Affinage

ORMDL3

ORM1-like protein 3 · UniProt Q8N138

Length
153 aa
Mass
17.5 kDa
Annotated
2026-04-29
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2007 High

    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

    PMID:17611496

    Open questions at the time
    • Causal variant(s) within the haplotype not pinpointed
    • Mechanism by which expression level alters disease risk unknown
  2. 2010 High

    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

    PMID:19819884

    Open questions at the time
    • Direct binding interface between ORMDL3 and SERCA not mapped
    • Stoichiometry and selectivity for SERCA isoforms undefined
  3. 2012 High

    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

    PMID:22546552 PMID:23011799 PMID:23461825

    Open questions at the time
    • How ATF6 selectivity is achieved at the molecular level is unknown
    • Relative contribution of each transcription factor in different cell types not resolved
  4. 2012 High

    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

    PMID:23100328

    Open questions at the time
    • Molecular target mediating mitochondrial Ca²⁺ uptake inhibition not identified
    • Whether this operates through sphingolipid changes or direct protein interaction unclear
  5. 2013 High

    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

    PMID:24056518

    Open questions at the time
    • Whether sphingolipid changes or ER stress mediates integrin upregulation in eosinophils not dissected
  6. 2015 High

    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

    PMID:25691431

    Open questions at the time
    • Structural basis of ORMDL3–SPT interaction not resolved
    • How ceramide sensing feeds back to ORMDL3-mediated SPT regulation not established
  7. 2015 High

    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

    PMID:26407610

    Open questions at the time
    • Whether mast cell effects are ceramide-dependent, Ca²⁺-dependent, or both not separated
  8. 2017 High

    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

    PMID:28275141 PMID:28889952

    Open questions at the time
    • 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
  9. 2017 High

    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

    PMID:28747345

    Open questions at the time
    • Whether B cell defects are cell-autonomous or reflect altered microenvironment not determined
  10. 2018 High

    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

    PMID:29572542

    Open questions at the time
    • Structural details of ORMDL3–S1PL interaction unknown
    • Whether this mechanism operates in all ORMDL3-expressing cell types not tested
  11. 2019 High

    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

    PMID:31330218

    Open questions at the time
    • Alternative lipid species (S1P, leukotrienes) as disease mediators not fully evaluated in this study
    • Human relevance of dissociation between ceramide and asthma phenotype unclear
  12. 2021 High

    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

    PMID:33643282 PMID:34560079

    Open questions at the time
    • Structural basis for 5-LO inhibition by ORMDL3 not determined
    • Relative contribution of sphingolipid vs. eicosanoid dysregulation to mast cell hyperactivation not separated
  13. 2021 High

    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

    PMID:33661765

    Open questions at the time
    • Transcriptional mechanism linking ORMDL3 to TPM1/TPM4 induction unknown
    • Whether Orai1 surface increase is direct or secondary to ER stress not established
  14. 2024 High

    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

    PMID:38417794

    Open questions at the time
    • Signal triggering ORMDL3 relocalization to MAMs not identified
    • Whether Fis-1 interaction requires sphingolipid changes unclear
  15. 2025 High

    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

    PMID:40126553

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0008289 lipid binding 4
Localization
GO:0005783 endoplasmic reticulum 5 GO:0005739 mitochondrion 1
Pathway
R-HSA-1430728 Metabolism 7 R-HSA-168256 Immune System 5 R-HSA-8953897 Cellular responses to stimuli 5 R-HSA-9612973 Autophagy 4 R-HSA-162582 Signal Transduction 3
Partners
ALOX5ATP2A2FIS1MAVSSGPL1SPTLC1SPTLC2USP10
Complex memberships
SPT complex (SPTLC1/SPTLC2/ORMDL3)

