--- id: Q09499 gene_symbol: ire-1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:6239 label: Caenorhabditis elegans description: 'IRE-1 is a conserved ER transmembrane stress sensor with dual enzymatic activities: a serine/threonine protein kinase and an endoribonuclease. The core function is sensing unfolded proteins in the ER lumen and transducing this signal to the cytosol through trans-autophosphorylation of its kinase domain, which activates its RNase domain to catalyze unconventional cytoplasmic splicing of xbp-1 mRNA, generating the active XBP-1s transcription factor that induces UPR target genes. IRE-1 also executes Regulated IRE1-Dependent Decay (RIDD) of select mRNAs including daf-7. The protein localizes to the ER membrane as a type I single-pass transmembrane protein with a luminal stress-sensing domain and cytosolic kinase-RNase effector domains. IRE-1 acts in one of three parallel UPR-ER branches (with PEK-1 and ATF-6), showing synthetic lethality with loss of a second branch. Neuronal IRE-1 also mediates cell-nonautonomous signaling including germline apoptosis regulation and anticipatory stress responses.' existing_annotations: - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: IRE-1 is an ER-localized protein. UniProt and experimental evidence from PMID:11779465 confirm ER membrane localization. This annotation is correct but the more specific term GO:0005789 (endoplasmic reticulum membrane) would be more accurate as IRE-1 is a transmembrane protein. action: ACCEPT reason: IRE-1 localizes to the ER as confirmed by multiple sources including UniProt subcellular location annotation. While GO:0005789 (ER membrane) is more precise, this broader term is acceptable for IBA-level evidence. The protein is a type I single-pass ER transmembrane sensor. supported_by: - reference_id: UniProt:Q09499 supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:11779465}; Single-pass type I membrane protein {ECO:0000269|PubMed:11779465}' - reference_id: file:worm/ire-1/ire-1-deep-research-falcon.md supporting_text: 'model: Edison Scientific Literature' - term: id: GO:0036498 label: IRE1-mediated unfolded protein response evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: This is the core biological process for IRE-1. The protein is the eponymous component of the IRE1-mediated UPR branch. In C. elegans, IRE-1 mediates xbp-1 mRNA splicing to generate XBP-1s transcription factor for UPR gene transcription (PMID:11779465, PMID:11780124). action: ACCEPT reason: This is the definitive core function of IRE-1. The annotation is well-supported by multiple studies demonstrating that C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress. supported_by: - reference_id: PMID:11779465 supporting_text: C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress - reference_id: PMID:11780124 supporting_text: Activation of the UPR causes IRE1-dependent splicing of a small intron from the XBP-1 mRNA both in C. elegans and mice - term: id: GO:0004521 label: RNA endonuclease activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: IRE-1 has an endoribonuclease domain that cleaves xbp-1 mRNA in a non-conventional cytoplasmic splicing reaction. The RNase activity also mediates RIDD (Regulated IRE1-Dependent Decay) of select mRNAs including daf-7. action: ACCEPT reason: 'RNA endonuclease activity is a core catalytic function of IRE-1. The RNase domain has two known outputs: (1) unconventional splicing of xbp-1 mRNA, and (2) RIDD of select mRNAs. This activity requires kinase domain activation.' supported_by: - reference_id: PMID:11780124 supporting_text: Purified mouse IRE1 accurately cleaved XBP-1 mRNA in vitro, indicating that XBP-1 mRNA is a direct target of IRE1 endonucleolytic activity - reference_id: file:worm/ire-1/ire-1-bioreason-rl-predictions.md supporting_text: "IRE-1's RNase has two outputs: (i) non-conventional cytoplasmic\ \ splicing of xbp-1 mRNA to produce XBP-1s; and (ii) regulated IRE1-dependent\ \ decay (RIDD) of select ER-targeted mRNAs" - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: IRE-1 contains a cytosolic serine/threonine protein kinase domain that undergoes trans-autophosphorylation to activate the endoribonuclease domain. Kinase activity is essential for RNase function. action: ACCEPT reason: The kinase domain is a core catalytic function of IRE-1. Trans-autophosphorylation of the kinase domain is required for activation of the endoribonuclease. The kinase-dead G723R mutation abolishes both xbp-1 splicing and RIDD activity. supported_by: - reference_id: UniProt:Q09499 supporting_text: The