ERN1 (IRE1α): Master Regulator of the Unfolded Protein Response
A comprehensive biomedical overview of the ERN1 gene, its protein product, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | ERN1 |
|---|---|
| Full Name | Endoplasmic Reticulum to Nucleus Signaling 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 17q25.3 |
| NCBI Gene ID | 2081 ncbi.nlm.nih.gov/gene/2081 |
| Ensembl ID | ENSG00000178607 |
| UniProt ID | O75460 |
| OMIM ID | 604033 |
| HGNC ID | HGNC:3449 |
| Aliases | IRE1, IRE1A, IRE1P, hIRE1p |
Description
The ERN1 gene encodes inositol-requiring enzyme 1 alpha (IRE1α), a transmembrane protein localized to the endoplasmic reticulum (ER). It functions as a dual enzyme with serine/threonine kinase and endoribonuclease activities. IRE1α is a central sensor of ER stress and initiates the unfolded protein response (UPR) by splicing XBP1 mRNA, leading to the production of the transcription factor XBP1s, which upregulates genes involved in protein folding, ER-associated degradation (ERAD), and lipid biosynthesis. ERN1 also activates the JNK pathway via its kinase domain, influencing apoptosis and inflammation. Its activity is critical for cellular homeostasis and is implicated in various diseases.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (multiple types) | Altered ERN1 expression/activity modulates UPR, promoting tumor cell survival under hypoxia and nutrient deprivation; XBP1 splicing drives proliferation and invasion. | COSMIC; multiple studies (e.g., in breast, hepatocellular, and colorectal cancers) show overexpression or hyperactivation. |
| Diabetes mellitus | Chronic ER stress in pancreatic β-cells leads to IRE1α-mediated JNK activation and apoptosis, contributing to β-cell failure. | OMIM; animal models and human islet studies. |
| Neurodegenerative diseases (e.g., Alzheimer's, Parkinson's) | ER stress and IRE1α activation are observed in affected neurons; aberrant UPR contributes to protein aggregation and cell death. | PubMed; post-mortem brain analyses. |
| Inflammatory bowel disease (IBD) | IRE1α hyperactivation in intestinal epithelial cells leads to apoptosis and loss of barrier integrity. | GWAS and functional studies (e.g., in mouse models). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Pancreas | 12.3 | Medium |
| Liver | 8.7 | Medium |
| Kidney | 7.9 | Medium |
| Brain | 6.5 | Low |
| Heart | 5.2 | Low |
| Lung | 4.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | 15.2 | High expression; used in UPR studies |
| HepG2 (liver cancer) | 12.8 | High; responsive to ER stress |
| MCF7 (breast cancer) | 10.1 | Moderate; ERN1 activity linked to survival |
| A549 (lung cancer) | 8.3 | Moderate |
| K562 (leukemia) | 5.6 | Low |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1849A>G (p.Thr617Ala) | Missense | Rare (MAF<0.01) | Alters kinase domain; potential effect on UPR signaling |
| c.3022C>T (p.Arg1008Cys) | Missense | Rare | In RNase domain; may affect XBP1 splicing |
| c.2074G>A (p.Glu692Lys) | Missense | Not reported in gnomAD | Predicted damaging; functional impact unknown |
| c.1234_1235insA | Frameshift | Somatic in cancer | Loss of function; may impair UPR |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (e.g., frameshift or truncating) reduce IRE1α kinase/RNase activity, impairing XBP1 splicing and UPR, leading to increased ER stress and apoptosis.
Gain of Function (GOF)
Gain-of-function mutations (e.g., some missense) may enhance kinase/RNase activity, leading to hyperactive UPR, chronic inflammation, and oncogenic signaling.
Dominant Negative (DN)
Dominant-negative mutations (e.g., kinase-dead) can dimerize with wild-type IRE1α, blocking its activation and downstream signaling, exacerbating ER stress.
View complete mutation data：
Gene Ontology (GO)
| • endoribonuclease activity | • protein serine/threonine kinase activity |
| • ATP binding | • endoplasmic reticulum membrane |
| • unfolded protein response | • IRE1-mediated unfolded protein response |
| • apoptotic process | • regulation of transcription |
Pathways
• Unfolded Protein Response (UPR)
• IRE1α-XBP1 pathway
• ER stress-induced apoptosis
• JNK signaling
Protein Summary
IRE1α is a 923-amino acid protein with an N-terminal luminal domain that senses ER stress, a transmembrane domain, and a cytoplasmic region containing kinase and endoribonuclease domains. Upon ER stress, IRE1α oligomerizes and autophosphorylates, activating its RNase domain to splice XBP1 mRNA. The spliced XBP1s translocates to the nucleus to induce UPR target genes. IRE1α also interacts with TRAF2 to activate JNK, promoting apoptosis under prolonged stress. Its activity is regulated by post-translational modifications and binding partners.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ERN1 Knockout HEK293 Cell Line | EDJ-KQ1003 | Human | 2081 | Details Get a Quote |
| ERN1 Knockout A-549 Cell Line | EDJ-KQ20051 | Human | 2081 | Details Get a Quote |
| ERN1 Knockout HeLa Cell Line | EDJ-KQ20053 | Human | 2081 | Details Get a Quote |
| ERN1 Knockout HCT 116 Cell Line | EDJ-KQ18732 | Human | 2081 | Details Get a Quote |
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