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 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. Genome-wide association study with systematic eQTL mapping in lymphoblastoid cell lines Nature High 17611496
2010 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. Heterologous overexpression and siRNA knockdown in cell lines with Ca²⁺ imaging; co-expression rescue experiments Human molecular genetics High 19819884
2012 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. Patch-clamp electrophysiology (I_CRAC measurement), SOCE assays, NFAT reporter, IL-2 measurement with ORMDL3 overexpression and knockdown Human molecular genetics High 23100328
2012 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. ORMDL3 transfection in bronchial epithelial cells; siRNA knockdown of ATF6α; STAT6-deficient mouse model; qPCR and protein quantification Proceedings of the National Academy of Sciences of the United States of America High 23011799
2013 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. ORMDL3 overexpression and siRNA knockdown in eosinophils; in vivo recruitment assay; FACS for surface markers; immunofluorescence for cytoskeletal changes Nature communications High 24056518
2014 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. Transgenic mouse model (cre-lox overexpression), methacholine challenge, histology, qPCR/Western blot for UPR branch markers Journal of immunology High 24623133
2015 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. In vitro ORMDL3 overexpression in epithelial cells and macrophages; lipidomic analysis; in vivo house dust mite asthma model The Journal of allergy and clinical immunology High 25842287
2015 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. SPT activity assays, stable complex analysis, sphingolipid mass spectrometry in HBECs and HeLa cells with ORMDL3 overexpression Journal of lipid research High 25691431
2015 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. ORMDL3 siRNA knockdown and overexpression in mast cells; Western blot for signaling intermediates; ELISA for cytokines; in vivo passive cutaneous anaphylaxis model with siRNA Cellular and molecular life sciences High 26407610
2016 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. Ormdl3 knockout mice; adeno-associated viral vector epithelial reconstitution; Alternaria challenge; lung function, eosinophilia, UPR pathway markers The Journal of allergy and clinical immunology High 27623174
2017 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. ORMDL3 transfection of ASM cells; precision-cut lung slice contractility assay; Ca²⁺ imaging; BrdU proliferation assay; hORMDL3Zp3-Cre transgenic mouse ASM analysis The Journal of allergy and clinical immunology High 28889952
2017 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. 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 of immunology High 28275141
2017 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. 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 of immunology High 28747345
2018 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. FRET analysis; Co-IP; S1PL activity assay; ORMDL3 knockdown; C317A S1PL mutant; mast cell degranulation assays; mouse lung exposures Cellular & molecular immunology High 29572542
2019 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. ORMDL3 siRNA knockdown and overexpression in A549 and primary NHBE cells; cytokine ELISA; transcript profiling; SPT inhibitor (myriocin); metabolite analysis American journal of respiratory and critical care medicine High 30339462
2019 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. Ormdl3 transgenic and KO mice; mass spectrometry-based sphingolipidomics; HDM and Alternaria challenge models; lung function, cytokine, and immunoglobulin measurement The Journal of allergy and clinical immunology High 31330218
2019 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. Ormdl3-/- mice; cold exposure and β3-agonist treatment; mass spectrometry lipidomics; UCP1 expression; ceramide inhibitor rescue experiment Molecular metabolism High 34954108
2021 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. Smooth-muscle-selective ORMDL3 transgenic mice (hORMDL3Myh11eGFP-cre); FACS, BrdU incorporation, Ca²⁺ imaging, Orai1 surface expression, in vitro histamine contractility; TPM1/TPM4 siRNA JCI insight High 33661765
