ca²⁺ influx, thereby reducing NFAT nuclear translocation and IL-2 production.","method":"Patch-clamp electrophysiology (I_CRAC measurement), SOCE assays, NFAT reporter, IL-2 measurement with ORMDL3 overexpression and knockdown","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — direct electrophysiological measurement of I_CRAC combined with functional signaling readouts; mechanistic rescue experiments","pmids":["23100328"],"is_preprint":false},{"year":2012,"finding":"ORMDL3 transfection in human bronchial epithelial cells selectively activates the ATF6 branch of the UPR (but not IRE1 or PERK) and induces expression of metalloproteases (MMP-9, ADAM-8), CC/CXC chemokines, and OAS genes; STAT6-dependent allergen/cytokine (IL-4/IL-13) signaling induces ORMDL3 expression in airway epithelium.","method":"ORMDL3 transfection in bronchial epithelial cells; siRNA knockdown of ATF6α; STAT6-deficient mouse model; qPCR and protein quantification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — overexpression and KD with multiple gene expression readouts; genetic (STAT6-KO) and in vivo validation","pmids":["23011799"],"is_preprint":false},{"year":2013,"finding":"ORMDL3 promotes eosinophil trafficking by increasing integrin expression (CD49d, CD18) and regulating IL-3-induced CD48 expression; ORMDL3 overexpression causes cytoskeletal rearrangement, ERK1/2 phosphorylation, and NF-κB nuclear translocation, while knockdown reduces adhesion and in vivo recruitment.","method":"ORMDL3 overexpression and siRNA knockdown in eosinophils; in vivo recruitment assay; FACS for surface markers; immunofluorescence for cytoskeletal changes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — gain and loss of function with both in vitro and in vivo readouts; multiple orthogonal methods","pmids":["24056518"],"is_preprint":false},{"year":2014,"finding":"Universal overexpression of human ORMDL3 in mice (hORMDL3zp3-Cre) causes increased airway smooth muscle, subepithelial fibrosis, mucus, and airway hyperresponsiveness, associated with selective activation of ATF6α and induction of its target gene SERCA2b, TGF-β1, and ADAM8.","method":"Transgenic mouse model (cre-lox overexpression), methacholine challenge, histology, qPCR/Western blot for UPR branch markers","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — in vivo transgenic model with multiple phenotypic and molecular readouts; selective UPR branch activation confirmed","pmids":["24623133"],"is_preprint":false},{"year":2015,"finding":"ORMDL3 overexpression dysregulates ceramide homeostasis in a complex, dose-dependent manner: small increases in expression decrease ceramide levels, while higher overexpression in lung epithelial cells and macrophages increases ceramide production and promotes chronic inflammation.","method":"In vitro ORMDL3 overexpression in epithelial cells and macrophages; lipidomic analysis; in vivo house dust mite asthma model","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — lipidomics combined with in vivo and in vitro models; dose-dependent mechanistic observation","pmids":["25842287"],"is_preprint":false},{"year":2015,"finding":"ORMDL proteins (including ORMDL3) form stable complexes with serine palmitoyltransferase (SPT) and negatively regulate de novo sphingolipid biosynthesis; however, ORMDL is expressed in functional excess relative to SPT, so elevated ORMDL3 expression alone does not further suppress sphingolipid biosynthesis in bronchial epithelial cells.","method":"SPT activity assays, stable complex analysis, sphingolipid mass spectrometry in HBECs and HeLa cells with ORMDL3 overexpression","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 — direct enzymatic assay of SPT activity combined with stable complex analysis and lipidomics; mechanistic nuance established in vitro","pmids":["25691431"],"is_preprint":false},{"year":2015,"finding":"In antigen-activated mast cells, reduced ORMDL3 expression enhances AKT (Ser473) phosphorylation, IκBα phosphorylation and degradation, NF-κB p65 nuclear translocation, proinflammatory cytokine production (TNF-α, IL-6, IL-13), and chemotaxis; endogenous ORMDL3 is thus a negative regulator of FcεRI-triggered NF-κB/AKT signaling in mast cells.","method":"ORMDL3 siRNA knockdown and overexpression in mast cells; Western blot for signaling intermediates; ELISA for cytokines; in vivo passive cutaneous anaphylaxis model with siRNA","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 — gain and loss of function with both in vitro signaling readouts and in vivo PCA validation","pmids":["26407610"],"is_preprint":false},{"year":2016,"finding":"ORMDL3 is required in pulmonary bronchial epithelium for Alternaria-induced allergic airways disease; it drives the ATF6-mediated UPR arm through XBP1 and ER-associated degradation, and also mediates uric acid release; reconstitution of ORMDL3 in bronchial epithelium of knockout mice reinstates susceptibility.","method":"Ormdl3 knockout mice; adeno-associated viral vector epithelial reconstitution; Alternaria challenge; lung function, eosinophilia, UPR pathway markers","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with in vivo reconstitution experiment; multiple mechanistic readouts for UPR pathway","pmids":["27623174"],"is_preprint":false},{"year":2017,"finding":"ORMDL3 expression in airway smooth muscle (ASM) increases ASM proliferation and contractility in vitro and in precision-cut lung slices, associated with increased intracellular Ca²⁺ oscillations and upregulation of SERCA2b.","method":"ORMDL3 transfection of ASM cells; precision-cut lung slice contractility assay; Ca²⁺ imaging; BrdU proliferation assay; hORMDL3Zp3-Cre transgenic mouse ASM analysis","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — in vitro and ex vivo functional assays with transgenic mouse validation; multiple readouts","pmids":["28889952"],"is_preprint":false},{"year":2017,"finding":"Selective epithelial knockout of ORMDL3 paradoxically increases allergen-induced airway hyperresponsiveness (AHR) associated with significantly elevated sphingosine-1-phosphate (S1P) levels; S1P directly increases airway smooth muscle contractility.","method":"Cre-lox epithelial-specific ORMDL3 KO mice; OVA allergen challenge; methacholine AHR; S1P measurement by mass spectrometry; siRNA in airway epithelial cells; ASM contractility assay with S1P","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with in vivo functional readouts; lipidomics; direct causal link via S1P-ASM contractility assay","pmids":["28275141"],"is_preprint":false},{"year":2017,"finding":"ORMDL3 facilitates survival of splenic B cells by promoting autophagy through an ATF6α-Beclin1 pathway; Ormdl3 KO mice have reduced mature B cells, decreased IgG/IgM secretion, and increased B cell apoptosis.","method":"Ormdl3 knockout mice; flow cytometry for B cell populations; ELISA for immunoglobulins; Western blot for autophagy markers; in vitro and in vivo ATF6-Beclin1 pathway analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO model with multiple in vivo and in vitro mechanistic readouts; pathway validated by ATF6 knockdown","pmids":["28747345"],"is_preprint":false},{"year":2018,"finding":"AhR ligands promote ORMDL3-dependent S1P generation by inducing oxidative modification (oxidation at residue Cys317) of S1P lyase (S1PL), reducing S1PL activity; ORMDL3 forms a complex with S1PL (confirmed by FRET), and ORMDL3 knockdown blocks AhR-mediated S1PL oxidation and S1P accumulation.","method":"FRET analysis; Co-IP; S1PL activity assay; ORMDL3 knockdown; C317A S1PL mutant; mast cell degranulation assays; mouse lung exposures","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1-2 — FRET confirmation of physical interaction, mutagenesis, enzymatic activity assay, and in vivo validation","pmids":["29572542"],"is_preprint":false},{"year":2019,"finding":"ORMDL3 knockdown reduces IL6 and IL8 release and ER stress following IL1B stimulation and strongly reduces expression of the rhinovirus receptor ICAM1; ORMDL3 acts through sphingolipid regulation (ceramide, S1P) and ER stress pathways to modulate cellular inflammation.","method":"ORMDL3 siRNA knockdown and overexpression in A549 and primary NHBE cells; cytokine ELISA; transcript profiling; SPT inhibitor (myriocin); metabolite analysis","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 — gain and loss of function with multiple orthogonal readouts; validated in primary cells","pmids":["30339462"],"is_preprint":false},{"year":2019,"finding":"ORMDL3 regulates systemic ceramide levels in vivo: ORMDL3 overexpression reduces ceramide in liver and serum, while ORMDL3 deficiency increases them; however, genetically altering Ormdl3 expression does not alter key asthma features (eosinophilia, TH2 cytokines, AHR) across multiple allergen models.","method":"Ormdl3 transgenic and KO mice; mass spectrometry-based sphingolipidomics; HDM and Alternaria challenge models; lung function, cytokine, and immunoglobulin measurement","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1-2 — lipidomics in genetic mouse models with rigorous phenotyping; dissociates sphingolipid and asthma phenotypes","pmids":["31330218"],"is_preprint":false},{"year":2019,"finding":"ORMDL3 ablation in adipose tissue impairs BAT thermogenesis and WAT browning by increasing ceramide generation; ceramide synthesis inhibition rescues the thermogenic defect in Ormdl3-/- mice.","method":"Ormdl3-/- mice; cold exposure and β3-agonist treatment; mass spectrometry lipidomics; UCP1 expression; ceramide