ERN1 (IRE1alpha) is a single-pass type I transmembrane protein of the endoplasmic reticulum (ER) and the most conserved sensor of the unfolded protein response (UPR). Its ER-luminal domain senses misfolded proteins: in unstressed cells it is held monomeric by the Hsp70 chaperone BiP/HSPA5 (recruited by the J-protein ERdj4/DNAJB9), and accumulating unfolded proteins release BiP and promote dimerization and higher-order oligomerization. Dimerization brings together the cytosolic serine/threonine kinase domains, which trans-autophosphorylate and allosterically activate the C-terminal KEN endoribonuclease domain. The RNase excises a 26-nucleotide intron from XBP1 mRNA in the cytoplasm; after ligation by RtcB the frameshifted mRNA encodes XBP1s, a potent bZIP transcription factor that induces ER chaperone, ERAD and lipid-synthesis genes. ERN1 also degrades ER-localized mRNAs (regulated IRE1-dependent decay, RIDD) and, through recruitment of TRAF2/ASK1, activates JNK signaling and can promote apoptosis under unresolved ER stress. Its activity is tuned by many cytosolic and luminal partners, including HSP90, HSP72, BI-1/TMBIM6, PDIA6 and RACK1-PP2A, and it couples ER homeostasis to secretory-cell physiology such as insulin production and growth-factor-driven vascular cell proliferation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IDA PMID:9637683 A stress response pathway from the endoplasmic reticulum to ... | KEEP AS NON CORE | Summary: Mg2+ is the cofactor for IRE1 kinase (and RNase) activity; assays were done in Mg2+-containing buffers. Reason: Metal cofactor binding is consistent with a protein kinase but is inferred from assay buffer requirements rather than a dedicated binding study; it is not an informative description of ERN1 function. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt COFACTOR: Name=Mg(2+) PMID:9637683 1 m m MnCl 2 , 1 m m MgCl 2 |
| GO:0000287 magnesium ion binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Mg2+ is the cofactor for IRE1 kinase (and RNase) activity; assays were done in Mg2+-containing buffers. Reason: Metal cofactor binding is consistent with a protein kinase but is inferred from assay buffer requirements rather than a dedicated binding study; it is not an informative description of ERN1 function. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt COFACTOR: Name=Mg(2+) |
| GO:0001935 endothelial cell proliferation | IDA PMID:23529610 Vascular endothelial cell growth-activated XBP1 splicing in ... | MODIFY | Summary: IRE1alpha knockdown decreased VEGF-driven endothelial cell proliferation, which is mediated by XBP1s and downstream Akt/GSK3beta/beta-catenin/E2F2 signaling. Reason: ERN1 does not itself execute cell proliferation; it acts upstream as the XBP1-splicing enzyme. A regulatory term is more accurate, and this is a non-core, context-specific role. Proposed replacements: positive regulation of endothelial cell proliferation Supporting Evidence: PMID:23529610 We found that vascular endothelial cell growth factor induced the kinase insert domain receptor internalization and interaction through C-terminal domain with the unspliced XBP1 and the inositol requiring enzyme 1 Ξ± in the endoplasmic reticulum, leading to inositol requiring enzyme 1 Ξ± phosphorylation and XBP1 mRNA splicing PMID:23529610 Knockdown of XBP1 or inositol requiring enzyme 1 Ξ± decreased endothelial cell proliferation via suppression of Akt/GSK3Ξ² phosphorylation, Ξ²-catenin nuclear translocation, and E2F2 expression. |
| GO:0004519 endonuclease activity | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic assignment of a general nuclease activity parent term. Reason: Correct parent of the experimentally established RNA endonuclease activity of the KEN domain. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0004521 RNA endonuclease activity | IBA GO_REF:0000033 | ACCEPT | Summary: ERN1/IRE1alpha is a site-specific endoribonuclease whose KEN domain cleaves the XBP1 mRNA intron (and yeast HAC1 mRNA in vitro); RNase activity depends on dimerization and autophosphorylation. Reason: Core catalytic activity of ERN1, supported by multiple direct biochemical assays and by the phylogenetically conserved IRE1 family (IBA). Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA PMID:22013210 Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1Ξ±), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0004521 RNA endonuclease activity | IDA PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | ACCEPT | Summary: ERN1/IRE1alpha is a site-specific endoribonuclease whose KEN domain cleaves the XBP1 mRNA intron (and yeast HAC1 mRNA in vitro); RNase activity depends on dimerization and autophosphorylation. Reason: Core catalytic activity of ERN1, supported by multiple direct biochemical assays and by the phylogenetically conserved IRE1 family (IBA). Supporting Evidence: PMID:11779465 C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress. |
| GO:0004521 RNA endonuclease activity | IDA PMID:19328063 BAX inhibitor-1 is a negative regulator of the ER stress sen... | ACCEPT | Summary: ERN1/IRE1alpha is a site-specific endoribonuclease whose KEN domain cleaves the XBP1 mRNA intron (and yeast HAC1 mRNA in vitro); RNase activity depends on dimerization and autophosphorylation. Reason: Core catalytic activity of ERN1, supported by multiple direct biochemical assays and by the phylogenetically conserved IRE1 family (IBA). Supporting Evidence: PMID:19328063 This phenotype was associated with the formation of a stable protein complex between BI-1 and IRE1alpha, decreasing its ribonuclease activity. |
| GO:0004521 RNA endonuclease activity | IDA PMID:20625543 HSP72 protects cells from ER stress-induced apoptosis via en... | ACCEPT | Summary: ERN1/IRE1alpha is a site-specific endoribonuclease whose KEN domain cleaves the XBP1 mRNA intron (and yeast HAC1 mRNA in vitro); RNase activity depends on dimerization and autophosphorylation. Reason: Core catalytic activity of ERN1, supported by multiple direct biochemical assays and by the phylogenetically conserved IRE1 family (IBA). Supporting Evidence: PMID:20625543 Regulation of the UPR was associated with the formation of a stable protein complex between Hsp72 and the cytosolic domain of IRE1alpha. Finally, Hsp72 enhanced the RNase activity of recombinant IRE1alpha in vitro, suggesting a direct regulation. |
| GO:0004521 RNA endonuclease activity | IDA PMID:21317875 Structure of the Ire1 autophosphorylation complex and implic... | ACCEPT | Summary: ERN1/IRE1alpha is a site-specific endoribonuclease whose KEN domain cleaves the XBP1 mRNA intron (and yeast HAC1 mRNA in vitro); RNase activity depends on dimerization and autophosphorylation. Reason: Core catalytic activity of ERN1, supported by multiple direct biochemical assays and by the phylogenetically conserved IRE1 family (IBA). Supporting Evidence: PMID:21317875 We show that the Xbp1-specific ribonuclease activity depends on autophosphorylation PMID:21317875 Activation of Ire1 by association of its N-terminal ER luminal domains promotes autophosphorylation by its cytoplasmic kinase domain, leading to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA generating an active Xbp1s transcriptional activator. |
| GO:0004521 RNA endonuclease activity | IDA PMID:9637683 A stress response pathway from the endoplasmic reticulum to ... | ACCEPT | Summary: ERN1/IRE1alpha is a site-specific endoribonuclease whose KEN domain cleaves the XBP1 mRNA intron (and yeast HAC1 mRNA in vitro); RNase activity depends on dimerization and autophosphorylation. Reason: Core catalytic activity of ERN1, supported by multiple direct biochemical assays and by the phylogenetically conserved IRE1 family (IBA). Supporting Evidence: PMID:9637683 hIre1p expressed in mammalian cells displayed intrinsic autophosphorylation activity and an endoribonuclease activity that cleaved the 5' splice site of yeast HAC1 mRNA, a substrate for the endoribonuclease activity of yeast Ire1p. |
