Affinage

ERN2

Serine/threonine-protein kinase/endoribonuclease IRE2 · UniProt Q76MJ5

Length
926 aa
Mass
102.5 kDa
Annotated
2026-06-09
35 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERN2 (IRE1β) is a mucosal epithelial-restricted ER stress sensor with dual kinase/endoribonuclease activity that governs lipid handling and mucus production in the intestine and airway (PMID:18460335, PMID:35727638). In enterocytes it selectively accelerates degradation of MTP mRNA to restrain microsomal triglyceride transfer protein levels and thereby limit chylomicron assembly, an activity not shared by the ubiquitous homolog IRE1α; loss of ERN2 raises intestinal MTP, lipid absorption, and atherosclerotic burden in vivo (PMID:18460335, PMID:22556338). In its other principal role, ERN2 splices XBP1 mRNA to generate XBP1S, expanding ER capacity to support goblet cell maturation and mucus barrier assembly in response to gut microbiota, with ERN2 loss producing dysbiosis and colitis susceptibility (PMID:35727638). In airway epithelia ERN2 acts downstream of IL-1β and the transcription factor SPDEF, and via XBP1S, which binds the proximal MUC5B promoter, drives MUC5B and MUC5AC mucin expression contributing to mucus hyperconcentration in cystic fibrosis (PMID:31524632, PMID:30973754). Its RNase activity additionally mediates a physical interaction with AGR2 that promotes MUC5AC hypersecretion in neutrophilic asthma (PMID:41483622). ERN2 is a SPDEF target gene also implicated in mucus production in pancreatic ductal adenocarcinoma differentiation (PMID:38262672), and together with IRE1α it suppresses colorectal tumorigenesis (PMID:40654814).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2008 High

    Established a tissue-specific catabolic function for ERN2 distinct from IRE1α: it post-transcriptionally degrades MTP mRNA in enterocytes to limit chylomicron production.

    Evidence Ire1b−/− mice, primary enterocyte knockdown, mRNA stability and lipid secretion assays

    PMID:18460335

    Open questions at the time
    • Whether MTP mRNA is a direct RNase cleavage substrate was not biochemically resolved
    • Mechanism of substrate selectivity over IRE1α not defined
  2. 2012 High

    Confirmed the physiological consequence of ERN2-mediated MTP regulation by linking its loss to enhanced lipid absorption and atherosclerosis in vivo.

    Evidence Ire1b−/−/Apoe−/− double-knockout mice, lipid absorption and plaque quantification

    PMID:22556338

    Open questions at the time
    • Does not establish the molecular trigger for ERN2 activation in enterocytes
    • Tissue-autonomy of the effect not dissected
  3. 2019 High

    Placed ERN2 in an airway mucin-induction pathway downstream of IL-1β and SPDEF and identified XBP1S as the effector binding the MUC5B promoter, defining how ER stress signaling drives mucin gene expression.

    Evidence Primary HBE cells, CF tissue, transgenic mice, MUC5B promoter reporters/ChIP, KIRA6 inhibition, XBP1 CRISPR KO

    PMID:30973754 PMID:31524632

    Open questions at the time
    • How IL-1β/SPDEF signaling activates ERN2 RNase activity not resolved
    • MUC5AC regulation mechanism less defined than MUC5B
  4. 2022 High

    Demonstrated that microbiota induce ERN2-dependent XBP1 splicing to expand ER function for goblet cell maturation and mucus barrier assembly, and that IRE1α cannot substitute in this context.

    Evidence Ern2−/− conventional and germ-free mice, colonization experiments, Xbp1 splicing assays, goblet cell histology, colitis transfer

    PMID:35727638

    Open questions at the time
    • Microbial signal and receptor activating ERN2 not identified
    • Basis for non-redundancy with ERN1 unexplained
  5. 2024 Medium

    Extended the SPDEF-ERN2-mucus axis to disease by identifying ERN2 as a SPDEF target supporting classical PDA differentiation and tumor growth.