inhibitor rescue experiment","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with lipidomics and pharmacological rescue; multiple mechanistic readouts","pmids":["34954108"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 expressed in ASM induces hypertrophy, hyperplasia (via TPM1 and TPM4 upregulation), and increased contractility; increased contractility is associated with elevated intracellular Ca²⁺, increased surface Orai1 Ca²⁺ channels, and increased SERCA2b expression; siRNA knockdown of TPM1/TPM4 confirms their role in ORMDL3-mediated ASM proliferation.","method":"Smooth-muscle-selective ORMDL3 transgenic mice (hORMDL3Myh11eGFP-cre); FACS, BrdU incorporation, Ca²⁺ imaging, Orai1 surface expression, in vitro histamine contractility; TPM1/TPM4 siRNA","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — cell-type-selective transgenic model with multiple mechanistic readouts and targeted siRNA knockdown of downstream effectors","pmids":["33661765"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 functions as a negative regulator of antigen-mediated mast cell activation (degranulation and cytokine/chemokine production) through an ATF6-UPR-autophagy pathway; ORMDL3 overexpression upregulates SERCA2b, ATF6, Beclin1, and LC3BII, and ATF6 knockdown or autophagy inhibition reverses the suppressive effect.","method":"ORMDL3 overexpression and knockdown in MC/9 cells; ATF6 knockdown; autophagy inhibition; degranulation assay; ELISA; passive cutaneous anaphylaxis in vivo","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — gain/loss of function with epistasis experiments (ATF6 KD, autophagy inhibition) and in vivo PCA validation","pmids":["33679742"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 deficiency in mast cells increases sphingolipid levels; simultaneous ORMDL2 and ORMDL3 deficiency further elevates sphingolipids including S1P, and potentiates IgE-mediated degranulation, cytokine production (IL-4, IL-6, TNF-α), and NF-κB signaling, while both single and double KO increases antigen-induced chemotaxis.","method":"Single and double Ormdl2/Ormdl3 KO mice; sphingolipid mass spectrometry; degranulation assays; cytokine ELISA; passive cutaneous and systemic anaphylaxis models","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — double-KO genetic epistasis with lipidomics and multiple in vitro and in vivo functional assays","pmids":["33643282"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 physically interacts with 5-lipoxygenase (5-LO) in endoplasmic reticulum domains; ORMDL3-deficient mast cells produce increased leukotriene metabolites (LTB4, LTC4, etc.) in addition to elevated sphingolipids; 5-LO also interacts with SPT subunits SPTLC1/SPTLC2, revealing crosstalk between sphingolipid and eicosanoid biosynthesis pathways.","method":"Co-IP/physical interaction assays; lipidomic analysis of ORMDL3 KO mast cells; 5-LO and SPTLC1 siRNA knockdown; immunofluorescence colocalization","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — physical interaction confirmed by Co-IP; functional crosstalk validated by lipidomics and gene knockdown","pmids":["34560079"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 overexpression promotes autophagy in human bronchial epithelial cells and subsequent cell death by interacting with SERCA2 to impair intracellular Ca²⁺ mobilization; increased ORMDL3 expression correlates with autophagy-related gene expression (LC3B, ATG3, ATG7, ATG16L1) in patient-derived bronchial epithelial cells.","method":"Electron microscopy for autophagosomes; RFP-GFP-LC3B autophagic flux assay; Western blot for autophagy proteins; immunoprecipitation for SERCA2 interaction; Ca²⁺ mobilization assays; coexpression analysis in primary human cells","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution of ORMDL3-SERCA2 interaction by IP combined with functional Ca²⁺ and autophagy assays; validated in patient-derived primary cells","pmids":["35353673"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 regulates cigarette smoke-induced ER stress in human airway smooth muscle cells by modulating activating transcription factor 6 (ATF6) and PERK UPR pathways; ORMDL3 knockdown reduces cigarette smoke-mediated inflammation, cell proliferation/apoptosis changes, and mitochondrial fission.","method":"ORMDL3 siRNA knockdown in primary HASMCs from non-smokers/smokers/COPD; cigarette smoke medium exposure; Western blot for UPR and mitochondrial markers; cell viability and proliferation assays","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — siRNA KD in primary patient-derived cells with multiple UPR/mitochondrial readouts","pmids":["34624393"],"is_preprint":false},{"year":2024,"finding":"ORMDL3 contributes to NLRP3 inflammasome activation by localizing to mitochondria-associated membranes (MAMs) and mitochondria during inflammation, promoting mitochondrial fragmentation and enhanced ER-mitochondria contacts; ORMDL3 physically interacts with the mitochondrial fission protein Fis-1; ORMDL3 knockdown reduces IL-1β release and colitis severity in vivo.","method":"Co-IP for ORMDL3-Fis1 interaction; ORMDL3 overexpression and KD in human macrophages; mitochondrial morphology imaging; NLRP3 inflammasome assays; IL-1β ELISA; DSS-colitis mouse model with ORMDL3 KD","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — Co-IP identifies novel Fis-1 interaction; subcellular localization with functional consequence demonstrated; in vivo validation in colitis model","pmids":["38417794"],"is_preprint":false},{"year":2025,"finding":"ORMDL3 is a negative regulator of type I IFN signaling: it interacts with MAVS and promotes proteasome-mediated degradation of RIG-I by disrupting the stabilizing interaction between USP10 and RIG-I (USP10 removes K48-linked ubiquitin from RIG-I); ORMDL3 inhibition enhances anti-tumor immunity in vivo by increasing CD8⁺ T cells and IFN in the tumor microenvironment.","method":"IP-MS to identify ORMDL3 interactors (MAVS, USP10); Co-IP; ubiquitination assays (K48-linkage); RIG-I protein stability assays; syngeneic subcutaneous tumor models in C57BL/6 mice","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — IP-MS discovery followed by Co-IP validation, ubiquitination mechanistic dissection, and in vivo tumor model","pmids":["40126553"],"is_preprint":false},{"year":2013,"finding":"STAT6, upon IL-4 or IL-13 stimulation, directly binds to the ORMDL3 promoter and transactivates ORMDL3 expression; STAT6 and p300 form a complex that co-occupies the ORMDL3 promoter as demonstrated by sequential ChIP.","method":"Luciferase reporter assays; EMSA; ChIP and Re-ChIP; STAT6 overexpression and siRNA knockdown; Co-IP","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 — EMSA + ChIP + Re-ChIP + Co-IP + functional reporter assays; multiple orthogonal methods","pmids":["23461825"],"is_preprint":false},{"year":2012,"finding":"Transcription factors Ets-1, p300, and CREB cooperatively drive ORMDL3 transcription by binding to its proximal promoter region (-84/+58); sequential ChIP confirms co-occupancy; CREB expression is activated by Ets-1 and p300 and correlates with ORMDL3 levels in recurrent wheeze patients.","method":"5'-RACE; deletion luciferase reporter assays; mutational analysis; RNAi; sequential ChIP (Re-ChIP); RT-PCR of patient samples","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal promoter analysis methods; sequential ChIP confirms cooperative binding","pmids":["22546552"],"is_preprint":false},{"year":2013,"finding":"The cAMP/PKA/CREB pathway regulates basal ORMDL3 transcription: a CRE element (-27/-20) in the mouse ORMDL3 core promoter binds CREB; PKA activation (forskolin) increases CREB phosphorylation and ORMDL3 expression, while PKA inhibition (H-89) reduces it.","method":"Deletion luciferase reporter assays; EMSA; ChIP; CREB overexpression and knockdown; PKA activator/inhibitor treatments in NIH3T3 cells","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — EMSA + ChIP + functional reporter assays + pharmacological validation; multiple methods","pmids":["23577138"],"is_preprint":false},{"year":2017,"finding":"IRF-3 directly binds to the ORMDL3 promoter and upregulates ORMDL3 transcription following RSV infection; IRF-3 overexpression and knockdown confirm its transactivating role on ORMDL3.","method":"EMSA; ChIP; luciferase reporter with mutational analysis; IRF-3 overexpression and RNAi; patient peripheral blood lymphocyte samples","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 2 — EMSA + ChIP + mutational reporter assays + gain/loss of function; validated in patient samples","pmids":["28336364"],"is_preprint":false},{"year":2015,"finding":"E3 ubiquitin ligase Cbl-b suppresses ORMDL3 expression by reducing STAT6 phosphorylation, thereby reducing STAT6 binding to the ORMDL3 promoter; IL-4-induced STAT6 phosphorylation is required for ORMDL3 transactivation.","method":"Luciferase reporter assays; qRT-PCR; Cbl-b overexpression; ChIP; STAT6 phosphorylation Western blot; patient peripheral blood samples","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic assays (ChIP, reporter) combined with patient sample validation; single lab","pmids":["26112603"],"is_preprint":false},{"year":2019,"finding":"p300-mediated histone H3 acetylation at the ORMDL3 promoter activates ORMDL3 transcription; loss of p300 HAT activity reduces ORMDL3 promoter activity and expression; p300 and acetyl-H3 ChIP enrichment at the ORMDL3 promoter is increased in asthmatic mice; p300 inhibitor (C646) reduces ORMDL3 expression