| GO:0004521 RNA endonuclease activity | IEA GO_REF:0000120 | ACCEPT | Summary: ERN1/IRE1alpha is a site-specific endoribonuclease whose KEN domain cleaves the XBP1 mRNA intron (and yeast HAC1 mRNA in vitro); RNase activity depends on dimerization and autophosphorylation. Reason: Core catalytic activity of ERN1, supported by multiple direct biochemical assays and by the phylogenetically conserved IRE1 family (IBA). Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA PMID:22013210 Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1Ξ±), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0004540 RNA nuclease activity | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic assignment of a general nuclease activity parent term. Reason: Correct parent of the experimentally established RNA endonuclease activity of the KEN domain. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic assignment of protein kinase activity from the kinase domain. Reason: Correct parent of the experimentally supported protein serine/threonine kinase activity. Supporting Evidence: PMID:21317875 Furthermore, we demonstrate that activated Ire1Ξ± is a competent protein kinase, able to phosphorylate a heterologous peptide substrate. |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IRE1alpha has intrinsic serine/threonine kinase activity: it trans-autophosphorylates upon dimerization, which is required for RNase activation, and can phosphorylate a heterologous peptide substrate. Reason: Directly demonstrated kinase activity; physiologically the principal substrate is IRE1 itself (trans-autophosphorylation in the activation loop) and this activity licenses the endoribonuclease. Supporting Evidence: PMID:21317875 Furthermore, we demonstrate that activated Ire1Ξ± is a competent protein kinase, able to phosphorylate a heterologous peptide substrate. PMID:21317875 We show that the Xbp1-specific ribonuclease activity depends on autophosphorylation file:human/ERN1/ERN1-uniprot.txt The kinase domain is activated by trans- autophosphorylation following homodimerization |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:21317875 Structure of the Ire1 autophosphorylation complex and implic... | ACCEPT | Summary: IRE1alpha has intrinsic serine/threonine kinase activity: it trans-autophosphorylates upon dimerization, which is required for RNase activation, and can phosphorylate a heterologous peptide substrate. Reason: Directly demonstrated kinase activity; physiologically the principal substrate is IRE1 itself (trans-autophosphorylation in the activation loop) and this activity licenses the endoribonuclease. Supporting Evidence: PMID:21317875 Furthermore, we demonstrate that activated Ire1Ξ± is a competent protein kinase, able to phosphorylate a heterologous peptide substrate. PMID:21317875 We show that the Xbp1-specific ribonuclease activity depends on autophosphorylation file:human/ERN1/ERN1-uniprot.txt The kinase domain is activated by trans- autophosphorylation following homodimerization |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:9637683 A stress response pathway from the endoplasmic reticulum to ... | ACCEPT | Summary: IRE1alpha has intrinsic serine/threonine kinase activity: it trans-autophosphorylates upon dimerization, which is required for RNase activation, and can phosphorylate a heterologous peptide substrate. Reason: Directly demonstrated kinase activity; physiologically the principal substrate is IRE1 itself (trans-autophosphorylation in the activation loop) and this activity licenses the endoribonuclease. Supporting Evidence: PMID:9637683 hIre1p expressed in mammalian cells displayed intrinsic autophosphorylation activity and an endoribonuclease activity that cleaved the 5' splice site of yeast HAC1 mRNA, a substrate for the endoribonuclease activity of yeast Ire1p. file:human/ERN1/ERN1-uniprot.txt The kinase domain is activated by trans- autophosphorylation following homodimerization |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IRE1alpha has intrinsic serine/threonine kinase activity: it trans-autophosphorylates upon dimerization, which is required for RNase activation, and can phosphorylate a heterologous peptide substrate. Reason: Directly demonstrated kinase activity; physiologically the principal substrate is IRE1 itself (trans-autophosphorylation in the activation loop) and this activity licenses the endoribonuclease. Supporting Evidence: PMID:21317875 Furthermore, we demonstrate that activated Ire1Ξ± is a competent protein kinase, able to phosphorylate a heterologous peptide substrate. PMID:21317875 We show that the Xbp1-specific ribonuclease activity depends on autophosphorylation file:human/ERN1/ERN1-uniprot.txt The kinase domain is activated by trans- autophosphorylation following homodimerization |
| GO:0005161 platelet-derived growth factor receptor binding | IPI PMID:26315405 XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vess... | KEEP AS NON CORE | Summary: PDGF-BB triggers XBP1 splicing in smooth muscle cells via interaction between PDGFRbeta and IRE1alpha (PMID:26315405). Reason: A reported cell-type-specific interaction that couples growth-factor receptor signaling to IRE1 activation; plausible but peripheral to the core ER-stress sensing role. Supporting Evidence: PMID:26315405 In vitro studies indicated that platelet-derived growth factor-BB triggered XBP1 splicing in SMCs via the interaction between platelet-derived growth factor receptor Ξ² and the inositol-requiring enzyme 1Ξ±. |
| GO:0005515 protein binding | IPI PMID:11278723 Activation of caspase-12, an endoplastic reticulum (ER) resi... | REMOVE | Summary: IPI evidence for physical interaction with TRAF2 and TAOK3/JIK (cytoplasmic-domain adaptors linking IRE1 to JNK/caspase-12 signaling). Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005515 protein binding | IPI PMID:11278723 Activation of caspase-12, an endoplastic reticulum (ER) resi... | REMOVE | Summary: IPI evidence for physical interaction with TRAF2 and TAOK3/JIK (cytoplasmic-domain adaptors linking IRE1 to JNK/caspase-12 signaling). Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005515 protein binding | IPI PMID:15234121 JAB1 participates in unfolded protein responses by associati... | REMOVE | Summary: IPI evidence for physical interaction with JAB1/COPS5. Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005515 protein binding | IPI PMID:18369366 Synoviolin promotes IRE1 ubiquitination and degradation in s... | REMOVE | Summary: IPI evidence for physical interaction with the E3 ligase SYVN1/HRD1, which ubiquitinates IRE1 and promotes its degradation. Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005515 protein binding | IPI PMID:19135427 USP14 inhibits ER-associated degradation via interaction wit... | REMOVE | Summary: IPI evidence for physical interaction with USP14 and ERAD components (Derlins, SEL1L, SYVN1). Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005515 protein binding | IPI PMID:19135427 USP14 inhibits ER-associated degradation via interaction wit... | REMOVE | Summary: IPI evidence for physical interaction with USP14 and ERAD components (Derlins, SEL1L, SYVN1). Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005515 protein binding | IPI PMID:19135427 USP14 inhibits ER-associated degradation via interaction wit... | REMOVE | Summary: IPI evidence for physical interaction with USP14 and ERAD components (Derlins, SEL1L, SYVN1). Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005515 protein binding | IPI PMID:19135427 USP14 inhibits ER-associated degradation via interaction wit... | REMOVE | Summary: IPI evidence for physical interaction with USP14 and ERAD components (Derlins, SEL1L, SYVN1). Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005515 protein binding | IPI PMID:19135427 USP14 inhibits ER-associated degradation via interaction wit... | REMOVE | Summary: IPI evidence for physical interaction with USP14 and ERAD components (Derlins, SEL1L, SYVN1). Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005515 protein binding | IPI PMID:19328063 BAX inhibitor-1 is a negative regulator of the ER stress sen... | REMOVE | Summary: IPI evidence for physical interaction with BI-1/TMBIM6, a negative regulator of IRE1 RNase activity. Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:19328063 This phenotype was associated with the formation of a stable protein complex between BI-1 and IRE1alpha, decreasing its ribonuclease activity. |