    Evidence Mouse PDA models, organoids, orthotopic grafts, single-cell profiling

    PMID:38262672

    Open questions at the time
    • ERN2-specific molecular mechanism in PDA not isolated from AGR2
    • Causal contribution of ERN2 vs other SPDEF targets not separated
  6. 2024 Medium

    Showed that inflammatory TNF signaling in Paneth cells transcriptionally suppresses Ern1/Ern2 to abolish steady-state UPR, linking ERN2 downregulation to antimicrobial defense failure and sepsis.

    Evidence Paneth-cell P55-deletion and IFNAR1-deficient mice, antimicrobial peptide and bacterial translocation assays

    PMID:39243761

    Open questions at the time
    • ERN2-only contribution not isolated from co-downregulated Ern1
    • Direct RNase targets in Paneth cells not identified
  7. 2026 Medium

    Identified a physical ERN2-AGR2 interaction as the effector arm of an ERN2/XBP1-AGR2 axis driving MUC5AC hypersecretion in neutrophilic asthma.

    Evidence NA mouse model, HBE135-E6E7 ER stress model, lentiviral ERN2 knockdown, 4μ8C inhibitor, Co-IP, molecular dynamics simulation

    PMID:41483622

    Open questions at the time
    • Co-IP not reciprocally validated and interaction interface inferred from simulation
    • Whether the interaction depends on ERN2 catalytic activity not directly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The upstream activating signals and the direct RNase substrate repertoire that distinguish ERN2 from IRE1α across mucosal tissues remain undefined.
  • No structural model of ERN2 substrate recognition in the corpus
  • Determinants of MTP mRNA versus XBP1 mRNA selectivity unresolved
  • Mechanism of ERN2-specific activation by microbiota and cytokines unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 3 GO:0003723 RNA binding 2 GO:0140299 molecular sensor activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
AGR2XBP1