and airway remodeling in vivo.","method":"Luciferase reporter with p300 WT and HAT-deletion plasmids; ChIP for p300 and aceH3; OVA mouse model; C646 treatment; Western blot and IHC","journal":"International immunopharmacology","confidence":"High","confidence_rationale":"Tier 2 — reporter assays + ChIP + in vivo pharmacological validation; multiple methods","pmids":["31536903"],"is_preprint":false},{"year":2018,"finding":"STING promotes ORMDL3 transcription through TBK1-mediated phosphorylation of IRF3 and STAT6, which then form a complex that binds to the ORMDL3 promoter.","method":"Luciferase reporter assays; Co-IP; ChIP; siRNA knockdown of STING, TBK1, IRF3, STAT6; patient sample correlation","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP + ChIP + reporter assays; single lab, moderate evidence","pmids":["30009792"],"is_preprint":false},{"year":2023,"finding":"ORMDL3 promotes ferroptosis in Alzheimer's disease models through the PERK/ATF4/HSPA5 pathway; ORMDL3 knockdown reduces oxidative stress and ferroptosis markers in AD mice and BV-2 microglial cells.","method":"APPswe/PS1dE9 mouse model; BV-2 cell model; ORMDL3 knockdown; ferroptosis and oxidative stress markers; Western blot for PERK/ATF4/HSPA5 pathway","journal":"IET nanobiotechnology","confidence":"Medium","confidence_rationale":"Tier 2 — loss of function in both in vitro and in vivo AD models; pathway assignment by marker analysis; single lab","pmids":["36680386"],"is_preprint":false},{"year":2019,"finding":"ORMDL3 mediates ox-LDL-induced autophagy in endothelial cells by regulating BECN1 expression; ORMDL3 knockdown reduces both ox-LDL-induced and basal autophagy and BECN1 levels, and increases sensitivity to ox-LDL-induced cell death.","method":"ORMDL3 siRNA knockdown in endothelial cells; Western blot for BECN1 and autophagy markers; cell death assays; ox-LDL stimulation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 — single KD approach in cell line with autophagy readouts; single lab","pmids":["26603569"],"is_preprint":false},{"year":2017,"finding":"ORMDL3 overexpression in ORMDL3 transgenic mice is associated with increased OAS2 antiviral pathway and RNaseL activity; RV-infected hORMDL3zp3-Cre mice have reduced viral load and reduced airway inflammation with increased IFN-α, IFN-β, and IFN-λ.","method":"hORMDL3zp3-Cre transgenic mice; RV infection; qRT-PCR for viral load; bronchoalveolar lavage cell counts; RNaseL-deficient mice; IFN measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo transgenic and KO mouse models; multiple antiviral pathway readouts; single lab","pmids":["28827284"],"is_preprint":false},{"year":2019,"finding":"ORMDL3 overexpression in airway epithelial cells promotes airway barrier dysfunction by inducing SPHK1 distribution and activity and downstream ERK activation, leading to decreased TEER and reduced junctional complex proteins (Claudin-18, E-cadherin); SPHK1 inhibition reverses this effect.","method":"ORMDL3 overexpression in 16HBE cells; TEER measurement; SPHK1 activity assay; ERK phosphorylation Western blot; SPHK1 inhibitor; in vivo OVA-RSV mouse model","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — gain of function with pharmacological rescue; multiple mechanistic readouts; single lab","pmids":["31173170"],"is_preprint":false},{"year":2021,"finding":"ORMDL3 overexpression in macrophages leads to impaired TLR4-mediated autophagy and altered ceramide composition (increased de novo sphinganine production upon activation); phagocytosis is not affected, but autophagy specifically downstream of TLR4 is reduced.","method":"ORMDL3 knock-in transgenic mouse macrophages; gene expression analysis; phagocytosis assays; TLR4-induced autophagy assay; mass spectrometry lipidomics","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic macrophage model with lipidomics and functional assays; pathway specificity demonstrated; single lab","pmids":["30897694"],"is_preprint":false}],"current_model":"ORMDL3 is an ER-resident transmembrane protein that functions as a negative homeostatic regulator of serine palmitoyltransferase (SPT) — the rate-limiting enzyme for sphingolipid biosynthesis — by forming stable complexes with SPT, thereby modulating ceramide and sphingosine-1-phosphate levels; it also inhibits SERCA to reduce ER Ca²⁺ stores and trigger the ATF6 branch of the unfolded protein response, promotes NLRP3 inflammasome activation by enhancing ER-mitochondria contacts and interacting with the mitochondrial fission protein Fis-1, suppresses innate antiviral signaling by interacting with MAVS and promoting USP10-RIG-I complex disruption to drive RIG-I proteasomal degradation, and modulates inflammatory signaling in multiple immune cell types (mast cells, eosinophils, T cells, B cells) through Ca²⁺, NF-κB/AKT, and UPR-autophagy pathways, with its transcription regulated by STAT6, CREB/PKA, p300-mediated histone acetylation, Ets-1, IRF-3, and STING-TBK1 signaling."},"narrative":{"teleology":[{"year":2007,"claim":"The genetic basis of ORMDL3 in disease was established when cis-regulatory SNPs at 17q21 were found to control ORMDL3 expression and associate with childhood asthma, identifying ORMDL3 as a disease-relevant ER transmembrane protein whose expression level matters functionally.","evidence":"GWAS with eQTL mapping in lymphoblastoid cell lines across multiple cohorts","pmids":["17611496"],"confidence":"High","gaps":["Causal variant(s) within the haplotype not pinpointed","Mechanism by which expression level alters disease risk unknown"]},{"year":2010,"claim":"A key molecular mechanism was uncovered when ORMDL3 was shown to inhibit SERCA, depleting ER Ca²⁺ stores, raising cytosolic Ca²⁺, and triggering the UPR — establishing ORMDL3 as a regulator of ER calcium homeostasis.","evidence":"Overexpression, siRNA knockdown, Ca²⁺ imaging, and SERCA co-expression rescue in cell lines","pmids":["19819884"],"confidence":"High","gaps":["Direct binding interface between ORMDL3 and SERCA not mapped","Stoichiometry and selectivity for SERCA isoforms undefined"]},{"year":2012,"claim":"The UPR branch selectivity and transcriptional regulation of ORMDL3 were defined: ORMDL3 selectively activates ATF6 (not IRE1/PERK) in airway epithelium, and its own transcription is driven cooperatively by Ets-1/CREB/p300 at the proximal promoter and by STAT6 upon IL-4/IL-13 signaling.","evidence":"ATF6α siRNA epistasis in bronchial epithelial cells; STAT6-KO mice; 5'-RACE, deletion reporter assays, sequential ChIP, EMSA for promoter elements","pmids":["23011799","22546552","23461825"],"confidence":"High","gaps":["How ATF6 selectivity is achieved at the molecular level is unknown","Relative contribution of each transcription factor in different cell types not resolved"]},{"year":2012,"claim":"ORMDL3's role in adaptive immunity was established through its regulation of CRAC channels and NFAT signaling: ORMDL3 inhibits mitochondrial Ca²⁺ uptake, thereby reducing store-operated Ca²⁺ entry, NFAT nuclear translocation, and IL-2 production in T cells.","evidence":"Patch-clamp I_CRAC measurement, SOCE assays, NFAT reporter, and IL-2 quantification with ORMDL3 overexpression and knockdown in T lymphocytes","pmids":["23100328"],"confidence":"High","gaps":["Molecular target mediating mitochondrial Ca²⁺ uptake inhibition not identified","Whether this operates through sphingolipid changes or direct protein interaction unclear"]},{"year":2013,"claim":"ORMDL3 was shown to promote eosinophil trafficking through integrin upregulation, ERK1/2 activation, and NF-κB signaling, extending its immune modulatory role beyond lymphocytes to innate effector cells.","evidence":"Gain/loss-of-function in eosinophils with in vivo recruitment assays and surface marker FACS","pmids":["24056518"],"confidence":"High","gaps":["Whether sphingolipid changes or ER stress mediates integrin upregulation in eosinophils not dissected"]},{"year":2015,"claim":"The direct biochemical basis of ORMDL3's lipid regulatory function was defined: ORMDL3 forms stable complexes with SPT and negatively regulates de novo sphingolipid synthesis, though it exists in functional excess over SPT so modest overexpression alone does not further suppress synthesis.","evidence":"SPT activity assays, stable complex analysis, and sphingolipid mass spectrometry in HBECs and HeLa cells","pmids":["25691431"],"confidence":"High","gaps":["Structural basis of ORMDL3–SPT interaction not resolved","How ceramide sensing feeds back to ORMDL3-mediated SPT regulation not established"]},{"year":2015,"claim":"ORMDL3 was established as a negative regulator of FcεRI-mediated mast cell activation, restraining AKT/NF-κB signaling and proinflammatory cytokine release, with in vivo validation in anaphylaxis models.","evidence":"ORMDL3 siRNA knockdown and overexpression in mast cells; Western blot for AKT/IκBα/NF-κB; passive cutaneous anaphylaxis model","pmids":["26407610"],"confidence":"High","gaps":["Whether mast cell effects are ceramide-dependent, Ca²⁺-dependent, or both not separated"]},{"year":2017,"claim":"Tissue-specific functions were dissected: epithelial ORMDL3 knockout paradoxically increased AHR through elevated S1P driving ASM contractility, while ORMDL3 overexpression in ASM increased proliferation and contractility via Ca²⁺/Orai1/SERCA2b, revealing opposing roles in different compartments.","evidence":"Epithelial-specific conditional KO with S1P mass spectrometry; ASM-specific transgenic mice with Ca²⁺ imaging and contractility assays","pmids":["28275141","28889952"],"confidence":"High","gaps":["Mechanism