| GO:0005515 protein binding | IPI PMID:20103773 A crucial role for RACK1 in the regulation of glucose-stimul... | REMOVE | Summary: IPI evidence for physical interaction with RACK1, which scaffolds PP2A-mediated dephosphorylation of IRE1. Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:20103773 RACK1 mediated the glucose-inducible assembly of a complex containing IRE1alpha, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1alpha by PP2A, thereby inhibiting glucose-stimulated IRE1alpha activation and attenuating IRE1alpha-dependent increases in insulin production. |
| GO:0005515 protein binding | IPI PMID:23529610 Vascular endothelial cell growth-activated XBP1 splicing in ... | REMOVE | Summary: IPI evidence for physical interaction with the VEGF receptor KDR. Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:23529610 We found that vascular endothelial cell growth factor induced the kinase insert domain receptor internalization and interaction through C-terminal domain with the unspliced XBP1 and the inositol requiring enzyme 1 Ξ± in the endoplasmic reticulum, leading to inositol requiring enzyme 1 Ξ± phosphorylation and XBP1 mRNA splicing |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | REMOVE | Summary: IPI evidence for physical interaction with TRAF2 (proximity ligation assay screen). Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005515 protein binding | IPI PMID:25742138 Yip1A, a novel host factor for the activation of the IRE1 pa... | REMOVE | Summary: IPI evidence for physical interaction with YIPF5/Yip1A. Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005515 protein binding | IPI PMID:27238082 Compounds Triggering ER Stress Exert Anti-Melanoma Effects a... | MODIFY | Summary: Interaction of IRE1alpha with HSPA5/BiP, the ER Hsp70 chaperone that binds the luminal domain and keeps IRE1 monomeric/inactive in unstressed cells. Reason: The generic protein binding term is uninformative. The partner (P11021, HSPA5/BiP) is an Hsp70-family chaperone and its association with the IRE1 luminal domain is well established, so GO:0030544 Hsp70 protein binding is the more informative replacement. Proposed replacements: Hsp70 protein binding Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP PMID:29198525 ERdj4 associates with IRE1LD and recruits BiP through the stimulation of ATP hydrolysis, forcibly disrupting IRE1 dimers. Unfolded proteins compete for BiP and restore IRE1LD to its default, dimeric, and active state. PMID:12637535 In addition, the peptide binding domain of the endoplasmic reticulum protein chaperone BiP interacted with the N-terminal region within the NLD. |
| GO:0005515 protein binding | IPI PMID:28128204 A critical role of DDRGK1 in endoplasmic reticulum homoeosta... | REMOVE | Summary: IPI evidence for physical interaction with DDRGK1, which stabilizes IRE1. Reason: Generic protein binding is uninformative about ERN1 molecular function; removal does not imply the interaction is false. These partners mostly regulate IRE1 activity, stability or downstream signaling and are better captured by process or complex terms. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0005524 ATP binding | IDA PMID:9637683 A stress response pathway from the endoplasmic reticulum to ... | ACCEPT | Summary: IRE1alpha binds ATP in its kinase domain; the nucleotide-binding pocket is required for autophosphorylation and allosterically for RNase activation. Reason: ATP binding is intrinsic to the kinase activity and is structurally established. Supporting Evidence: PMID:9637683 hIre1p expressed in mammalian cells displayed intrinsic autophosphorylation activity and an endoribonuclease activity that cleaved the 5' splice site of yeast HAC1 mRNA, a substrate for the endoribonuclease activity of yeast Ire1p. PMID:21317875 We have determined the crystal structure of the cytoplasmic portion of dephosphorylated human Ire1Ξ± bound to ADP, revealing the 'phosphoryl-transfer' competent dimeric face-to-face complex |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: IRE1alpha binds ATP in its kinase domain; the nucleotide-binding pocket is required for autophosphorylation and allosterically for RNase activation. Reason: ATP binding is intrinsic to the kinase activity and is structurally established. Supporting Evidence: PMID:21317875 We have determined the crystal structure of the cytoplasmic portion of dephosphorylated human Ire1Ξ± bound to ADP, revealing the 'phosphoryl-transfer' competent dimeric face-to-face complex |
| GO:0005637 nuclear inner membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic orthology transfer of nuclear inner membrane localization. Reason: Human IRE1alpha is an ER membrane protein concentrated around the nuclear envelope (whose outer membrane is continuous with the ER), and its catalytic domain carries a nuclear exclusion signal. A specific inner nuclear membrane localization is not established for human ERN1. Supporting Evidence: PMID:9637683 Overexpressed hIre1p was localized to the ER with particular concentration around the nuclear envelope and some colocalization with the nuclear pore complex. PMID:19622636 Here, we show that the catalytic domain of IRE1 contains a nuclear exclusion signal to prevent IRE1 from mislocalizing to the nucleus. |
| GO:0005737 cytoplasm | IDA PMID:19622636 Unconventional splicing of XBP1 mRNA occurs in the cytoplasm... | KEEP AS NON CORE | Summary: The cytosolic kinase/RNase portion of IRE1 acts in the cytoplasm, where XBP1 mRNA splicing predominantly occurs; the catalytic domain carries a nuclear exclusion signal. Reason: Broadly correct in that the catalytic domains face the cytosol, but ERN1 is an ER membrane protein; ER membrane is the informative location. Supporting Evidence: PMID:19622636 Here, we show that the catalytic domain of IRE1 contains a nuclear exclusion signal to prevent IRE1 from mislocalizing to the nucleus. PMID:19622636 From these observations, we concluded that unconventional splicing of XBP1 mRNA occurs predominantly in the cytoplasm. |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic orthology transfer of mitochondrion localization. Reason: ERN1 is an ER-membrane protein; it can be enriched at ER-mitochondria contact sites but is not a mitochondrial protein. The IEA transfer overstates localization. ORGANELLES check (2026-10-25): the Ensembl projection's source is mouse Ern1 (Q9EQY0), whose only GO:0005739 row is an MGI IDA from PMID:23028046, a study of anthrax lethal toxin and MLN64 in macrophages whose cached abstract does not mention IRE1 (abstract only; PMC full text could not be retrieved), so the assay behind it is unknown here and the source is not called wrong. Human ERN1 has a signal peptide, one TM segment and a curated ER-membrane location, and is not in MitoCarta3.0. A crude mitochondrial fraction would co-purify the ER-mitochondria contact-site (MAM) pool of an ER-membrane protein, the lesson from STOM, so the organelle claim is not supported and the row stays MARK_AS_OVER_ANNOTATED (not REMOVE: the mapping faithfully transfers a real source row). No sub-compartment row. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:9637683}; Single-pass type I membrane protein |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: IRE1alpha resides in the endoplasmic reticulum. Reason: Correct; the more specific ER membrane term is also annotated. Supporting Evidence: PMID:9637683 Overexpressed hIre1p was localized to the ER with particular concentration around the nuclear envelope and some colocalization with the nuclear pore complex. |
