ERN1
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]
Full Name
Endoplasmic Reticulum To Nucleus Signaling 1
Research Area
Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) (PubMed:11779464, PubMed:11175748, PubMed:12637535, PubMed:9637683, PubMed:21317875, PubMed:28128204).
In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP (PubMed:21317875).
Accumulation of misfolded proteins in the endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal domain to homodimerize, promoting autophosphorylation of the kinase domain and subsequent activation of the endoribonuclease activity (PubMed:21317875).
The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA (PubMed:11779464, PubMed:24508390, PubMed:21317875).
The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes (PubMed:11779464, PubMed:24508390, PubMed:21317875).
Acts as an upstream signal for ER stress-induced GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane by modulating the expression and localization of SEC16A (PubMed:21884936, PubMed:28067262).
Biological Process
Cellular response to glucose stimulus Source: ParkinsonsUK-UCL
Cellular response to hydrogen peroxide Source: Ensembl
Cellular response to unfolded protein Source: ParkinsonsUK-UCL
Cellular response to vascular endothelial growth factor stimulus Source: UniProtKB
Endothelial cell proliferation Source: UniProtKB
Insulin metabolic process Source: ParkinsonsUK-UCL
Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: GO_Central
IRE1-mediated unfolded protein response Source: UniProtKB
mRNA catabolic process Source: ParkinsonsUK-UCL
mRNA cleavage Source: UniProtKB
mRNA cleavage involved in mRNA processing Source: ParkinsonsUK-UCL
mRNA splicing, via endonucleolytic cleavage and ligation Source: UniProtKB
Peptidyl-serine autophosphorylation Source: ParkinsonsUK-UCL
Peptidyl-serine trans-autophosphorylation Source: ParkinsonsUK-UCL
Positive regulation of endoplasmic reticulum unfolded protein response Source: UniProtKB
Positive regulation of JUN kinase activity Source: ParkinsonsUK-UCL
Positive regulation of RNA splicing Source: UniProtKB
Positive regulation of vascular associated smooth muscle cell proliferation Source: BHF-UCL
Protein autophosphorylation Source: ParkinsonsUK-UCL
Protein phosphorylation Source: UniProtKB
Regulation of cell cycle Source: UniProtKB
Regulation of macroautophagy Source: ParkinsonsUK-UCL
Response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
Cellular Location
Endoplasmic reticulum membrane
Topology
Lumenal: 19-443
Helical: 444-464
Cytoplasmic: 465-977
PTM
Autophosphorylated following homodimerization. Autophosphorylation promotes activation of the endoribonuclease domain.
ADP-ribosylated by PARP16 upon ER stress, which increases both kinase and endonuclease activities.