by which epithelial ORMDL3 loss elevates S1P not fully elucidated","Relative in vivo contribution of epithelial vs. smooth muscle ORMDL3 to airway disease unresolved"]},{"year":2017,"claim":"ORMDL3 was shown to promote B cell survival through an ATF6α–Beclin-1 autophagy axis, as Ormdl3 KO mice displayed reduced mature B cells, impaired immunoglobulin secretion, and increased apoptosis.","evidence":"Ormdl3 KO mice; flow cytometry; ELISA for Ig; ATF6 knockdown epistasis; autophagy marker analysis","pmids":["28747345"],"confidence":"High","gaps":["Whether B cell defects are cell-autonomous or reflect altered microenvironment not determined"]},{"year":2018,"claim":"A novel lipid-metabolism interaction was revealed: ORMDL3 physically associates with S1P lyase (S1PL) and facilitates AhR-ligand-induced oxidative inactivation of S1PL at Cys317, thereby promoting S1P accumulation.","evidence":"FRET and Co-IP for ORMDL3–S1PL interaction; C317A mutant; S1PL activity assay; mast cell degranulation; in vivo lung exposure","pmids":["29572542"],"confidence":"High","gaps":["Structural details of ORMDL3–S1PL interaction unknown","Whether this mechanism operates in all ORMDL3-expressing cell types not tested"]},{"year":2019,"claim":"In vivo lipidomic studies confirmed ORMDL3 regulates systemic ceramide levels — overexpression decreases and deficiency increases ceramides — but dissociated this from canonical Th2 asthma features, challenging a simple ceramide-driven asthma model.","evidence":"Ormdl3 transgenic and KO mice with mass spectrometry sphingolipidomics across multiple allergen challenge models","pmids":["31330218"],"confidence":"High","gaps":["Alternative lipid species (S1P, leukotrienes) as disease mediators not fully evaluated in this study","Human relevance of dissociation between ceramide and asthma phenotype unclear"]},{"year":2021,"claim":"ORMDL3's regulatory scope was extended to lipid mediator crosstalk and mast cell effector functions: ORMDL3 physically interacts with 5-lipoxygenase at the ER, and its deficiency increases both sphingolipid and leukotriene production, while double ORMDL2/3 KO further amplifies these effects and potentiates IgE-mediated degranulation.","evidence":"Co-IP for ORMDL3–5-LO; lipidomics of single and double KO mast cells; degranulation and anaphylaxis models","pmids":["34560079","33643282"],"confidence":"High","gaps":["Structural basis for 5-LO inhibition by ORMDL3 not determined","Relative contribution of sphingolipid vs. eicosanoid dysregulation to mast cell hyperactivation not separated"]},{"year":2021,"claim":"ASM-selective transgenic models refined the contractility mechanism: ORMDL3 induces ASM hypertrophy and hyperplasia through TPM1/TPM4 upregulation and increases contractility via elevated surface Orai1 and SERCA2b, providing downstream effectors for the calcium phenotype.","evidence":"Smooth-muscle-selective hORMDL3 transgenic mice; TPM1/TPM4 siRNA knockdown; Orai1 surface expression; Ca²⁺ imaging","pmids":["33661765"],"confidence":"High","gaps":["Transcriptional mechanism linking ORMDL3 to TPM1/TPM4 induction unknown","Whether Orai1 surface increase is direct or secondary to ER stress not established"]},{"year":2024,"claim":"ORMDL3 was discovered to relocalize to mitochondria-associated membranes during inflammation, where it interacts with Fis-1 to promote mitochondrial fragmentation, enhance ER–mitochondria contacts, and activate the NLRP3 inflammasome.","evidence":"Co-IP for ORMDL3–Fis1; mitochondrial morphology imaging; NLRP3 inflammasome and IL-1β assays in macrophages; DSS-colitis mouse model","pmids":["38417794"],"confidence":"High","gaps":["Signal triggering ORMDL3 relocalization to MAMs not identified","Whether Fis-1 interaction requires sphingolipid changes unclear"]},{"year":2025,"claim":"A new immunoregulatory axis was revealed: ORMDL3 interacts with MAVS and promotes RIG-I degradation by disrupting the USP10–RIG-I deubiquitination complex, thereby suppressing type I IFN signaling; ORMDL3 inhibition enhances anti-tumor immunity.","evidence":"IP-MS identification of MAVS and USP10 as ORMDL3 interactors; Co-IP; K48-ubiquitination and RIG-I stability assays; syngeneic tumor models","pmids":["40126553"],"confidence":"High","gaps":["Whether ORMDL3–MAVS interaction is direct or bridged by other factors not established","Therapeutic potential of ORMDL3 inhibition in tumors not tested beyond syngeneic models"]},{"year":null,"claim":"Major unresolved questions include the structural basis of ORMDL3's interactions with its multiple partners (SPT, SERCA, S1PL, 5-LO, Fis-1, MAVS), how ORMDL3 partitions between ER and MAM pools, and the extent to which its sphingolipid-dependent and sphingolipid-independent functions (Ca²⁺, UPR, RIG-I degradation) are mechanistically separable in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of ORMDL3 alone or in complex","Sphingolipid-dependent vs. -independent functions not genetically separated in vivo","Relative contribution of ORMDL3 vs. ORMDL1/2 paralogs to each function incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,7,8,13,24]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[6,7,15,20]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,7,20,21]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,11,13,15,16,19,20]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,3,9,14,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4,8,19,24]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12,18,21,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,8,24]}],"complexes":["SPT complex (SPTLC1/SPTLC2/ORMDL3)"],"partners":["SPTLC1","SPTLC2","ATP2A2","SGPL1","ALOX5","FIS1","MAVS","USP10"],"other_free_text":[]},"mechanistic_narrative":"ORMDL3 is an endoplasmic reticulum-resident transmembrane protein that serves as a central homeostatic regulator of sphingolipid metabolism and ER stress signaling, with broad consequences for immune cell activation, airway remodeling, and innate antiviral defense. ORMDL3 forms stable complexes with serine palmitoyltransferase (SPT) to negatively regulate de novo sphingolipid biosynthesis and interacts with SERCA to reduce ER Ca²⁺ stores, thereby selectively activating the ATF6 branch of the unfolded protein response and downstream autophagy through ATF6–Beclin-1 signaling [PMID:25691431, PMID:19819884, PMID:23011799, PMID:28747345]. Through these ER stress and sphingolipid pathways, ORMDL3 modulates FcεRI-triggered NF-κB/AKT signaling in mast cells, NFAT-dependent T cell activation via CRAC channel regulation, B cell survival, eosinophil trafficking, and NLRP3 inflammasome activation by promoting ER–mitochondria contacts through interaction with the mitochondrial fission factor Fis-1 [PMID:26407610, PMID:23100328, PMID:24056518, PMID:38417794]. ORMDL3 also suppresses innate antiviral type I interferon signaling by interacting with MAVS and promoting USP10–RIG-I complex disruption, leading to proteasomal degradation of RIG-I [PMID:40126553]."},"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 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disease","url":"https://pubmed.ncbi.nlm.nih.gov/28333149","citation_count":80,"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":"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":"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 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28889952","citation_count":64,"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":62,"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":58,"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 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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":36,"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 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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":"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":"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":"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":17,"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":17,"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":17,"is_preprint":false},{"pmid":"31173170","id":"PMC_31173170","title":"Investigating the regulatory role of ORMDL3 in airway barrier dysfunction using in vivo and 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37881318","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":"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":5,"is_preprint":false},{"pmid":"26064206","id":"PMC_26064206","title":"Association between ORMDL3 polymorphism and 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Istanbul","url":"https://pubmed.ncbi.nlm.nih.gov/38328715","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55904,"output_tokens":9340,"usd":0.153906},"stage2":{"model":"claude-opus-4-6","input_tokens":13288,"output_tokens":4189,"usd":0.256748},"total_usd":0.410654,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"ORMDL3 encodes a transmembrane protein anchored in the endoplasmic reticulum, and its expression level is regulated in cis by SNPs on chromosome 17q21 associated with childhood asthma.\",\n      \"method\": \"Genome-wide association study with systematic eQTL mapping in lymphoblastoid cell lines\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large-scale eQTL mapping replicated across multiple cohorts; foundational paper with >1200 citations\",\n      \"pmids\": [\"17611496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ORMDL3 overexpression increases resting cytosolic Ca²⁺, reduces ER Ca²⁺ release, and promotes activation of the unfolded protein response (UPR); co-expression of SERCA reverses these effects, consistent with a model in which ORMDL3 binds to and inhibits SERCA.