| GO:0005783 endoplasmic reticulum | IDA PMID:23529610 Vascular endothelial cell growth-activated XBP1 splicing in ... | ACCEPT | Summary: IRE1alpha resides in the endoplasmic reticulum. Reason: Correct; the more specific ER membrane term is also annotated. Supporting Evidence: PMID:23529610 We found that vascular endothelial cell growth factor induced the kinase insert domain receptor internalization and interaction through C-terminal domain with the unspliced XBP1 and the inositol requiring enzyme 1 Ξ± in the endoplasmic reticulum, leading to inositol requiring enzyme 1 Ξ± phosphorylation and XBP1 mRNA splicing |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:9637683 A stress response pathway from the endoplasmic reticulum to ... | ACCEPT | Summary: ERN1 is a single-pass type I ER membrane protein with a luminal stress-sensing domain and cytosolic kinase and KEN (RNase) domains. Reason: Core location, directly demonstrated and consistent with the topology. Supporting Evidence: PMID:9637683 Overexpressed hIre1p was localized to the ER with particular concentration around the nuclear envelope and some colocalization with the nuclear pore complex. file:human/ERN1/ERN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:9637683}; Single-pass type I membrane protein |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: ERN1 is a single-pass type I ER membrane protein with a luminal stress-sensing domain and cytosolic kinase and KEN (RNase) domains. Reason: Core location, directly demonstrated and consistent with the topology. Supporting Evidence: PMID:9637683 Overexpressed hIre1p was localized to the ER with particular concentration around the nuclear envelope and some colocalization with the nuclear pore complex. file:human/ERN1/ERN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:9637683}; Single-pass type I membrane protein |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-381091 | ACCEPT | Summary: ERN1 is a single-pass type I ER membrane protein with a luminal stress-sensing domain and cytosolic kinase and KEN (RNase) domains. Reason: Core location, directly demonstrated and consistent with the topology. Supporting Evidence: PMID:9637683 Overexpressed hIre1p was localized to the ER with particular concentration around the nuclear envelope and some colocalization with the nuclear pore complex. file:human/ERN1/ERN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:9637683}; Single-pass type I membrane protein |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-381109 | ACCEPT | Summary: ERN1 is a single-pass type I ER membrane protein with a luminal stress-sensing domain and cytosolic kinase and KEN (RNase) domains. Reason: Core location, directly demonstrated and consistent with the topology. Supporting Evidence: PMID:9637683 Overexpressed hIre1p was localized to the ER with particular concentration around the nuclear envelope and some colocalization with the nuclear pore complex. file:human/ERN1/ERN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:9637683}; Single-pass type I membrane protein |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-381217 | ACCEPT | Summary: ERN1 is a single-pass type I ER membrane protein with a luminal stress-sensing domain and cytosolic kinase and KEN (RNase) domains. Reason: Core location, directly demonstrated and consistent with the topology. Supporting Evidence: PMID:9637683 Overexpressed hIre1p was localized to the ER with particular concentration around the nuclear envelope and some colocalization with the nuclear pore complex. file:human/ERN1/ERN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:9637683}; Single-pass type I membrane protein |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-425923 | ACCEPT | Summary: ERN1 is a single-pass type I ER membrane protein with a luminal stress-sensing domain and cytosolic kinase and KEN (RNase) domains. Reason: Core location, directly demonstrated and consistent with the topology. Supporting Evidence: PMID:9637683 Overexpressed hIre1p was localized to the ER with particular concentration around the nuclear envelope and some colocalization with the nuclear pore complex. file:human/ERN1/ERN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:9637683}; Single-pass type I membrane protein |
| GO:0006397 mRNA processing | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic assignment of mRNA processing. Reason: IRE1alpha processes XBP1 mRNA by unconventional splicing; correct parent of GO:0070054. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0006401 RNA catabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Besides XBP1 splicing, IRE1alpha degrades ER-associated mRNAs (regulated IRE1-dependent decay, RIDD), as discussed in the cited review. Reason: RIDD is a recognized secondary output of IRE1 RNase activity; it is a genuine but non-core function relative to XBP1 splicing. Supporting Evidence: PMID:22013210 Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1Ξ±), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). |
| GO:0006402 mRNA catabolic process | TAS PMID:22013210 The unfolded protein response: integrating stress signals th... | KEEP AS NON CORE | Summary: Besides XBP1 splicing, IRE1alpha degrades ER-associated mRNAs (regulated IRE1-dependent decay, RIDD), as discussed in the cited review. Reason: RIDD is a recognized secondary output of IRE1 RNase activity; it is a genuine but non-core function relative to XBP1 splicing. Supporting Evidence: PMID:22013210 Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1Ξ±), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). |
| GO:0006468 protein phosphorylation | IDA PMID:9637683 A stress response pathway from the endoplasmic reticulum to ... | ACCEPT | Summary: IRE1alpha autophosphorylates and can phosphorylate heterologous substrates. Reason: Directly demonstrated by in vitro kinase assays. Supporting Evidence: PMID:9637683 hIre1p expressed in mammalian cells displayed intrinsic autophosphorylation activity and an endoribonuclease activity that cleaved the 5' splice site of yeast HAC1 mRNA, a substrate for the endoribonuclease activity of yeast Ire1p. |
| GO:0016241 regulation of macroautophagy | TAS PMID:22013210 The unfolded protein response: integrating stress signals th... | KEEP AS NON CORE | Summary: TAS from a review on IRE1alpha signaling; IRE1-JNK signaling has been linked to ER stress-induced autophagy. Reason: Plausible downstream consequence of IRE1-TRAF2-JNK signaling, reported in the cited review; indirect and non-core. Supporting Evidence: PMID:22013210 IRE1Ξ± signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. |
| GO:0019899 enzyme binding | IPI PMID:23103912 PARP16 is a tail-anchored endoplasmic reticulum protein requ... | KEEP AS NON CORE | Summary: PARP16 binds and ADP-ribosylates IRE1alpha, enhancing its kinase and RNase activities. Reason: The cited study shows that the tail-anchored ER protein PARP16 binds IRE1-alpha and ADP-ribosylates it, increasing its kinase and endonuclease activities (PMID:23103912), so the interaction with an enzyme is real and the annotation is true as stated. In this interaction ERN1 is the target that PARP16 modifies rather than a protein whose function is to bind enzymes, and the regulatory relationship is better described on PARP16; the term is therefore peripheral to ERN1's own activities and is kept as non-core rather than removed. Supporting Evidence: PMID:23103912 As is the case for other PARPs that function during stress, the enzymatic activity of PARP16 is upregulated during ER stress when it ADP-ribosylates itself, PERK and IRE1Ξ±. |