2021 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. ORMDL3 overexpression and knockdown in MC/9 cells; ATF6 knockdown; autophagy inhibition; degranulation assay; ELISA; passive cutaneous anaphylaxis in vivo Frontiers in immunology High 33679742
2021 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. Single and double Ormdl2/Ormdl3 KO mice; sphingolipid mass spectrometry; degranulation assays; cytokine ELISA; passive cutaneous and systemic anaphylaxis models Frontiers in immunology High 33643282
2021 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. Co-IP/physical interaction assays; lipidomic analysis of ORMDL3 KO mast cells; 5-LO and SPTLC1 siRNA knockdown; immunofluorescence colocalization Journal of lipid research High 34560079
2021 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. 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 American journal of respiratory cell and molecular biology High 35353673
2021 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. 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 The Journal of allergy and clinical immunology High 34624393
2024 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. 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 The Journal of biological chemistry High 38417794
2025 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. 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 eLife High 40126553
2013 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. Luciferase reporter assays; EMSA; ChIP and Re-ChIP; STAT6 overexpression and siRNA knockdown; Co-IP The FEBS journal High 23461825
2012 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. 5'-RACE; deletion luciferase reporter assays; mutational analysis; RNAi; sequential ChIP (Re-ChIP); RT-PCR of patient samples The international journal of biochemistry & cell biology High 22546552
2013 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. Deletion luciferase reporter assays; EMSA; ChIP; CREB overexpression and knockdown; PKA activator/inhibitor treatments in NIH3T3 cells PloS one High 23577138
2017 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. EMSA; ChIP; luciferase reporter with mutational analysis; IRF-3 overexpression and RNAi; patient peripheral blood lymphocyte samples The international journal of biochemistry & cell biology High 28336364
2015 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. Luciferase reporter assays; qRT-PCR; Cbl-b overexpression; ChIP; STAT6 phosphorylation Western blot; patient peripheral blood samples FEBS letters Medium 26112603
2019 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. Luciferase reporter with p300 WT and HAT-deletion plasmids; ChIP for p300 and aceH3; OVA mouse model; C646 treatment; Western blot and IHC International immunopharmacology High 31536903
2018 STING promotes ORMDL3 transcription through TBK1-mediated phosphorylation of IRF3 and STAT6, which then form a complex that binds to the ORMDL3 promoter. Luciferase reporter assays; Co-IP; ChIP; siRNA knockdown of STING, TBK1, IRF3, STAT6; patient sample correlation Experimental cell research Medium 30009792
2023 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. APPswe/PS1dE9 mouse model; BV-2 cell model; ORMDL3 knockdown; ferroptosis and oxidative stress markers; Western blot for PERK/ATF4/HSPA5 pathway IET nanobiotechnology Medium 36680386
2019 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. ORMDL3 siRNA knockdown in endothelial cells; Western blot for BECN1 and autophagy markers; cell death assays; ox-LDL stimulation Scientific reports Medium 26603569
2017 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. hORMDL3zp3-Cre transgenic mice; RV infection; qRT-PCR for viral load; bronchoalveolar lavage cell counts; RNaseL-deficient mice; IFN measurement Journal of immunology Medium 28827284
2019 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. ORMDL3 overexpression in 16HBE cells; TEER measurement; SPHK1 activity assay; ERK phosphorylation Western blot; SPHK1 inhibitor; in vivo OVA-RSV mouse model International journal of molecular medicine Medium 31173170
2021 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. ORMDL3 knock-in transgenic mouse macrophages; gene expression analysis; phagocytosis assays; TLR4-induced autophagy assay; mass spectrometry lipidomics International journal of molecular sciences Medium 30897694