\",\n      \"method\": \"Heterologous overexpression and siRNA knockdown in cell lines with Ca²⁺ imaging; co-expression rescue experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional methods (Ca²⁺ imaging, UPR reporter assays, siRNA KD, rescue by SERCA co-expression) in single well-controlled study\",\n      \"pmids\": [\"19819884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ORMDL3 negatively modulates Ca²⁺ release-activated Ca²⁺ current (I_CRAC) and store-operated calcium entry (SOCE) in T lymphocytes by inhibiting mitochondrial Ca²⁺ influx, thereby reducing NFAT nuclear translocation and IL-2 production.\",\n      \"method\": \"Patch-clamp electrophysiology (I_CRAC measurement), SOCE assays, NFAT reporter, IL-2 measurement with ORMDL3 overexpression and knockdown\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct electrophysiological measurement of I_CRAC combined with functional signaling readouts; mechanistic rescue experiments\",\n      \"pmids\": [\"23100328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ORMDL3 transfection in human bronchial epithelial cells selectively activates the ATF6 branch of the UPR (but not IRE1 or PERK) and induces expression of metalloproteases (MMP-9, ADAM-8), CC/CXC chemokines, and OAS genes; STAT6-dependent allergen/cytokine (IL-4/IL-13) signaling induces ORMDL3 expression in airway epithelium.\",\n      \"method\": \"ORMDL3 transfection in bronchial epithelial cells; siRNA knockdown of ATF6α; STAT6-deficient mouse model; qPCR and protein quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — overexpression and KD with multiple gene expression readouts; genetic (STAT6-KO) and in vivo validation\",\n      \"pmids\": [\"23011799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ORMDL3 promotes eosinophil trafficking by increasing integrin expression (CD49d, CD18) and regulating IL-3-induced CD48 expression; ORMDL3 overexpression causes cytoskeletal rearrangement, ERK1/2 phosphorylation, and NF-κB nuclear translocation, while knockdown reduces adhesion and in vivo recruitment.\",\n      \"method\": \"ORMDL3 overexpression and siRNA knockdown in eosinophils; in vivo recruitment assay; FACS for surface markers; immunofluorescence for cytoskeletal changes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss of function with both in vitro and in vivo readouts; multiple orthogonal methods\",\n      \"pmids\": [\"24056518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Universal overexpression of human ORMDL3 in mice (hORMDL3zp3-Cre) causes increased airway smooth muscle, subepithelial fibrosis, mucus, and airway hyperresponsiveness, associated with selective activation of ATF6α and induction of its target gene SERCA2b, TGF-β1, and ADAM8.\",\n      \"method\": \"Transgenic mouse model (cre-lox overexpression), methacholine challenge, histology, qPCR/Western blot for UPR branch markers\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic model with multiple phenotypic and molecular readouts; selective UPR branch activation confirmed\",\n      \"pmids\": [\"24623133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ORMDL3 overexpression dysregulates ceramide homeostasis in a complex, dose-dependent manner: small increases in expression decrease ceramide levels, while higher overexpression in lung epithelial cells and macrophages increases ceramide production and promotes chronic inflammation.\",\n      \"method\": \"In vitro ORMDL3 overexpression in epithelial cells and macrophages; lipidomic analysis; in vivo house dust mite asthma model\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — lipidomics combined with in vivo and in vitro models; dose-dependent mechanistic observation\",\n      \"pmids\": [\"25842287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ORMDL proteins (including ORMDL3) form stable complexes with serine palmitoyltransferase (SPT) and negatively regulate de novo sphingolipid biosynthesis; however, ORMDL is expressed in functional excess relative to SPT, so elevated ORMDL3 expression alone does not further suppress sphingolipid biosynthesis in bronchial epithelial cells.\",\n      \"method\": \"SPT activity assays, stable complex analysis, sphingolipid mass spectrometry in HBECs and HeLa cells with ORMDL3 overexpression\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct enzymatic assay of SPT activity combined with stable complex analysis and lipidomics; mechanistic nuance established in vitro\",\n      \"pmids\": [\"25691431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In antigen-activated mast cells, reduced ORMDL3 expression enhances AKT (Ser473) phosphorylation, IκBα phosphorylation and degradation, NF-κB p65 nuclear translocation, proinflammatory cytokine production (TNF-α, IL-6, IL-13), and chemotaxis; endogenous ORMDL3 is thus a negative regulator of FcεRI-triggered NF-κB/AKT signaling in mast cells.\",\n      \"method\": \"ORMDL3 siRNA knockdown and overexpression in mast cells; Western blot for signaling intermediates; ELISA for cytokines; in vivo passive cutaneous anaphylaxis model with siRNA\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss of function with both in vitro signaling readouts and in vivo PCA validation\",\n      \"pmids\": [\"26407610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ORMDL3 is required in pulmonary bronchial epithelium for Alternaria-induced allergic airways disease; it drives the ATF6-mediated UPR arm through XBP1 and ER-associated degradation, and also mediates uric acid release; reconstitution of ORMDL3 in bronchial epithelium of knockout mice reinstates susceptibility.\",\n      \"method\": \"Ormdl3 knockout mice; adeno-associated viral vector epithelial reconstitution; Alternaria challenge; lung function, eosinophilia, UPR pathway markers\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with in vivo reconstitution experiment; multiple mechanistic readouts for UPR pathway\",\n      \"pmids\": [\"27623174\"],\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 and in precision-cut lung slices, associated with increased intracellular Ca²⁺ oscillations and upregulation of SERCA2b.\",\n      \"method\": \"ORMDL3 transfection of ASM cells; precision-cut lung slice contractility assay; Ca²⁺ imaging; BrdU proliferation assay; hORMDL3Zp3-Cre transgenic mouse ASM analysis\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and ex vivo functional assays with transgenic mouse validation; multiple readouts\",\n      \"pmids\": [\"28889952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Selective epithelial knockout of ORMDL3 paradoxically increases allergen-induced airway hyperresponsiveness (AHR) associated with significantly elevated sphingosine-1-phosphate (S1P) levels; S1P directly increases airway smooth muscle contractility.\",\n      \"method\": \"Cre-lox epithelial-specific ORMDL3 KO mice; OVA allergen challenge; methacholine AHR; S1P measurement by mass spectrometry; siRNA in airway epithelial cells; ASM contractility assay with S1P\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with in vivo functional readouts; lipidomics; direct causal link via S1P-ASM contractility assay\",\n      \"pmids\": [\"28275141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ORMDL3 facilitates survival of splenic B cells by promoting autophagy through an ATF6α-Beclin1 pathway; Ormdl3 KO mice have reduced mature B cells, decreased IgG/IgM secretion, and increased B cell apoptosis.\",\n      \"method\": \"Ormdl3 knockout mice; flow cytometry for B cell populations; ELISA for immunoglobulins; Western blot for autophagy markers; in vitro and in vivo ATF6-Beclin1 pathway analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO model with multiple in vivo and in vitro mechanistic readouts; pathway validated by ATF6 knockdown\",\n      \"pmids\": [\"28747345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AhR ligands promote ORMDL3-dependent S1P generation by inducing oxidative modification (oxidation at residue Cys317) of S1P lyase (S1PL), reducing S1PL activity; ORMDL3 forms a complex with S1PL (confirmed by FRET), and ORMDL3 knockdown blocks AhR-mediated S1PL oxidation and S1P accumulation.\",\n      \"method\": \"FRET analysis; Co-IP; S1PL activity assay; ORMDL3 knockdown; C317A S1PL mutant; mast cell degranulation assays; mouse lung exposures\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — FRET confirmation of physical interaction, mutagenesis, enzymatic activity assay, and in vivo validation\",\n      \"pmids\": [\"29572542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ORMDL3 knockdown reduces IL6 and IL8 release and ER stress following IL1B stimulation and strongly reduces expression of the rhinovirus receptor ICAM1; ORMDL3 acts through sphingolipid regulation (ceramide, S1P) and ER stress pathways to modulate cellular inflammation.\",\n      \"method\": \"ORMDL3 siRNA knockdown and overexpression in A549 and primary NHBE cells; cytokine ELISA; transcript profiling; SPT inhibitor (myriocin); metabolite analysis\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss of function with multiple orthogonal readouts; validated in primary cells\",\n      \"pmids\": [\"30339462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ORMDL3 regulates systemic ceramide levels in vivo: ORMDL3 overexpression reduces ceramide in liver and serum, while ORMDL3 deficiency increases them; however, genetically altering Ormdl3 expression does not alter key asthma features (eosinophilia, TH2 cytokines, AHR) across multiple allergen models.