| GO:0030544 Hsp70 protein binding | IPI PMID:20625543 HSP72 protects cells from ER stress-induced apoptosis via en... | KEEP AS NON CORE | Summary: Cytosolic HSP72 (HSPA1A) forms a stable complex with the cytosolic domain of IRE1alpha and enhances its RNase activity. Reason: Well-supported regulatory interaction; luminal BiP (an Hsp70) binding is also a key regulatory interaction. Non-core relative to catalytic functions. Supporting Evidence: PMID:20625543 Regulation of the UPR was associated with the formation of a stable protein complex between Hsp72 and the cytosolic domain of IRE1alpha. Finally, Hsp72 enhanced the RNase activity of recombinant IRE1alpha in vitro, suggesting a direct regulation. |
| GO:0030968 endoplasmic reticulum unfolded protein response | IDA PMID:20625543 HSP72 protects cells from ER stress-induced apoptosis via en... | ACCEPT | Summary: ERN1 is a proximal sensor and transducer of the ER unfolded protein response. Reason: Correct parent terms of the IRE1-mediated UPR, in which ERN1 is the defining component. Supporting Evidence: PMID:20625543 We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. |
| GO:0030968 endoplasmic reticulum unfolded protein response | IEA GO_REF:0000002 | ACCEPT | Summary: ERN1 is a proximal sensor and transducer of the ER unfolded protein response. Reason: Correct parent terms of the IRE1-mediated UPR, in which ERN1 is the defining component. Supporting Evidence: PMID:9637683 These results demonstrate that hIre1p is an essential proximal sensor of the unfolded protein response pathway in mammalian cells. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000117 | MODIFY | Summary: Electronic assignment of generic protein-containing complex. Reason: Uninformative generic term; IRE1alpha forms stress-induced homo-oligomeric assemblies (Ire1 complex). Proposed replacements: Ire1 complex Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities |
| GO:0033120 positive regulation of RNA splicing | IDA PMID:19622636 Unconventional splicing of XBP1 mRNA occurs in the cytoplasm... | MODIFY | Summary: IRE1alpha catalyses the unconventional cytoplasmic splicing of XBP1 mRNA. Reason: ERN1 does not regulate splicing; it is the endonuclease that performs the cleavage step of XBP1 mRNA unconventional splicing. The process term GO:0070054 describes its role directly. Proposed replacements: mRNA splicing, via endonucleolytic cleavage and ligation Supporting Evidence: PMID:19622636 From these observations, we concluded that unconventional splicing of XBP1 mRNA occurs predominantly in the cytoplasm. file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0033120 positive regulation of RNA splicing | IEA GO_REF:0000120 | MODIFY | Summary: IRE1alpha catalyses the unconventional cytoplasmic splicing of XBP1 mRNA. Reason: ERN1 does not regulate splicing; it is the endonuclease that performs the cleavage step of XBP1 mRNA unconventional splicing. The process term GO:0070054 describes its role directly. Proposed replacements: mRNA splicing, via endonucleolytic cleavage and ligation Supporting Evidence: PMID:19622636 From these observations, we concluded that unconventional splicing of XBP1 mRNA occurs predominantly in the cytoplasm. file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0034620 cellular response to unfolded protein | IDA PMID:19328063 BAX inhibitor-1 is a negative regulator of the ER stress sen... | ACCEPT | Summary: ERN1 is a proximal sensor and transducer of the ER unfolded protein response. Reason: Correct parent terms of the IRE1-mediated UPR, in which ERN1 is the defining component. Supporting Evidence: PMID:19328063 BI-1-deficient cells displayed hyperactivation of the ER stress sensor IRE1alpha, leading to increased levels of its downstream target X-box-binding protein-1 (XBP-1) and upregulation of UPR target genes. |
| GO:0034620 cellular response to unfolded protein | IMP PMID:20625543 HSP72 protects cells from ER stress-induced apoptosis via en... | ACCEPT | Summary: ERN1 is a proximal sensor and transducer of the ER unfolded protein response. Reason: Correct parent terms of the IRE1-mediated UPR, in which ERN1 is the defining component. Supporting Evidence: PMID:20625543 We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. |
| GO:0034620 cellular response to unfolded protein | IMP PMID:21317875 Structure of the Ire1 autophosphorylation complex and implic... | ACCEPT | Summary: ERN1 is a proximal sensor and transducer of the ER unfolded protein response. Reason: Correct parent terms of the IRE1-mediated UPR, in which ERN1 is the defining component. Supporting Evidence: PMID:21317875 Activation of Ire1 by association of its N-terminal ER luminal domains promotes autophosphorylation by its cytoplasmic kinase domain, leading to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA generating an active Xbp1s transcriptional activator. |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:10650002 Coupling of stress in the ER to activation of JNK protein ki... | ACCEPT | Summary: ERN1 is a proximal sensor and transducer of the ER unfolded protein response. Reason: Correct parent terms of the IRE1-mediated UPR, in which ERN1 is the defining component. Supporting Evidence: PMID:10650002 Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. |
| GO:0035924 cellular response to vascular endothelial growth factor stimulus | IDA PMID:23529610 Vascular endothelial cell growth-activated XBP1 splicing in ... | KEEP AS NON CORE | Summary: VEGF induces KDR-IRE1alpha interaction, IRE1alpha phosphorylation and XBP1 splicing in endothelial cells. Reason: Context-specific activation of IRE1 by a growth factor receptor; supported but peripheral. Supporting Evidence: PMID:23529610 We found that vascular endothelial cell growth factor induced the kinase insert domain receptor internalization and interaction through C-terminal domain with the unspliced XBP1 and the inositol requiring enzyme 1 Ξ± in the endoplasmic reticulum, leading to inositol requiring enzyme 1 Ξ± phosphorylation and XBP1 mRNA splicing |
| GO:0036498 IRE1-mediated unfolded protein response | IBA GO_REF:0000033 | ACCEPT | Summary: ERN1 is the defining sensor/effector of the IRE1 branch of the UPR: it senses ER stress, autophosphorylates and splices XBP1 mRNA to produce the XBP1s transcription factor. Reason: Core biological process; extensively supported experimentally and phylogenetically. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) PMID:21317875 Activation of Ire1 by association of its N-terminal ER luminal domains promotes autophosphorylation by its cytoplasmic kinase domain, leading to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA generating an active Xbp1s transcriptional activator. |
| GO:0036498 IRE1-mediated unfolded protein response | IDA PMID:11779464 XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response... | ACCEPT | Summary: ERN1 is the defining sensor/effector of the IRE1 branch of the UPR: it senses ER stress, autophosphorylates and splices XBP1 mRNA to produce the XBP1s transcription factor. Reason: Core biological process; extensively supported experimentally and phylogenetically. Supporting Evidence: PMID:11779464 Here, we identified the transcription factor XBP1, a target of ATF6, as a mammalian substrate of such an unconventional mRNA splicing system and showed that only the spliced form of XBP1 can activate the UPR efficiently. |