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 1220 17611496
2009 Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. American journal of human genetics 244 19732864
2010 The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Human molecular genetics 218 19819884
2008 ORMDL3 gene is associated with asthma in three ethnically diverse populations. American journal of respiratory and critical care medicine 205 18310477
2012 ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6. Proceedings of the National Academy of Sciences of the United States of America 168 23011799
2014 ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma. Journal of immunology (Baltimore, Md. : 1950) 147 24623133
2008 A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. The Journal of allergy and clinical immunology 125 18395550
2015 Aberrant ORM (yeast)-like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice. The Journal of allergy and clinical immunology 107 25842287
2008 Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma. Allergy 103 19133921
2013 ORMDL3 promotes eosinophil trafficking and activation via regulation of integrins and CD48. Nature communications 98 24056518
2010 Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia. European journal of human genetics : EJHG 98 21150878
2017 Chromosome 17q21 Genes ORMDL3 and GSDMB in Asthma and Immune Diseases. Advances in immunology 97 28826527
2017 Upregulation of miR-665 promotes apoptosis and colitis in inflammatory bowel disease by repressing the endoplasmic reticulum stress components XBP1 and ORMDL3. Cell death & disease 80 28333149
2012 ORMDL3 modulates store-operated calcium entry and lymphocyte activation. Human molecular genetics 76 23100328
2016 Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease. The Journal of allergy and clinical immunology 72 27623174
2019 The ORMDL3 Asthma Gene Regulates ICAM1 and Has Multiple Effects on Cellular Inflammation. American journal of respiratory and critical care medicine 70 30339462
2019 ORMDL3 and allergic asthma: From physiology to pathology. The Journal of allergy and clinical immunology 69 31376405
2014 Risk of childhood asthma is associated with CpG-site polymorphisms, regional DNA methylation and mRNA levels at the GSDMB/ORMDL3 locus. Human molecular genetics 65 25256354
2017 Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma. The Journal of allergy and clinical immunology 64 28889952
2015 Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels. The Journal of allergy and clinical immunology 62 25930191
2015 ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis. Journal of lipid research 58 25691431
2017 Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate. Journal of immunology (Baltimore, Md. : 1950) 46 28275141
2014 The Association of GSDMB and ORMDL3 Gene Polymorphisms With Asthma: A Meta-Analysis. Allergy, asthma & immunology research 46 25729625
2012 GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness. Human immunology 44 22732088
2013 Functional analysis of the impact of ORMDL3 expression on inflammation and activation of the unfolded protein response in human airway epithelial cells. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 42 23369242
2013 17q21 locus and ORMDL3: an increased risk for childhood asthma. Pediatric research 36 24165737
2019 The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice. The Journal of allergy and clinical immunology 35 31330218
2020 ORMDL3 and Asthma: Linking Sphingolipid Regulation to Altered T Cell Function. Frontiers in immunology 31 33424845
2017 ORMDL3 Facilitates the Survival of Splenic B Cells via an ATF6α-Endoplasmic Reticulum Stress-Beclin1 Autophagy Regulatory Pathway. Journal of immunology (Baltimore, Md. : 1950) 30 28747345
2017 Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis. Scientific reports 29 28588209
2020 Long noncoding RNA SOX21-AS1 regulates the progression of triple-negative breast cancer through regulation of miR-520a-5p/ORMDL3 axis. Journal of cellular biochemistry 27 32277517
2015 ORMDL3 contributes to the risk of atherosclerosis in Chinese Han population and mediates oxidized low-density lipoprotein-induced autophagy in endothelial cells. Scientific reports 27 26603569
2012 Mechanisms elevating ORMDL3 expression in recurrent wheeze patients: role of Ets-1, p300 and CREB. The international journal of biochemistry & cell biology 27 22546552
2017 ORMDL3 is associated with airway remodeling in asthma via the ERK/MMP-9 pathway. Molecular medicine reports 26 28358425
2015 Negative regulatory roles of ORMDL3 in the FcεRI-triggered expression of proinflammatory mediators and chemotactic response in murine mast cells. Cellular and molecular life sciences : CMLS 26 26407610
2021 ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation via an ATF6-UPR-Autophagy-Dependent Pathway. Frontiers in immunology 23 33679742