\",\n      \"method\": \"Ormdl3 transgenic and KO mice; mass spectrometry-based sphingolipidomics; HDM and Alternaria challenge models; lung function, cytokine, and immunoglobulin measurement\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — lipidomics in genetic mouse models with rigorous phenotyping; dissociates sphingolipid and asthma phenotypes\",\n      \"pmids\": [\"31330218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ORMDL3 ablation in adipose tissue impairs BAT thermogenesis and WAT browning by increasing ceramide generation; ceramide synthesis inhibition rescues the thermogenic defect in Ormdl3-/- mice.\",\n      \"method\": \"Ormdl3-/- mice; cold exposure and β3-agonist treatment; mass spectrometry lipidomics; UCP1 expression; ceramide inhibitor rescue experiment\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with lipidomics and pharmacological rescue; multiple mechanistic readouts\",\n      \"pmids\": [\"34954108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 expressed in ASM induces hypertrophy, hyperplasia (via TPM1 and TPM4 upregulation), and increased contractility; increased contractility is associated with elevated intracellular Ca²⁺, increased surface Orai1 Ca²⁺ channels, and increased SERCA2b expression; siRNA knockdown of TPM1/TPM4 confirms their role in ORMDL3-mediated ASM proliferation.\",\n      \"method\": \"Smooth-muscle-selective ORMDL3 transgenic mice (hORMDL3Myh11eGFP-cre); FACS, BrdU incorporation, Ca²⁺ imaging, Orai1 surface expression, in vitro histamine contractility; TPM1/TPM4 siRNA\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-selective transgenic model with multiple mechanistic readouts and targeted siRNA knockdown of downstream effectors\",\n      \"pmids\": [\"33661765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 functions as a negative regulator of antigen-mediated mast cell activation (degranulation and cytokine/chemokine production) through an ATF6-UPR-autophagy pathway; ORMDL3 overexpression upregulates SERCA2b, ATF6, Beclin1, and LC3BII, and ATF6 knockdown or autophagy inhibition reverses the suppressive effect.\",\n      \"method\": \"ORMDL3 overexpression and knockdown in MC/9 cells; ATF6 knockdown; autophagy inhibition; degranulation assay; ELISA; passive cutaneous anaphylaxis in vivo\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss of function with epistasis experiments (ATF6 KD, autophagy inhibition) and in vivo PCA validation\",\n      \"pmids\": [\"33679742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 deficiency in mast cells increases sphingolipid levels; simultaneous ORMDL2 and ORMDL3 deficiency further elevates sphingolipids including S1P, and potentiates IgE-mediated degranulation, cytokine production (IL-4, IL-6, TNF-α), and NF-κB signaling, while both single and double KO increases antigen-induced chemotaxis.\",\n      \"method\": \"Single and double Ormdl2/Ormdl3 KO mice; sphingolipid mass spectrometry; degranulation assays; cytokine ELISA; passive cutaneous and systemic anaphylaxis models\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double-KO genetic epistasis with lipidomics and multiple in vitro and in vivo functional assays\",\n      \"pmids\": [\"33643282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 physically interacts with 5-lipoxygenase (5-LO) in endoplasmic reticulum domains; ORMDL3-deficient mast cells produce increased leukotriene metabolites (LTB4, LTC4, etc.) in addition to elevated sphingolipids; 5-LO also interacts with SPT subunits SPTLC1/SPTLC2, revealing crosstalk between sphingolipid and eicosanoid biosynthesis pathways.\",\n      \"method\": \"Co-IP/physical interaction assays; lipidomic analysis of ORMDL3 KO mast cells; 5-LO and SPTLC1 siRNA knockdown; immunofluorescence colocalization\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction confirmed by Co-IP; functional crosstalk validated by lipidomics and gene knockdown\",\n      \"pmids\": [\"34560079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 overexpression promotes autophagy in human bronchial epithelial cells and subsequent cell death by interacting with SERCA2 to impair intracellular Ca²⁺ mobilization; increased ORMDL3 expression correlates with autophagy-related gene expression (LC3B, ATG3, ATG7, ATG16L1) in patient-derived bronchial epithelial cells.\",\n      \"method\": \"Electron microscopy for autophagosomes; RFP-GFP-LC3B autophagic flux assay; Western blot for autophagy proteins; immunoprecipitation for SERCA2 interaction; Ca²⁺ mobilization assays; coexpression analysis in primary human cells\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution of ORMDL3-SERCA2 interaction by IP combined with functional Ca²⁺ and autophagy assays; validated in patient-derived primary cells\",\n      \"pmids\": [\"35353673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 regulates cigarette smoke-induced ER stress in human airway smooth muscle cells by modulating activating transcription factor 6 (ATF6) and PERK UPR pathways; ORMDL3 knockdown reduces cigarette smoke-mediated inflammation, cell proliferation/apoptosis changes, and mitochondrial fission.\",\n      \"method\": \"ORMDL3 siRNA knockdown in primary HASMCs from non-smokers/smokers/COPD; cigarette smoke medium exposure; Western blot for UPR and mitochondrial markers; cell viability and proliferation assays\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA KD in primary patient-derived cells with multiple UPR/mitochondrial readouts\",\n      \"pmids\": [\"34624393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ORMDL3 contributes to NLRP3 inflammasome activation by localizing to mitochondria-associated membranes (MAMs) and mitochondria during inflammation, promoting mitochondrial fragmentation and enhanced ER-mitochondria contacts; ORMDL3 physically interacts with the mitochondrial fission protein Fis-1; ORMDL3 knockdown reduces IL-1β release and colitis severity in vivo.\",\n      \"method\": \"Co-IP for ORMDL3-Fis1 interaction; ORMDL3 overexpression and KD in human macrophages; mitochondrial morphology imaging; NLRP3 inflammasome assays; IL-1β ELISA; DSS-colitis mouse model with ORMDL3 KD\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifies novel Fis-1 interaction; subcellular localization with functional consequence demonstrated; in vivo validation in colitis model\",\n      \"pmids\": [\"38417794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ORMDL3 is a negative regulator of type I IFN signaling: it interacts with MAVS and promotes proteasome-mediated degradation of RIG-I by disrupting the stabilizing interaction between USP10 and RIG-I (USP10 removes K48-linked ubiquitin from RIG-I); ORMDL3 inhibition enhances anti-tumor immunity in vivo by increasing CD8⁺ T cells and IFN in the tumor microenvironment.\",\n      \"method\": \"IP-MS to identify ORMDL3 interactors (MAVS, USP10); Co-IP; ubiquitination assays (K48-linkage); RIG-I protein stability assays; syngeneic subcutaneous tumor models in C57BL/6 mice\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — IP-MS discovery followed by Co-IP validation, ubiquitination mechanistic dissection, and in vivo tumor model\",\n      \"pmids\": [\"40126553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STAT6, upon IL-4 or IL-13 stimulation, directly binds to the ORMDL3 promoter and transactivates ORMDL3 expression; STAT6 and p300 form a complex that co-occupies the ORMDL3 promoter as demonstrated by sequential ChIP.\",\n      \"method\": \"Luciferase reporter assays; EMSA; ChIP and Re-ChIP; STAT6 overexpression and siRNA knockdown; Co-IP\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — EMSA + ChIP + Re-ChIP + Co-IP + functional reporter assays; multiple orthogonal methods\",\n      \"pmids\": [\"23461825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Transcription factors Ets-1, p300, and CREB cooperatively drive ORMDL3 transcription by binding to its proximal promoter region (-84/+58); sequential ChIP confirms co-occupancy; CREB expression is activated by Ets-1 and p300 and correlates with ORMDL3 levels in recurrent wheeze patients.\",\n      \"method\": \"5'-RACE; deletion luciferase reporter assays; mutational analysis; RNAi; sequential ChIP (Re-ChIP); RT-PCR of patient samples\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal promoter analysis methods; sequential ChIP confirms cooperative binding\",\n      \"pmids\": [\"22546552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The cAMP/PKA/CREB pathway regulates basal ORMDL3 transcription: a CRE element (-27/-20) in the mouse ORMDL3 core promoter binds CREB; PKA activation (forskolin) increases CREB phosphorylation and ORMDL3 expression, while PKA inhibition (H-89) reduces it.\",\n      \"method\": \"Deletion luciferase reporter assays; EMSA; ChIP; CREB overexpression and knockdown; PKA activator/inhibitor treatments in NIH3T3 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — EMSA + ChIP + functional reporter assays + pharmacological validation; multiple methods\",\n      \"pmids\": [\"23577138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IRF-3 directly binds to the ORMDL3 promoter and upregulates ORMDL3 transcription following RSV infection; IRF-3 overexpression and knockdown confirm its transactivating role on ORMDL3.