ERN1 Gene

Name	endoplasmic reticulum to nucleus signaling 1
Description	This gene encodes the transmembrane protein kinase inositol-requiring enzyme 1. The encoded protein contains two functional catalytic domains, a serine/threonine-protein kinase domain and an endoribonuclease domain. This protein functions as a sensor of unfolded proteins in the endoplasmic reticulum (ER) and triggers an intracellular signaling pathway termed the unfolded protein response (UPR). The UPR is an ER stress response that is conserved from yeast to mammals and activates genes involved in degrading misfolded proteins, regulating protein synthesis and activating molecular chaperones. This protein specifically mediates the splicing and activation of the stress response transcription factor X-box binding protein 1. [provided by RefSeq, Aug 2017]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The endoplasmic reticulum–resident sensor ERN1 (commonly known as IRE1α) is a pivotal regulator of the unfolded protein response (UPR) that integrates diverse signals to maintain cellular homeostasis. Upon accumulation of misfolded proteins in the ER, ERN1 becomes activated via dimerization and higher‐order oligomerization, thereby engaging its dual kinase and endoribonuclease activities. These activities mediate the unconventional splicing of X‐box binding protein 1 (XBP1) mRNA to generate an active transcription factor (XBP1s) that up‐regulates genes involved in protein folding, secretion, lipid biosynthesis, and ER expansion (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Structural studies have revealed that the precise dimerization interface and subsequent oligomer formation are critical for ERN1’s full catalytic activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its canonical role in splicing XBP1 mRNA, ERN1 also initiates regulated mRNA decay (RIDD) and modulates microRNA biogenesis, thus influencing apoptotic pathways and inflammatory signaling. For example, ERN1‐dependent cleavage events can down‐regulate specific microRNAs that normally restrain the translation of proapoptotic factors, thereby linking prolonged ER stress to apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In parallel, activation of ERN1 in immune cells has been shown to collaborate with pattern recognition receptors such as Toll‐like receptors and NOD proteins to promote cytokine production and inflammasome activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n ERN1 thereby functions as an integrative node that not only orchestrates adaptive responses via XBP1 splicing but also governs cellular fate decisions by modulating mRNA turnover and proinflammatory cascades. In metabolic tissues, transient ERN1 activation supports crucial functions such as insulin biosynthesis in pancreatic β-cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "and hepatic lipid homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Furthermore, in adipocytes and differentiating B lymphocytes, the ERN1–XBP1 axis is critical for cell maturation and differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore the multifaceted role of ERN1 as an integrative sensor that links ER stress to diverse downstream processes—including adaptive UPR signaling, apoptosis, inflammation, and metabolic as well as immunologic differentiation—thereby highlighting its potential as a therapeutic target in diseases ranging from diabetes and fatty liver to inflammatory disorders and cancer.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "H Yoshida, T Matsui, A Yamamoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0092-8674(01)00611-0"}], "href": "https://doi.org/10.1016/s0092-8674(01"}, {"type": "t", "text": "00611-0) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11779464"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11779464"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kyungho Lee, Witoon Tirasophon, Xiaohua Shen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.964702"}], "href": "https://doi.org/10.1101/gad.964702"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11850408"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11850408"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Hiderou Yoshida, Masaya Oku, Mie Suzuki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200508145"}], "href": "https://doi.org/10.1083/jcb.200508145"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16461360"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16461360"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jiahai Zhou, Chuan Yin Liu, Sung Hoon Back, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0606480103"}], "href": "https://doi.org/10.1073/pnas.0606480103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16973740"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16973740"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Han Li, Alexei V Korennykh, Shannon L Behrman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1010580107"}], "href": "https://doi.org/10.1073/pnas.1010580107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20798350"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20798350"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "John-Paul Upton, Likun Wang, Dan Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IRE1α cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1226191"}], "href": "https://doi.org/10.1126/science.1226191"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23042294"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23042294"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Fabio Martinon, Xi Chen, Ann-Hwee Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.1857"}], "href": "https://doi.org/10.1038/ni.1857"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20351694"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20351694"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Alana G Lerner, John-Paul Upton, P V K Praveen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2012.07.007"}], "href": "https://doi.org/10.1016/j.cmet.2012.07.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22883233"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22883233"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "A Marijke Keestra-Gounder, Mariana X Byndloss, Núbia Seyffert, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NOD1 and NOD2 signalling links ER stress with inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature17631"}], "href": "https://doi.org/10.1038/nature17631"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27007849"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27007849"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Kathryn L Lipson, Sonya G Fonseca, Shinsuke Ishigaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2006.07.007"}], "href": "https://doi.org/10.1016/j.cmet.2006.07.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16950141"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16950141"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Kezhong Zhang, Shiyu Wang, Jyoti Malhotra, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2011.52"}], "href": "https://doi.org/10.1038/emboj.2011.52"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21407177"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21407177"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Haibo Sha, Yin He, Hui Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The IRE1alpha-XBP1 pathway of the unfolded protein response is required for adipogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2009.04.009"}], "href": "https://doi.org/10.1016/j.cmet.2009.04.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19490910"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19490910"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Kezhong Zhang, Hetty N Wong, Benbo Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI21848"}], "href": "https://doi.org/10.1172/JCI21848"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15690081"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15690081"}]}]}]}
Synonyms	IRE1, IRE1A, HIRE1P, IRE1P
Proteins	ERN1_HUMAN
NCBI Gene ID	2081
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

ERN1 has 10,203 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 118 datasets.

Click the + buttons to view associations for ERN1 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

ERN1 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of ERN1 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of ERN1 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of ERN1 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of ERN1 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of ERN1 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of ERN1 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of ERN1 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of ERN1 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with ERN1 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with ERN1 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with ERN1 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of ERN1 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of ERN1 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of ERN1 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of ERN1 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing ERN1 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing ERN1 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with ERN1 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with ERN1 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	CORUM Protein Complexes	protein complexs containing ERN1 protein from the CORUM Protein Complexes dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of ERN1 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with ERN1 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with ERN1 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with ERN1 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with ERN1 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of ERN1 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by ERN1 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with ERN1 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with ERN1 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with ERN1 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with ERN1 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for ERN1 protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at ERN1 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of ERN1 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of ERN1 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing ERN1 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with ERN1 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with ERN1 gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of ERN1 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with ERN1 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.