kinase domain is activated by trans- autophosphorylation. Kinase activity is required for activation of the endoribonuclease domain (By similarity) - term: id: GO:0051082 label: unfolded protein binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: IRE-1 senses unfolded proteins in the ER lumen via its N-terminal luminal domain, which leads to enzyme auto-activation. This sensing function is fundamental to UPR activation. action: REMOVE reason: GO:0051082 is now formally obsolete. IRE-1 senses unfolded proteins in the ER lumen to trigger UPR signaling, but this is not chaperone-type unfolded protein binding. The sensing function is captured by the endoribonuclease and kinase activities plus UPR biological process annotations. supported_by: - reference_id: UniProt:Q09499 supporting_text: Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto- activation (PubMed:11779465) - term: id: GO:0070059 label: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: IRE-1 mediates ER stress-induced apoptosis through an XBP-1-independent pathway. In C. elegans, IRE-1 regulates germline apoptosis cell non-autonomously from sensory neurons. This pro-apoptotic role is distinct from the adaptive UPR response. action: KEEP_AS_NON_CORE reason: While the adaptive UPR response is the core function, IRE-1 also has pro-apoptotic signaling functions under severe or prolonged ER stress. In C. elegans, this is notably cell non-autonomous, with neuronal IRE-1 regulating germline apoptosis. This is a secondary function that occurs under specific stress conditions. supported_by: - reference_id: PMID:25340700 supporting_text: This process is mediated by the ER stress response sensor IRE-1, but is independent of its canonical downstream target XBP-1 - term: id: GO:0000166 label: nucleotide binding evidence_type: IEA original_reference_id: GO_REF:0000043 qualifier: enables review: summary: IRE-1 binds ATP for its kinase activity. This is a parent term of ATP binding which is more specific. action: ACCEPT reason: Correct annotation as the kinase domain requires nucleotide (ATP) binding for catalytic activity. The more specific term GO:0005524 (ATP binding) is also present and is preferred, but this broader term is acceptable for IEA evidence. supported_by: - reference_id: UniProt:Q09499 supporting_text: ATP-binding; Endoplasmic reticulum; Glycoprotein; Hydrolase; Kinase - term: id: GO:0003824 label: catalytic activity evidence_type: IEA original_reference_id: GO_REF:0000043 qualifier: enables review: summary: IRE-1 has dual catalytic activities - kinase and endoribonuclease. This is a very general parent term. action: ACCEPT reason: While very general, this accurately reflects that IRE-1 is a bifunctional enzyme. More specific child terms for both kinase and RNase activities are also annotated. supported_by: - reference_id: UniProt:Q09499 supporting_text: 'RecName: Full=Serine/threonine-protein kinase; EC=2.7.11.1; Includes: RecName: Full=Endoribonuclease; EC=3.1.26.-' - term: id: GO:0004521 label: RNA endonuclease activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: Duplicate annotation of RNA endonuclease activity from InterPro mapping. Same as the IBA annotation above. action: ACCEPT reason: Valid annotation via InterPro domain mapping. The KEN domain (IPR010513) and RNase_Ire1 (cd10422) domains support this function. Duplicates are acceptable when from different evidence sources. supported_by: - reference_id: UniProt:Q09499 supporting_text: InterPro; IPR010513; KEN_dom - term: id: GO:0004540 label: RNA nuclease activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: Parent term of RNA endonuclease activity. IRE-1 cleaves RNA endonucleolytically, not exonucleolytically. action: ACCEPT reason: Accurate general term for the RNase activity of IRE-1. The more specific child term GO:0004521 (RNA endonuclease activity) is also annotated and preferred. supported_by: - reference_id: UniProt:Q09499 supporting_text: 'Includes: RecName: Full=Endoribonuclease; EC=3.1.26.