\",\n      \"method\": \"EMSA; ChIP; luciferase reporter with mutational analysis; IRF-3 overexpression and RNAi; patient peripheral blood lymphocyte samples\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — EMSA + ChIP + mutational reporter assays + gain/loss of function; validated in patient samples\",\n      \"pmids\": [\"28336364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"E3 ubiquitin ligase Cbl-b suppresses ORMDL3 expression by reducing STAT6 phosphorylation, thereby reducing STAT6 binding to the ORMDL3 promoter; IL-4-induced STAT6 phosphorylation is required for ORMDL3 transactivation.\",\n      \"method\": \"Luciferase reporter assays; qRT-PCR; Cbl-b overexpression; ChIP; STAT6 phosphorylation Western blot; patient peripheral blood samples\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic assays (ChIP, reporter) combined with patient sample validation; single lab\",\n      \"pmids\": [\"26112603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p300-mediated histone H3 acetylation at the ORMDL3 promoter activates ORMDL3 transcription; loss of p300 HAT activity reduces ORMDL3 promoter activity and expression; p300 and acetyl-H3 ChIP enrichment at the ORMDL3 promoter is increased in asthmatic mice; p300 inhibitor (C646) reduces ORMDL3 expression and airway remodeling in vivo.\",\n      \"method\": \"Luciferase reporter with p300 WT and HAT-deletion plasmids; ChIP for p300 and aceH3; OVA mouse model; C646 treatment; Western blot and IHC\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reporter assays + ChIP + in vivo pharmacological validation; multiple methods\",\n      \"pmids\": [\"31536903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"STING promotes ORMDL3 transcription through TBK1-mediated phosphorylation of IRF3 and STAT6, which then form a complex that binds to the ORMDL3 promoter.\",\n      \"method\": \"Luciferase reporter assays; Co-IP; ChIP; siRNA knockdown of STING, TBK1, IRF3, STAT6; patient sample correlation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP + ChIP + reporter assays; single lab, moderate evidence\",\n      \"pmids\": [\"30009792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ORMDL3 promotes ferroptosis in Alzheimer's disease models through the PERK/ATF4/HSPA5 pathway; ORMDL3 knockdown reduces oxidative stress and ferroptosis markers in AD mice and BV-2 microglial cells.\",\n      \"method\": \"APPswe/PS1dE9 mouse model; BV-2 cell model; ORMDL3 knockdown; ferroptosis and oxidative stress markers; Western blot for PERK/ATF4/HSPA5 pathway\",\n      \"journal\": \"IET nanobiotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss of function in both in vitro and in vivo AD models; pathway assignment by marker analysis; single lab\",\n      \"pmids\": [\"36680386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ORMDL3 mediates ox-LDL-induced autophagy in endothelial cells by regulating BECN1 expression; ORMDL3 knockdown reduces both ox-LDL-induced and basal autophagy and BECN1 levels, and increases sensitivity to ox-LDL-induced cell death.\",\n      \"method\": \"ORMDL3 siRNA knockdown in endothelial cells; Western blot for BECN1 and autophagy markers; cell death assays; ox-LDL stimulation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single KD approach in cell line with autophagy readouts; single lab\",\n      \"pmids\": [\"26603569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ORMDL3 overexpression in ORMDL3 transgenic mice is associated with increased OAS2 antiviral pathway and RNaseL activity; RV-infected hORMDL3zp3-Cre mice have reduced viral load and reduced airway inflammation with increased IFN-α, IFN-β, and IFN-λ.\",\n      \"method\": \"hORMDL3zp3-Cre transgenic mice; RV infection; qRT-PCR for viral load; bronchoalveolar lavage cell counts; RNaseL-deficient mice; IFN measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic and KO mouse models; multiple antiviral pathway readouts; single lab\",\n      \"pmids\": [\"28827284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ORMDL3 overexpression in airway epithelial cells promotes airway barrier dysfunction by inducing SPHK1 distribution and activity and downstream ERK activation, leading to decreased TEER and reduced junctional complex proteins (Claudin-18, E-cadherin); SPHK1 inhibition reverses this effect.\",\n      \"method\": \"ORMDL3 overexpression in 16HBE cells; TEER measurement; SPHK1 activity assay; ERK phosphorylation Western blot; SPHK1 inhibitor; in vivo OVA-RSV mouse model\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain of function with pharmacological rescue; multiple mechanistic readouts; single lab\",\n      \"pmids\": [\"31173170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ORMDL3 overexpression in macrophages leads to impaired TLR4-mediated autophagy and altered ceramide composition (increased de novo sphinganine production upon activation); phagocytosis is not affected, but autophagy specifically downstream of TLR4 is reduced.\",\n      \"method\": \"ORMDL3 knock-in transgenic mouse macrophages; gene expression analysis; phagocytosis assays; TLR4-induced autophagy assay; mass spectrometry lipidomics\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic macrophage model with lipidomics and functional assays; pathway specificity demonstrated; single lab\",\n      \"pmids\": [\"30897694\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ORMDL3 is an ER-resident transmembrane protein that functions as a negative homeostatic regulator of serine palmitoyltransferase (SPT) — the rate-limiting enzyme for sphingolipid biosynthesis — by forming stable complexes with SPT, thereby modulating ceramide and sphingosine-1-phosphate levels; it also inhibits SERCA to reduce ER Ca²⁺ stores and trigger the ATF6 branch of the unfolded protein response, promotes NLRP3 inflammasome activation by enhancing ER-mitochondria contacts and interacting with the mitochondrial fission protein Fis-1, suppresses innate antiviral signaling by interacting with MAVS and promoting USP10-RIG-I complex disruption to drive RIG-I proteasomal degradation, and modulates inflammatory signaling in multiple immune cell types (mast cells, eosinophils, T cells, B cells) through Ca²⁺, NF-κB/AKT, and UPR-autophagy pathways, with its transcription regulated by STAT6, CREB/PKA, p300-mediated histone acetylation, Ets-1, IRF-3, and STING-TBK1 signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ORMDL3 is an endoplasmic reticulum-resident transmembrane protein that serves as a central homeostatic regulator of sphingolipid metabolism and ER stress signaling, with broad consequences for immune cell activation, airway remodeling, and innate antiviral defense. ORMDL3 forms stable complexes with serine palmitoyltransferase (SPT) to negatively regulate de novo sphingolipid biosynthesis and interacts with SERCA to reduce ER Ca²⁺ stores, thereby selectively activating the ATF6 branch of the unfolded protein response and downstream autophagy through ATF6–Beclin-1 signaling [PMID:25691431, PMID:19819884, PMID:23011799, PMID:28747345]. Through these ER stress and sphingolipid pathways, ORMDL3 modulates FcεRI-triggered NF-κB/AKT signaling in mast cells, NFAT-dependent T cell activation via CRAC channel regulation, B cell survival, eosinophil trafficking, and NLRP3 inflammasome activation by promoting ER–mitochondria contacts through interaction with the mitochondrial fission factor Fis-1 [PMID:26407610, PMID:23100328, PMID:24056518, PMID:38417794]. ORMDL3 also suppresses innate antiviral type I interferon signaling by interacting with MAVS and promoting USP10–RIG-I complex disruption, leading to proteasomal degradation of RIG-I [PMID:40126553].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"The genetic basis of ORMDL3 in disease was established when cis-regulatory SNPs at 17q21 were found to control ORMDL3 expression and associate with childhood asthma, identifying ORMDL3 as a disease-relevant ER transmembrane protein whose expression level matters functionally.\",\n      \"evidence\": \"GWAS with eQTL mapping in lymphoblastoid cell lines across multiple cohorts\",\n      \"pmids\": [\"17611496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal variant(s) within the haplotype not pinpointed\", \"Mechanism by which expression level alters disease risk unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A key molecular mechanism was uncovered when ORMDL3 was shown to inhibit SERCA, depleting ER Ca²⁺ stores, raising cytosolic Ca²⁺, and triggering the UPR — establishing ORMDL3 as a regulator of ER calcium homeostasis.\",\n      \"evidence\": \"Overexpression, siRNA knockdown, Ca²⁺ imaging, and SERCA co-expression rescue in cell lines\",\n      \"pmids\": [\"19819884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface between ORMDL3 and SERCA not mapped\", \"Stoichiometry and selectivity for SERCA isoforms undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The UPR branch selectivity and transcriptional regulation of ORMDL3 were defined: ORMDL3 selectively activates ATF6 (not IRE1/PERK) in airway epithelium, and its own transcription is driven cooperatively by Ets-1/CREB/p300 at the proximal promoter and by STAT6 upon IL-4/IL-13 signaling.