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 IRE1β (ERN2) selectively degrades MTP (microsomal triglyceride transfer protein) mRNA through increased posttranscriptional degradation in enterocytes, thereby inhibiting chylomicron production. This activity is specific to IRE1β and not shared by its ubiquitous homolog IRE1α. Knockdown of IRE1β enhanced MTP expression, and Ire1b−/− mice fed high-fat/cholesterol diets secreted more chylomicrons and expressed more intestinal MTP. Ire1b−/− mouse model, primary enterocyte isolation, cell culture knockdown, mRNA stability assays, lipid secretion measurements Cell metabolism High 18460335
2012 Loss of Ire1β in Apoe−/− mice results in increased intestinal MTP expression, enhanced lipid absorption, hyperlipidemia, and greater atherosclerotic plaque burden compared to Apoe−/− controls, confirming that ERN2/IRE1β regulates intestinal lipid absorption in vivo. Ire1b−/−/Apoe−/− double-knockout mouse model, lipid absorption assays, atherosclerotic plaque quantification, intestinal MTP protein measurement Circulation research High 22556338
2019 ERN2/IRE1β acts downstream of IL-1β and the transcription factor SPDEF in airway epithelial cells to upregulate mucin gene expression (MUC5B and MUC5AC), contributing to mucus hyperconcentration in cystic fibrosis airways. Human bronchial epithelial (HBE) cell cultures, CF lung tissue mRNA analysis, cytokine stimulation experiments, gene expression analysis The Journal of clinical investigation Medium 31524632
2019 ERN2/IRE1β acts as an ER stress sensor that, through its downstream effector spliced XBP1 (XBP1S), regulates MUC5B and MUC5AC expression in airway epithelia. XBP1S binds the proximal MUC5B promoter and differentially upregulates MUC5B in the context of the rs35705950 risk variant. KIRA6 (IRE1 kinase inhibitor) and XBP1 CRISPR-Cas9 knockout blocked cytokine-induced MUC5B expression. Primary human airway epithelial cells, transgenic mouse models, XBP1S overexpression, MUC5B promoter reporter assays, KIRA6 inhibitor, CRISPR-Cas9 XBP1 knockout, ChIP/binding assays American journal of respiratory and critical care medicine High 30973754
2022 ERN2/IRE1β is required for microbiota-induced goblet cell maturation and mucus barrier assembly in the colon. ERN2 acts by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Although ERN1 can also splice Xbp1, it did not act redundantly with ERN2 in this context. Loss of ERN2 resulted in dysbiotic microbiota and increased susceptibility to colitis. Ern2−/− mice (conventionally raised and germ-free), germ-free colonization experiments, Xbp1 mRNA splicing assays, histological analysis of goblet cells, colitis susceptibility transfer experiments The Journal of clinical investigation High 35727638
2024 The transcription factor SPDEF promotes classical pancreatic ductal adenocarcinoma differentiation through target genes AGR2 and ERN2/IRE1β that regulate mucus production. Inactivation of the SPDEF programme impairs tumor growth and facilitates subtype interconversion from classical towards basal-like differentiation. Mouse PDA models, organoids, cell lines, orthotopically grafted tumor models, immunolabeling, single-cell expression profiling Gut Medium 38262672
2025 IRE1α and IRE1β protect intestinal epithelium and suppress colorectal tumorigenesis through distinct mechanisms. IRE1α-mediated splicing of Xbp1 mRNA was maintained following Ire1β deletion but was abolished in double Ire1α−/−Ire1β−/− mice. Single deletion of either Ire1α or Ire1β produced a growth advantage increasing tumor burden in AOM-DSS and APCmin models, whereas double deletion caused progressive intestinal injury and tumorigenesis with loss of defense-associated mRNAs and gain of inflammatory mRNAs. Intestine-specific Ire1α deletion, germline Ire1β deletion, double-KO mice, RNA-Seq, AOM-DSS and APCmin tumorigenesis models, Xbp1 splicing assays bioRxivpreprint Medium 40654814
2024 TNF signaling in Paneth cells transcriptionally downregulates Ern1 and Ern2 (IRE1 key UPR mediators), abolishing steady-state UPR, causing reduced antimicrobial peptide production and bacterial translocation leading to sepsis. This effect required TNF receptor P55 and IFNAR1. PC-specific P55 deletion mice, IFNAR1-deficient mice, gene expression analysis, antimicrobial peptide measurement, bacterial translocation assays Cell host & microbe Medium 39243761
2026 ERN2/IRE1β promotes mucus hypersecretion in neutrophilic asthma via the ERN2/XBP1-AGR2 axis, increasing MUC5AC secretion. Inhibiting ERN2 in vivo (with 4μ8C) and in vitro (lentiviral knockdown) reduced mucus secretion, ER stress markers, and inflammatory cytokines. The physical interaction between ERN2 and AGR2 was confirmed by Co-IP and molecular dynamics simulation. NA mouse model, HBE135-E6E7 cell ER stress model, lentivirus-mediated ERN2 knockdown, 4μ8C inhibitor, Co-immunoprecipitation, molecular dynamics simulation, BALF analysis International immunopharmacology Medium 41483622