| GO:0036498 IRE1-mediated unfolded protein response | IDA PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | ACCEPT | Summary: ERN1 is the defining sensor/effector of the IRE1 branch of the UPR: it senses ER stress, autophosphorylates and splices XBP1 mRNA to produce the XBP1s transcription factor. Reason: Core biological process; extensively supported experimentally and phylogenetically. Supporting Evidence: PMID:11779465 C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress. |
| GO:0036498 IRE1-mediated unfolded protein response | IDA PMID:19328063 BAX inhibitor-1 is a negative regulator of the ER stress sen... | ACCEPT | Summary: ERN1 is the defining sensor/effector of the IRE1 branch of the UPR: it senses ER stress, autophosphorylates and splices XBP1 mRNA to produce the XBP1s transcription factor. Reason: Core biological process; extensively supported experimentally and phylogenetically. Supporting Evidence: PMID:19328063 BI-1-deficient cells displayed hyperactivation of the ER stress sensor IRE1alpha, leading to increased levels of its downstream target X-box-binding protein-1 (XBP-1) and upregulation of UPR target genes. |
| GO:0036498 IRE1-mediated unfolded protein response | IDA PMID:29198525 A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and... | ACCEPT | Summary: ERN1 is the defining sensor/effector of the IRE1 branch of the UPR: it senses ER stress, autophosphorylates and splices XBP1 mRNA to produce the XBP1s transcription factor. Reason: Core biological process; extensively supported experimentally and phylogenetically. Supporting Evidence: PMID:29198525 ERdj4 associates with IRE1LD and recruits BiP through the stimulation of ATP hydrolysis, forcibly disrupting IRE1 dimers. Unfolded proteins compete for BiP and restore IRE1LD to its default, dimeric, and active state. |
| GO:0036498 IRE1-mediated unfolded protein response | IDA PMID:9637683 A stress response pathway from the endoplasmic reticulum to ... | ACCEPT | Summary: ERN1 is the defining sensor/effector of the IRE1 branch of the UPR: it senses ER stress, autophosphorylates and splices XBP1 mRNA to produce the XBP1s transcription factor. Reason: Core biological process; extensively supported experimentally and phylogenetically. Supporting Evidence: PMID:9637683 These results demonstrate that hIre1p is an essential proximal sensor of the unfolded protein response pathway in mammalian cells. |
| GO:0036498 IRE1-mediated unfolded protein response | IEA GO_REF:0000120 | ACCEPT | Summary: ERN1 is the defining sensor/effector of the IRE1 branch of the UPR: it senses ER stress, autophosphorylates and splices XBP1 mRNA to produce the XBP1s transcription factor. Reason: Core biological process; extensively supported experimentally and phylogenetically. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) PMID:21317875 Activation of Ire1 by association of its N-terminal ER luminal domains promotes autophosphorylation by its cytoplasmic kinase domain, leading to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA generating an active Xbp1s transcriptional activator. |
| GO:0036498 IRE1-mediated unfolded protein response | IMP PMID:28128204 A critical role of DDRGK1 in endoplasmic reticulum homoeosta... | ACCEPT | Summary: ERN1 is the defining sensor/effector of the IRE1 branch of the UPR: it senses ER stress, autophosphorylates and splices XBP1 mRNA to produce the XBP1s transcription factor. Reason: Core biological process; extensively supported experimentally and phylogenetically. Supporting Evidence: PMID:28128204 Depletion of DDRGK1 represses IRE1Ξ±-XBP1 signalling |
| GO:0042802 identical protein binding | IPI PMID:12637535 Structure and intermolecular interactions of the luminal dim... | MODIFY | Summary: IRE1alpha self-associates through its luminal domain and its cytosolic kinase domain. Reason: Self-association of ERN1 is homodimerization/oligomerization; the more specific GO:0042803 term is already used and better describes it. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:12637535 Previously we demonstrated that the NLD forms a stable ligand-independent dimer linked by disulfide bridges. |
| GO:0042802 identical protein binding | IPI PMID:21317875 Structure of the Ire1 autophosphorylation complex and implic... | MODIFY | Summary: IRE1alpha self-associates through its luminal domain and its cytosolic kinase domain. Reason: Self-association of ERN1 is homodimerization/oligomerization; the more specific GO:0042803 term is already used and better describes it. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:21317875 We have determined the crystal structure of the cytoplasmic portion of dephosphorylated human Ire1Ξ± bound to ADP, revealing the 'phosphoryl-transfer' competent dimeric face-to-face complex |
| GO:0042803 protein homodimerization activity | IDA PMID:29198525 A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and... | ACCEPT | Summary: Stress-induced homodimerization/oligomerization of IRE1alpha drives trans-autophosphorylation and RNase activation. Reason: Dimerization is the central activation mechanism and is directly demonstrated structurally and biochemically. Supporting Evidence: PMID:29198525 ERdj4 associates with IRE1LD and recruits BiP through the stimulation of ATP hydrolysis, forcibly disrupting IRE1 dimers. Unfolded proteins compete for BiP and restore IRE1LD to its default, dimeric, and active state. |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000120 | ACCEPT | Summary: Stress-induced homodimerization/oligomerization of IRE1alpha drives trans-autophosphorylation and RNase activation. Reason: Dimerization is the central activation mechanism and is directly demonstrated structurally and biochemically. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities |
| GO:0042803 protein homodimerization activity | IPI PMID:21317875 Structure of the Ire1 autophosphorylation complex and implic... | ACCEPT | Summary: Stress-induced homodimerization/oligomerization of IRE1alpha drives trans-autophosphorylation and RNase activation. Reason: Dimerization is the central activation mechanism and is directly demonstrated structurally and biochemically. Supporting Evidence: PMID:21317875 We have determined the crystal structure of the cytoplasmic portion of dephosphorylated human Ire1Ξ± bound to ADP, revealing the 'phosphoryl-transfer' competent dimeric face-to-face complex |
| GO:0042803 protein homodimerization activity | ISS GO_REF:0000024 | ACCEPT | Summary: Stress-induced homodimerization/oligomerization of IRE1alpha drives trans-autophosphorylation and RNase activation. Reason: Dimerization is the central activation mechanism and is directly demonstrated structurally and biochemically. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities |
| GO:0043531 ADP binding | IDA PMID:21317875 Structure of the Ire1 autophosphorylation complex and implic... | KEEP AS NON CORE | Summary: The crystal structure of the IRE1alpha cytoplasmic domain was solved bound to ADP. Reason: Nucleotide binding in the kinase pocket is real; ADP binding per se is a facet of ATP-site occupancy rather than a distinct function. Supporting Evidence: PMID:21317875 We have determined the crystal structure of the cytoplasmic portion of dephosphorylated human Ire1Ξ± bound to ADP, revealing the 'phosphoryl-transfer' competent dimeric face-to-face complex |
| GO:0046330 positive regulation of JNK cascade | IDA PMID:10650002 Coupling of stress in the ER to activation of JNK protein ki... | KEEP AS NON CORE | Summary: IRE1alpha activates JNK through recruitment of TRAF2 to its cytoplasmic domain; IRE1alpha-/- fibroblasts are impaired in ER stress-induced JNK activation. Reason: Well-supported scaffolding output of ERN1, distinct from its RNase-dependent core role. Supporting Evidence: PMID:10650002 Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. |