\",\n      \"evidence\": \"ATF6α siRNA epistasis in bronchial epithelial cells; STAT6-KO mice; 5'-RACE, deletion reporter assays, sequential ChIP, EMSA for promoter elements\",\n      \"pmids\": [\"23011799\", \"22546552\", \"23461825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATF6 selectivity is achieved at the molecular level is unknown\", \"Relative contribution of each transcription factor in different cell types not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"ORMDL3's role in adaptive immunity was established through its regulation of CRAC channels and NFAT signaling: ORMDL3 inhibits mitochondrial Ca²⁺ uptake, thereby reducing store-operated Ca²⁺ entry, NFAT nuclear translocation, and IL-2 production in T cells.\",\n      \"evidence\": \"Patch-clamp I_CRAC measurement, SOCE assays, NFAT reporter, and IL-2 quantification with ORMDL3 overexpression and knockdown in T lymphocytes\",\n      \"pmids\": [\"23100328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target mediating mitochondrial Ca²⁺ uptake inhibition not identified\", \"Whether this operates through sphingolipid changes or direct protein interaction unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"ORMDL3 was shown to promote eosinophil trafficking through integrin upregulation, ERK1/2 activation, and NF-κB signaling, extending its immune modulatory role beyond lymphocytes to innate effector cells.\",\n      \"evidence\": \"Gain/loss-of-function in eosinophils with in vivo recruitment assays and surface marker FACS\",\n      \"pmids\": [\"24056518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether sphingolipid changes or ER stress mediates integrin upregulation in eosinophils not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The direct biochemical basis of ORMDL3's lipid regulatory function was defined: ORMDL3 forms stable complexes with SPT and negatively regulates de novo sphingolipid synthesis, though it exists in functional excess over SPT so modest overexpression alone does not further suppress synthesis.\",\n      \"evidence\": \"SPT activity assays, stable complex analysis, and sphingolipid mass spectrometry in HBECs and HeLa cells\",\n      \"pmids\": [\"25691431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ORMDL3–SPT interaction not resolved\", \"How ceramide sensing feeds back to ORMDL3-mediated SPT regulation not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"ORMDL3 was established as a negative regulator of FcεRI-mediated mast cell activation, restraining AKT/NF-κB signaling and proinflammatory cytokine release, with in vivo validation in anaphylaxis models.\",\n      \"evidence\": \"ORMDL3 siRNA knockdown and overexpression in mast cells; Western blot for AKT/IκBα/NF-κB; passive cutaneous anaphylaxis model\",\n      \"pmids\": [\"26407610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mast cell effects are ceramide-dependent, Ca²⁺-dependent, or both not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Tissue-specific functions were dissected: epithelial ORMDL3 knockout paradoxically increased AHR through elevated S1P driving ASM contractility, while ORMDL3 overexpression in ASM increased proliferation and contractility via Ca²⁺/Orai1/SERCA2b, revealing opposing roles in different compartments.\",\n      \"evidence\": \"Epithelial-specific conditional KO with S1P mass spectrometry; ASM-specific transgenic mice with Ca²⁺ imaging and contractility assays\",\n      \"pmids\": [\"28275141\", \"28889952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which epithelial ORMDL3 loss elevates S1P not fully elucidated\", \"Relative in vivo contribution of epithelial vs. smooth muscle ORMDL3 to airway disease unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"ORMDL3 was shown to promote B cell survival through an ATF6α–Beclin-1 autophagy axis, as Ormdl3 KO mice displayed reduced mature B cells, impaired immunoglobulin secretion, and increased apoptosis.\",\n      \"evidence\": \"Ormdl3 KO mice; flow cytometry; ELISA for Ig; ATF6 knockdown epistasis; autophagy marker analysis\",\n      \"pmids\": [\"28747345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether B cell defects are cell-autonomous or reflect altered microenvironment not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A novel lipid-metabolism interaction was revealed: ORMDL3 physically associates with S1P lyase (S1PL) and facilitates AhR-ligand-induced oxidative inactivation of S1PL at Cys317, thereby promoting S1P accumulation.\",\n      \"evidence\": \"FRET and Co-IP for ORMDL3–S1PL interaction; C317A mutant; S1PL activity assay; mast cell degranulation; in vivo lung exposure\",\n      \"pmids\": [\"29572542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of ORMDL3–S1PL interaction unknown\", \"Whether this mechanism operates in all ORMDL3-expressing cell types not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"In vivo lipidomic studies confirmed ORMDL3 regulates systemic ceramide levels — overexpression decreases and deficiency increases ceramides — but dissociated this from canonical Th2 asthma features, challenging a simple ceramide-driven asthma model.\",\n      \"evidence\": \"Ormdl3 transgenic and KO mice with mass spectrometry sphingolipidomics across multiple allergen challenge models\",\n      \"pmids\": [\"31330218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Alternative lipid species (S1P, leukotrienes) as disease mediators not fully evaluated in this study\", \"Human relevance of dissociation between ceramide and asthma phenotype unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ORMDL3's regulatory scope was extended to lipid mediator crosstalk and mast cell effector functions: ORMDL3 physically interacts with 5-lipoxygenase at the ER, and its deficiency increases both sphingolipid and leukotriene production, while double ORMDL2/3 KO further amplifies these effects and potentiates IgE-mediated degranulation.\",\n      \"evidence\": \"Co-IP for ORMDL3–5-LO; lipidomics of single and double KO mast cells; degranulation and anaphylaxis models\",\n      \"pmids\": [\"34560079\", \"33643282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for 5-LO inhibition by ORMDL3 not determined\", \"Relative contribution of sphingolipid vs. eicosanoid dysregulation to mast cell hyperactivation not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ASM-selective transgenic models refined the contractility mechanism: ORMDL3 induces ASM hypertrophy and hyperplasia through TPM1/TPM4 upregulation and increases contractility via elevated surface Orai1 and SERCA2b, providing downstream effectors for the calcium phenotype.\",\n      \"evidence\": \"Smooth-muscle-selective hORMDL3 transgenic mice; TPM1/TPM4 siRNA knockdown; Orai1 surface expression; Ca²⁺ imaging\",\n      \"pmids\": [\"33661765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional mechanism linking ORMDL3 to TPM1/TPM4 induction unknown\", \"Whether Orai1 surface increase is direct or secondary to ER stress not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ORMDL3 was discovered to relocalize to mitochondria-associated membranes during inflammation, where it interacts with Fis-1 to promote mitochondrial fragmentation, enhance ER–mitochondria contacts, and activate the NLRP3 inflammasome.\",\n      \"evidence\": \"Co-IP for ORMDL3–Fis1; mitochondrial morphology imaging; NLRP3 inflammasome and IL-1β assays in macrophages; DSS-colitis mouse model\",\n      \"pmids\": [\"38417794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering ORMDL3 relocalization to MAMs not identified\", \"Whether Fis-1 interaction requires sphingolipid changes unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A new immunoregulatory axis was revealed: ORMDL3 interacts with MAVS and promotes RIG-I degradation by disrupting the USP10–RIG-I deubiquitination complex, thereby suppressing type I IFN signaling; ORMDL3 inhibition enhances anti-tumor immunity.\",\n      \"evidence\": \"IP-MS identification of MAVS and USP10 as ORMDL3 interactors; Co-IP; K48-ubiquitination and RIG-I stability assays; syngeneic tumor models\",\n      \"pmids\": [\"40126553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ORMDL3–MAVS interaction is direct or bridged by other factors not established\", \"Therapeutic potential of ORMDL3 inhibition in tumors not tested beyond syngeneic models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis of ORMDL3's interactions with its multiple partners (SPT, SERCA, S1PL, 5-LO, Fis-1, MAVS), how ORMDL3 partitions between ER and MAM pools, and the extent to which its sphingolipid-dependent and sphingolipid-independent functions (Ca²⁺, UPR, RIG-I degradation) are mechanistically separable in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of ORMDL3 alone or in complex\", \"Sphingolipid-dependent vs. -independent functions not genetically separated in vivo\", \"Relative contribution of ORMDL3 vs. ORMDL1/2 paralogs to each function incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 7, 8, 13, 24]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [6, 7, 15, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 7, 20, 21]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 11, 13, 15, 16, 19, 20]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 3, 9, 14, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4, 8, 19, 24]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12, 18, 21, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 8, 24]}\n    ],\n    \"complexes\": [\n      \"SPT complex (SPTLC1/SPTLC2/ORMDL3)\"\n    ],\n    \"partners\": [\n      \"SPTLC1\",\n      \"SPTLC2\",\n      \"ATP2A2\",\n      \"SGPL1\",\n      \"ALOX5\",\n      \"FIS1\",\n      \"MAVS\",\n      \"USP10\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}