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 IRE1/bZIP60-mediated unfolded protein response plays distinct roles in plant immunity and abiotic stress responses. PloS one 192 22359644
2007 AP2-ERF transcription factors mediate Nod factor dependent Mt ENOD11 activation in root hairs via a novel cis-regulatory motif. The Plant cell 153 17827349
2016 Activation of autophagy by unfolded proteins during endoplasmic reticulum stress. The Plant journal : for cell and molecular biology 140 26616142
2019 IL-1β dominates the promucin secretory cytokine profile in cystic fibrosis. The Journal of clinical investigation 119 31524632
2008 IRE1beta inhibits chylomicron production by selectively degrading MTP mRNA. Cell metabolism 108 18460335
2012 Medicago truncatula ERN transcription factors: regulatory interplay with NSP1/NSP2 GRAS factors and expression dynamics throughout rhizobial infection. Plant physiology 106 23077241
2019 XBP1S Regulates MUC5B in a Promoter Variant-Dependent Pathway in Idiopathic Pulmonary Fibrosis Airway Epithelia. American journal of respiratory and critical care medicine 67 30973754
2022 The epithelial-specific ER stress sensor ERN2/IRE1β enables host-microbiota crosstalk to affect colon goblet cell development. The Journal of clinical investigation 56 35727638
2022 Gene losses in the common vampire bat illuminate molecular adaptations to blood feeding. Science advances 47 35333583
2016 Divergence and Conservation of the Major UPR Branch IRE1-bZIP Signaling Pathway across Eukaryotes. Scientific reports 45 27256815
2016 The Symbiosis-Related ERN Transcription Factors Act in Concert to Coordinate Rhizobial Host Root Infection. Plant physiology 44 27208242
2021 Evolution of the unfolded protein response in plants. Plant, cell & environment 40 33840122
2019 A Functional Unfolded Protein Response Is Required for Normal Vegetative Development. Plant physiology 36 30710050
2018 Liver-directed microRNA-7a depletion induces nonalcoholic fatty liver disease by stabilizing YY1-mediated lipogenic pathways in zebrafish. Biochimica et biophysica acta. Molecular and cell biology of lipids 35 29678641
2005 Carboxyl-terminus determinants of the iron transporter DMT1/SLC11A2 isoform II (-IRE/1B) mediate internalization from the plasma membrane into recycling endosomes. Biochemistry 29 16142913
2017 Function and evolution of a Lotus japonicus AP2/ERF family transcription factor that is required for development of infection threads. DNA research : an international journal for rapid publication of reports on genes and genomes 28 28028038
2024 A mucus production programme promotes classical pancreatic ductal adenocarcinoma. Gut 24 38262672
2012 Increased intestinal lipid absorption caused by Ire1β deficiency contributes to hyperlipidemia and atherosclerosis in apolipoprotein E-deficient mice. Circulation research 23 22556338
2024 Paneth cell TNF signaling induces gut bacterial translocation and sepsis. Cell host & microbe 22 39243761
2016 The aqueous extract of Glycyrrhiza inflata can upregulate unfolded protein response-mediated chaperones to reduce tau misfolding in cell models of Alzheimer's disease. Drug design, development and therapy 22 27013866
2022 Goblet cells need some stress. The Journal of clinical investigation 21 36047499
2022 Communication and Cross-Regulation between Chemically Fueled Sender and Receiver Reaction Networks. Angewandte Chemie (International ed. in English) 18 36354214
2020 EEF1A2 and ERN2 could potentially discriminate metastatic status of mediastinal lymph node in lung adenocarcinomas harboring EGFR 19Del/L858R mutations. Thoracic cancer 11 32881299
2018 Maternal Protein Restriction Induces Alterations in Hepatic Unfolded Protein Response-Related Molecules in Adult Rat Offspring. Frontiers in endocrinology 11 30524373
2022 Autophagy triggered by iron-mediated ER stress is an important stress response to the early phase of Pi starvation in plants. The Plant journal : for cell and molecular biology 9 35306710
2024 IRE1 is implicated in protein synthesis regulation under ER stress conditions in plants. Plant physiology and biochemistry : PPB 6 39084166
2023 Enhanced ileum function in weaned piglets via Laminaria digitata and alginate lyase dietary inclusion: A combined proteomics and metabolomics analysis. Journal of proteomics 5 37775079
2025 IRE1α and IRE1β Protect Intestinal Epithelium and Suppress Colorectal Tumorigenesis through Distinct Mechanisms. bioRxiv : the preprint server for biology 3 40654814
2020 An in-vitro mechanical strain three-dimensional culture model: periodontal ligament cell viability, apoptosis, and endoplasmic reticulum stress response. European journal of oral sciences 3 32141124
2025 Control of Rhizobia Endosymbiosis by Coupling ER Expansion with Enhanced UPR. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 39985282
2026 ERN2/XBP1-AGR2 mediated endoplasmic reticulum stress increased neutrophilic asthma mucus secretion. International immunopharmacology 0 41483622
2026 A Bioluminescent Reporter System for Real-Time Monitoring of the Unfolded Protein Response in Plants. Plant biotechnology journal 0 41873905
2026 Unveiling Colorectal Cancer Cell Heterogeneity: Identification of Biomarkers and Disease-driving Cell Subpopulations through Scissor and CIBERSORTx on Integrated Transcriptomic Profiling. Computational biology and chemistry 0 41904900
2026 Airway mucus in infection. Frontiers in physiology 0 41940030
2025 CRISPR-Cas9-Mediated ATF6B Gene Editing Enhances Membrane Protein Production in HEK293T Cells. Bioengineering (Basel, Switzerland) 0 40281769

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