| GO:0046330 positive regulation of JNK cascade | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IRE1alpha activates JNK through recruitment of TRAF2 to its cytoplasmic domain; IRE1alpha-/- fibroblasts are impaired in ER stress-induced JNK activation. Reason: Well-supported scaffolding output of ERN1, distinct from its RNase-dependent core role. Supporting Evidence: PMID:10650002 Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. |
| GO:0051879 Hsp90 protein binding | IDA PMID:12446770 Heat shock protein 90 modulates the unfolded protein respons... | KEEP AS NON CORE | Summary: HSP90 associates with the cytoplasmic domain of IRE1alpha and is required for its stability. Reason: ERN1 is an HSP90 client; the interaction is real but reflects client status rather than a core function. Supporting Evidence: PMID:12446770 We found that HSP90 associates with the cytoplasmic domains of both kinases. |
| GO:0070054 mRNA splicing, via endonucleolytic cleavage and ligation | IDA PMID:11779464 XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response... | ACCEPT | Summary: IRE1alpha excises the 26-nt intron from XBP1 mRNA; the exons are joined by the RtcB ligase. Reason: Core process executed by ERN1's endoribonuclease activity. Supporting Evidence: PMID:11779464 Here, we identified the transcription factor XBP1, a target of ATF6, as a mammalian substrate of such an unconventional mRNA splicing system and showed that only the spliced form of XBP1 can activate the UPR efficiently. file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0070054 mRNA splicing, via endonucleolytic cleavage and ligation | IDA PMID:19328063 BAX inhibitor-1 is a negative regulator of the ER stress sen... | ACCEPT | Summary: IRE1alpha excises the 26-nt intron from XBP1 mRNA; the exons are joined by the RtcB ligase. Reason: Core process executed by ERN1's endoribonuclease activity. Supporting Evidence: PMID:19328063 This phenotype was associated with the formation of a stable protein complex between BI-1 and IRE1alpha, decreasing its ribonuclease activity. file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0070054 mRNA splicing, via endonucleolytic cleavage and ligation | IDA PMID:19622636 Unconventional splicing of XBP1 mRNA occurs in the cytoplasm... | ACCEPT | Summary: IRE1alpha excises the 26-nt intron from XBP1 mRNA; the exons are joined by the RtcB ligase. Reason: Core process executed by ERN1's endoribonuclease activity. Supporting Evidence: PMID:19622636 From these observations, we concluded that unconventional splicing of XBP1 mRNA occurs predominantly in the cytoplasm. file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0070054 mRNA splicing, via endonucleolytic cleavage and ligation | IDA PMID:21317875 Structure of the Ire1 autophosphorylation complex and implic... | ACCEPT | Summary: IRE1alpha excises the 26-nt intron from XBP1 mRNA; the exons are joined by the RtcB ligase. Reason: Core process executed by ERN1's endoribonuclease activity. Supporting Evidence: PMID:21317875 Activation of Ire1 by association of its N-terminal ER luminal domains promotes autophosphorylation by its cytoplasmic kinase domain, leading to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA generating an active Xbp1s transcriptional activator. file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0070054 mRNA splicing, via endonucleolytic cleavage and ligation | IMP PMID:20625543 HSP72 protects cells from ER stress-induced apoptosis via en... | ACCEPT | Summary: IRE1alpha excises the 26-nt intron from XBP1 mRNA; the exons are joined by the RtcB ligase. Reason: Core process executed by ERN1's endoribonuclease activity. Supporting Evidence: PMID:20625543 We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0070054 mRNA splicing, via endonucleolytic cleavage and ligation | IMP PMID:21317875 Structure of the Ire1 autophosphorylation complex and implic... | ACCEPT | Summary: IRE1alpha excises the 26-nt intron from XBP1 mRNA; the exons are joined by the RtcB ligase. Reason: Core process executed by ERN1's endoribonuclease activity. Supporting Evidence: PMID:21317875 Activation of Ire1 by association of its N-terminal ER luminal domains promotes autophosphorylation by its cytoplasmic kinase domain, leading to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA generating an active Xbp1s transcriptional activator. file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0070054 mRNA splicing, via endonucleolytic cleavage and ligation | TAS PMID:22013210 The unfolded protein response: integrating stress signals th... | ACCEPT | Summary: IRE1alpha excises the 26-nt intron from XBP1 mRNA; the exons are joined by the RtcB ligase. Reason: Core process executed by ERN1's endoribonuclease activity. Supporting Evidence: PMID:22013210 Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1Ξ±), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). file:human/ERN1/ERN1-uniprot.txt The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Under unresolved ER stress, IRE1alpha promotes apoptosis, e.g. via TRAF2-ASK1-JNK signaling. Reason: ERN1 contributes to ER stress-induced apoptotic signaling through its scaffolding of TRAF2/ASK1 and RIDD; this is supported in mammals and conserved in the family (IBA), but is secondary to its adaptive UPR role. Supporting Evidence: PMID:10650002 Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. PMID:23000344 Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling. |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Under unresolved ER stress, IRE1alpha promotes apoptosis, e.g. via TRAF2-ASK1-JNK signaling. Reason: ERN1 contributes to ER stress-induced apoptotic signaling through its scaffolding of TRAF2/ASK1 and RIDD; this is supported in mammals and conserved in the family (IBA), but is secondary to its adaptive UPR role. Supporting Evidence: PMID:10650002 Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. PMID:23000344 Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling. |
| GO:0070301 cellular response to hydrogen peroxide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic orthology transfer of cellular response to hydrogen peroxide. Reason: No direct evidence that human ERN1 functions specifically in hydrogen peroxide responses; at most an indirect consequence of oxidative ER stress. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) |
| GO:0071333 cellular response to glucose stimulus | IDA PMID:20103773 A crucial role for RACK1 in the regulation of glucose-stimul... | KEEP AS NON CORE | Summary: Glucose stimulates IRE1alpha activation in pancreatic beta cells, regulated by a RACK1-PP2A complex. Reason: Physiological, cell-type-specific activation context for ERN1 (beta-cell proinsulin load). Supporting Evidence: PMID:20103773 RACK1 mediated the glucose-inducible assembly of a complex containing IRE1alpha, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1alpha by PP2A, thereby inhibiting glucose-stimulated IRE1alpha activation and attenuating IRE1alpha-dependent increases in insulin production. |
| GO:0071333 cellular response to glucose stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Glucose stimulates IRE1alpha activation in pancreatic beta cells, regulated by a RACK1-PP2A complex. Reason: Physiological, cell-type-specific activation context for ERN1 (beta-cell proinsulin load). Supporting Evidence: PMID:20103773 RACK1 mediated the glucose-inducible assembly of a complex containing IRE1alpha, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1alpha by PP2A, thereby inhibiting glucose-stimulated IRE1alpha activation and attenuating IRE1alpha-dependent increases in insulin production. |