2018 Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase. Cellular & molecular immunology 23 29572542
2013 Signal transducer and activator of transcription 6 directly regulates human ORMDL3 expression. The FEBS journal 23 23461825
2011 Association of ORMDL3, STAT6 and TBXA2R gene polymorphisms with asthma. International journal of immunogenetics 23 22017802
2017 Sphingolipids, ORMDL3 and asthma: what is the evidence? Current opinion in clinical nutrition and metabolic care 22 28030368
2017 Association of ORMDL3 with rhinovirus-induced endoplasmic reticulum stress and type I Interferon responses in human leucocytes. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 22 28192616
2021 Single cell sequencing analysis identifies genetics-modulated ORMDL3+ cholangiocytes having higher metabolic effects on primary biliary cholangitis. Journal of nanobiotechnology 20 34872583
2021 ORMDL3 regulates cigarette smoke-induced endoplasmic reticulum stress in airway smooth muscle cells. The Journal of allergy and clinical immunology 19 34624393
2020 ORMDL3/GSDMB genotype as a risk factor for early-onset adult asthma is linked to total serum IgE levels but not to allergic sensitization. Allergology international : official journal of the Japanese Society of Allergology 18 32444308
2013 A polymorphism in ORMDL3 is associated not only with asthma without rhinitis but also with chronic obstructive pulmonary disease. Journal of investigational allergology & clinical immunology 18 23964555
2021 Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation. Molecular metabolism 17 34954108
2020 MiR-200a and miR-200b restrain inflammation by targeting ORMDL3 to regulate the ERK/MMP-9 pathway in asthma. Experimental lung research 17 32820688
2019 Investigating the regulatory role of ORMDL3 in airway barrier dysfunction using in vivo and in vitro models. International journal of molecular medicine 17 31173170
2019 ORMDL3 knockdown in the lungs alleviates airway inflammation and airway remodeling in asthmatic mice via JNK1/2-MMP-9 pathway. Biochemical and biophysical research communications 17 31255288
2022 Asthma Susceptibility Gene ORMDL3 Promotes Autophagy in Human Bronchial Epithelium. American journal of respiratory cell and molecular biology 15 35353673
2018 ORMDL3 and its implication in inflammatory disorders. International journal of rheumatic diseases 15 29879314
2013 Promoter characterization and role of cAMP/PKA/CREB in the basal transcription of the mouse ORMDL3 gene. PloS one 15 23577138
2019 p300 mediates the histone acetylation of ORMDL3 to affect airway inflammation and remodeling in asthma. International immunopharmacology 14 31536903
2017 Mechanisms and roles by which IRF-3 mediates the regulation of ORMDL3 transcription in respiratory syncytial virus infection. The international journal of biochemistry & cell biology 14 28336364
2023 Neutrophilia in severe asthma is reduced in Ormdl3 overexpressing mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 13 36753412
2021 ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling. Frontiers in immunology 13 33643282
2019 Ceramide Imbalance and Impaired TLR4-Mediated Autophagy in BMDM of an ORMDL3-Overexpressing Mouse Model. International journal of molecular sciences 13 30897694
2019 The role of ORMDL3/ATF6 in compensated beta cell proliferation during early diabetes. Aging 13 31061237
2017 ORMDL3 may participate in the pathogenesis of bronchial epithelial‑mesenchymal transition in asthmatic mice with airway remodeling. Molecular medicine reports 13 29115563
2021 ORMDL3 expression in ASM regulates hypertrophy, hyperplasia via TPM1 and TPM4, and contractility. JCI insight 12 33661765
2018 Single nucleotide polymorphisms in asthma candidate genes TBXA2R, ADAM33 FCER1B and ORMDL3 in Pakistani asthmatics a case control study. Asthma research and practice 12 29588858
2017 Rhinovirus Infection of ORMDL3 Transgenic Mice Is Associated with Reduced Rhinovirus Viral Load and Airway Inflammation. Journal of immunology (Baltimore, Md. : 1950) 12 28827284
2024 ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome. The Journal of biological chemistry 10 38417794
2023 The inhibition of ORMDL3 prevents Alzheimer's disease through ferroptosis by PERK/ATF4/HSPA5 pathway. IET nanobiotechnology 10 36680386
2022 ORMDL3 Promotes Angiogenesis in Chronic Asthma Through the ERK1/2/VEGF/MMP-9 Pathway. Frontiers in pediatrics 10 35252072
2020 At last - linking ORMDL3 polymorphisms, decreased sphingolipid synthesis, and asthma susceptibility. The Journal of clinical investigation 10 31929192
2018 Methylation status of ORMDL3 regulates cytokine production and p-ERK/MMP9 pathway expression. Experimental cell research 10 30217493
2015 Correlation between the genetic polymorphism of ORMDL3 gene and asthma risk: a meta-analysis. Genetics and molecular research : GMR 9 26125920
2023 Histone acetylation regulates ORMDL3 expression-mediated NLRP3 inflammasome overexpression during RSV-allergic exacerbation mice. Journal of cellular physiology 8 37877592