| GO:0106310 protein serine kinase activity | EXP PMID:21317875 Structure of the Ire1 autophosphorylation complex and implic... | ACCEPT | Summary: IRE1alpha has intrinsic serine/threonine kinase activity: it trans-autophosphorylates upon dimerization, which is required for RNase activation, and can phosphorylate a heterologous peptide substrate. Reason: Directly demonstrated kinase activity; physiologically the principal substrate is IRE1 itself (trans-autophosphorylation in the activation loop) and this activity licenses the endoribonuclease. Supporting Evidence: PMID:21317875 Furthermore, we demonstrate that activated Ire1Ξ± is a competent protein kinase, able to phosphorylate a heterologous peptide substrate. PMID:21317875 We show that the Xbp1-specific ribonuclease activity depends on autophosphorylation file:human/ERN1/ERN1-uniprot.txt The kinase domain is activated by trans- autophosphorylation following homodimerization |
| GO:0106310 protein serine kinase activity | EXP PMID:9637683 A stress response pathway from the endoplasmic reticulum to ... | ACCEPT | Summary: IRE1alpha has intrinsic serine/threonine kinase activity: it trans-autophosphorylates upon dimerization, which is required for RNase activation, and can phosphorylate a heterologous peptide substrate. Reason: Directly demonstrated kinase activity; physiologically the principal substrate is IRE1 itself (trans-autophosphorylation in the activation loop) and this activity licenses the endoribonuclease. Supporting Evidence: PMID:9637683 hIre1p expressed in mammalian cells displayed intrinsic autophosphorylation activity and an endoribonuclease activity that cleaved the 5' splice site of yeast HAC1 mRNA, a substrate for the endoribonuclease activity of yeast Ire1p. file:human/ERN1/ERN1-uniprot.txt The kinase domain is activated by trans- autophosphorylation following homodimerization |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IRE1alpha has intrinsic serine/threonine kinase activity: it trans-autophosphorylates upon dimerization, which is required for RNase activation, and can phosphorylate a heterologous peptide substrate. Reason: Directly demonstrated kinase activity; physiologically the principal substrate is IRE1 itself (trans-autophosphorylation in the activation loop) and this activity licenses the endoribonuclease. Supporting Evidence: PMID:21317875 Furthermore, we demonstrate that activated Ire1Ξ± is a competent protein kinase, able to phosphorylate a heterologous peptide substrate. PMID:21317875 We show that the Xbp1-specific ribonuclease activity depends on autophosphorylation file:human/ERN1/ERN1-uniprot.txt The kinase domain is activated by trans- autophosphorylation following homodimerization |
| GO:1900103 positive regulation of endoplasmic reticulum unfolded protein response | IMP PMID:28128204 A critical role of DDRGK1 in endoplasmic reticulum homoeosta... | MARK AS OVER ANNOTATED | Summary: Depletion of the IRE1alpha-stabilizing factor DDRGK1 represses IRE1alpha-XBP1 signaling. Reason: ERN1 is a core executor of the ER UPR (GO:0036498), not a regulator of it; the regulatory term is redundant with, and less accurate than, its participation annotations. Supporting Evidence: PMID:28128204 Depletion of DDRGK1 represses IRE1Ξ±-XBP1 signalling |
| GO:1901142 insulin metabolic process | IDA PMID:20103773 A crucial role for RACK1 in the regulation of glucose-stimul... | MARK AS OVER ANNOTATED | Summary: IRE1alpha activation increases insulin production in beta cells (PMID:20103773). Reason: Insulin metabolic process is an indirect downstream outcome of IRE1-dependent ER capacity in beta cells; ERN1 does not participate in insulin metabolism itself. Supporting Evidence: PMID:20103773 RACK1 mediated the glucose-inducible assembly of a complex containing IRE1alpha, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1alpha by PP2A, thereby inhibiting glucose-stimulated IRE1alpha activation and attenuating IRE1alpha-dependent increases in insulin production. |
| GO:1904707 positive regulation of vascular associated smooth muscle cell proliferation | IMP PMID:26315405 XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vess... | KEEP AS NON CORE | Summary: PDGF-BB triggers IRE1alpha-dependent XBP1 splicing and XBP1s promotes SMC proliferation and migration. Reason: Context-specific upstream regulatory role mediated via XBP1s; non-core. Supporting Evidence: PMID:26315405 In vitro studies indicated that platelet-derived growth factor-BB triggered XBP1 splicing in SMCs via the interaction between platelet-derived growth factor receptor Ξ² and the inositol-requiring enzyme 1Ξ±. PMID:26315405 The spliced XBP1 (XBP1s) increased SMC migration via PI3K/Akt activation and proliferation via downregulating calponin h1 (CNN1). |
| GO:1990332 Ire1 complex | NAS PMID:19328063 BAX inhibitor-1 is a negative regulator of the ER stress sen... | ACCEPT | Summary: IRE1alpha forms homodimers/oligomers upon ER stress. Reason: The Ire1 complex (homo-oligomer) is the active signaling unit of ERN1. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities PMID:19328063 This phenotype was associated with the formation of a stable protein complex between BI-1 and IRE1alpha, decreasing its ribonuclease activity. |
| GO:1990597 AIP1-IRE1 complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer of AIP1(DAB2IP)-IRE1 complex membership from mouse. Reason: UniProt notes the DAB2IP interaction (by similarity) that is required for TRAF2 recruitment; plausible signaling complex, non-core. Supporting Evidence: file:human/ERN1/ERN1-uniprot.txt Interacts with DAB2IP (via PH domain); the interaction occurs in a endoplasmic reticulum stress- induced dependent manner and is required for subsequent recruitment of TRAF2 to ERN1/IRE1 |
| GO:1990604 IRE1-TRAF2-ASK1 complex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IRE1alpha recruits TRAF2 and ASK1 to form a pro-apoptotic JNK-activating signaling complex. Reason: Supported signaling complex underlying IRE1-JNK output; non-core. Supporting Evidence: PMID:10650002 Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. |
| GO:1990604 IRE1-TRAF2-ASK1 complex | IDA PMID:23000344 Ursolic acid induces ER stress response to activate ASK1-JNK... | KEEP AS NON CORE | Summary: IRE1alpha recruits TRAF2 and ASK1 to form a pro-apoptotic JNK-activating signaling complex. Reason: Supported signaling complex underlying IRE1-JNK output; non-core. Supporting Evidence: PMID:23000344 Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling. PMID:10650002 Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. |
| GO:1990630 IRE1-RACK1-PP2A complex | IDA PMID:20103773 A crucial role for RACK1 in the regulation of glucose-stimul... | KEEP AS NON CORE | Summary: Glucose induces assembly of an IRE1alpha-RACK1-PP2A complex promoting IRE1 dephosphorylation. Reason: Supported regulatory complex in beta cells; non-core. Supporting Evidence: PMID:20103773 RACK1 mediated the glucose-inducible assembly of a complex containing IRE1alpha, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1alpha by PP2A, thereby inhibiting glucose-stimulated IRE1alpha activation and attenuating IRE1alpha-dependent increases in insulin production. |
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Download this section (compressed HTML)Q: Does human IRE1alpha luminal domain bind unfolded polypeptides directly (as for yeast Ire1), or is activation governed predominantly by BiP/ERdj4 competition?
Q: What determines the switch between XBP1 splicing and RIDD/apoptotic outputs of IRE1alpha under prolonged ER stress?
Q: Are the many reported cytosolic interactors (TRAF2, JAB1, USP14, RACK1, PARP16, DDRGK1) assembled into a single UPRosome scaffold or into distinct context-specific complexes?
Experiment: In cells expressing kinase-dead but RNase-activatable IRE1alpha (e.g. ATP-site mutants rescued by 1NM-PP1), quantify XBP1 splicing versus RIDD target decay to separate kinase-dependent and kinase-independent outputs.
Experiment: Reconstitute IRE1alpha luminal domain with BiP, ERdj4 and model unfolded substrates in vitro to measure how each controls dimer/oligomer assembly.
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