2021 Crosstalk between ORMDL3, serine palmitoyltransferase, and 5-lipoxygenase in the sphingolipid and eicosanoid metabolic pathways. Journal of lipid research 8 34560079
2016 Associations between NOD2, IRGM and ORMDL3 polymorphisms and pediatric-onset inflammatory bowel disease in the Lithuanian population. Medicina (Kaunas, Lithuania) 8 27932194
2015 E3 ubiquitin ligase Cbl-b suppresses human ORMDL3 expression through STAT6 mediation. FEBS letters 8 26112603
2014 Genetic variation in ORMDL3 gene may contribute to the risk of asthma: a meta-analysis. Human immunology 8 25167772
2023 Evaluation of the association between clinical parameters and ADAM33 and ORMDL3 asthma gene single-nucleotide polymorphisms with the severity of COVID-19. International immunopharmacology 7 37499392
2023 From gene identifications to therapeutic targets for asthma: Focus on great potentials of TSLP, ORMDL3, and GSDMB. Chinese medical journal pulmonary and critical care medicine 7 39171126
2020 Increased expression of serine palmitoyl transferase and ORMDL3 polymorphism are associated with eosinophilic inflammation and airflow limitation in aspirin-exacerbated respiratory disease. PloS one 7 33031402
2013 All-trans retinoic acid modulates ORMDL3 expression via transcriptional regulation. PloS one 7 24204796
2008 ORMDL3--guilt by association? Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 7 18754760
2023 ORMDL3‑mediated bronchial epithelial pyroptosis leads to lung inflammation in obese mice with asthma. Molecular medicine reports 6 37594074
2021 ORMDL3 overexpression facilitates FcεRI-mediated transcription of proinflammatory cytokines and thapsigargin-mediated PERK phosphorylation in RBL-2H3 cells. Immunity, inflammation and disease 6 34288557
2021 Single-base editing of rs12603332 on chromosome 17q21 with a cytosine base editor regulates ORMDL3 and ATF6α expression. Allergy 6 34525218
2018 Correction to: Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase. Cellular & molecular immunology 6 29769657
2011 Characterization of a novel isoform of the human ORMDL3 gene. Cell and tissue research 6 22015541
2024 Simultaneous deletion of ORMDL1 and ORMDL3 proteins disrupts immune cell homeostasis. Frontiers in immunology 5 38715613
2023 A Common Functional Variant at the Enhancer of the Rheumatoid Arthritis Risk Gene ORMDL3 Regulates its Expression Through Allele-Specific JunD Binding. Phenomics (Cham, Switzerland) 5 37881318
2021 ORMDL3 regulates poly I:C induced inflammatory responses in airway epithelial cells. BMC pulmonary medicine 5 34001091
2020 Treatment of Allergic Asthma with Fenretinide Formulation (LAU-7b) Downregulates ORMDL Sphingolipid Biosynthesis Regulator 3 (Ormdl3) Expression and Normalizes Ceramide Imbalance. The Journal of pharmacology and experimental therapeutics 5 32273303
2018 STING positively regulates human ORMDL3 expression through TBK1-IRF3-STAT6 complex mediation. Experimental cell research 5 30009792
2016 Benomyl-induced effects of ORMDL3 overexpression via oxidative stress in human bronchial epithelial cells. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 5 27784618
2015 Association between ORMDL3 polymorphism and susceptibility to asthma: a meta-analysis. International journal of clinical and experimental medicine 5 26064206
2022 Increased expression of ORMDL3 in allergic asthma: a case control and in vitro study. The Journal of asthma : official journal of the Association for the Care of Asthma 4 35321632
2019 Regulatory interaction between the ZPBP2-ORMDL3/Zpbp2-Ormdl3 region and the circadian clock. PloS one 4 31560728
2014 [Down-regulatory effects of budesonide on expression of STAT6 and ORMDL3 in lung tissues of asthmatic mice]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 4 24568918
2025 ORMDL3 restrains type I interferon signaling and anti-tumor immunity by promoting RIG-I degradation. eLife 3 40126553
2023 Overexpression of ORMDL3 confers sexual dimorphism in diet-induced non-alcoholic steatohepatitis. Molecular metabolism 3 38081412
2020 ORMDL3 modulates airway epithelial cell repair in children with asthma under glucocorticoid treatment via regulating IL-33. Pulmonary pharmacology & therapeutics 3 33035699
2019 Association between peripheral blood mononuclear cell ORMDL3 expression and the asthma predictive index in preschool children. The Journal of international medical research 3 31342811
2015 ORMDL3 variants associated with bronchiolitis susceptibility in a Chinese population. Genetics and molecular research : GMR 3 26782568
2023 Ormdl3 regulation of specific ceramides is dispensable for mouse β-cell function and glucose homeostasis under obesogenic conditions. Frontiers in endocrinology 2 37124760
2023 Association of childhood asthma with Gasdermin B (GSDMB) and Oromucoid-like 3 (ORMDL3) genes. Northern clinics of Istanbul 2 38328715