-' - term: id: GO:0004672 label: protein kinase activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: IRE-1 has protein kinase activity via its cytosolic kinase domain. This is a parent term of protein serine/threonine kinase activity. action: ACCEPT reason: Accurate annotation from InterPro domain mapping. The Pkinase domain (PF00069) is present. More specific child term for Ser/Thr kinase is also annotated. supported_by: - reference_id: UniProt:Q09499 supporting_text: InterPro; IPR000719; Prot_kinase_dom - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Duplicate annotation of protein serine/threonine kinase activity from combined automated methods. action: ACCEPT reason: Valid annotation consistent with the kinase domain function. The IBA annotation is also present. Duplicates from different evidence sources are acceptable. supported_by: - reference_id: UniProt:Q09499 supporting_text: GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:WormBase - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: IRE-1 kinase domain binds ATP as substrate for phosphotransfer reactions. action: ACCEPT reason: Core molecular function required for kinase activity. ATP binding is essential for the trans-autophosphorylation that activates the RNase domain. supported_by: - reference_id: UniProt:Q09499 supporting_text: 'CATALYTIC ACTIVITY: Reaction=L-seryl' - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: IRE-1 is a type I single-pass ER transmembrane protein with luminal stress-sensing domain and cytosolic effector domains. action: ACCEPT reason: This is the correct and specific localization for IRE-1 as an ER membrane protein. More accurate than the broader GO:0005783 (ER) term. supported_by: - reference_id: UniProt:Q09499 supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:11779465}; Single-pass type I membrane protein {ECO:0000269|PubMed:11779465}' - term: id: GO:0006397 label: mRNA processing evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: IRE-1 processes xbp-1 mRNA through unconventional cytoplasmic splicing, removing a small intron to generate the active XBP-1s form. action: ACCEPT reason: Valid annotation reflecting the mRNA splicing function. The term captures the processing of xbp-1 mRNA, though the more specific IRE1-mediated UPR term is preferred for capturing the biological context. supported_by: - reference_id: PMID:11780124 supporting_text: Activation of the UPR causes IRE1-dependent splicing of a small intron from the XBP-1 mRNA - term: id: GO:0006986 label: response to unfolded protein evidence_type: IEA original_reference_id: GO_REF:0000043 qualifier: involved_in review: summary: IRE-1 is a primary sensor and responder to unfolded proteins in the ER lumen. action: ACCEPT reason: Core biological process annotation. IRE-1 detects unfolded proteins via its luminal domain and activates the UPR to restore ER homeostasis. supported_by: - reference_id: PMID:11779465 supporting_text: The unfolded protein response (UPR) is a transcriptional and translational intracellular signaling pathway activated by the accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) - term: id: GO:0010468 label: regulation of gene expression evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: IRE-1 regulates gene expression by activating XBP-1s transcription factor through xbp-1 mRNA splicing. action: ACCEPT reason: Valid annotation as IRE-1 ultimately regulates expression of UPR target genes through XBP-1s. However, this is a very broad term; more specific terms like GO:0045944 (positive regulation of transcription by RNA polymerase II) are also annotated and more informative. supported_by: - reference_id: UniProt:Q09499 supporting_text: The active endoribonuclease domain splices xbp-1 precursor mRNA to produce the mature form which then induces transcription of UPR target genes (PubMed:11779465) - term: id: GO:0016301 label: kinase activity evidence_type: IEA original_reference_id: GO_REF:0000043 qualifier: enables review: summary: General parent term for the kinase activity of IRE-1. action: ACCEPT reason: Valid but general annotation. More specific child terms for protein Ser/Thr kinase activity are also present. supported_by: - reference_id: UniProt:Q09499 supporting_text: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family - term: id: GO:0016740 label: transferase activity evidence_type: IEA original_reference_id: GO_REF:0000043 qualifier: enables review: summary: Very general parent term capturing the phosphotransferase function of the kinase domain. action: ACCEPT reason: Valid but extremely general annotation. More specific terms are preferred. supported_by: - reference_id: UniProt:Q09499 supporting_text: Serine/threonine-protein kinase; EC=2.7.11.1 - term: id: GO:0016787 label: hydrolase activity evidence_type: IEA original_reference_id: GO_REF:0000043 qualifier: enables review: summary: General parent term for the endoribonuclease activity which hydrolyzes phosphodiester bonds in RNA. action: ACCEPT reason: Valid but general annotation. More specific RNA nuclease terms are preferred. supported_by: - reference_id: UniProt:Q09499 supporting_text: Endoribonuclease; EC=3.1.26.- - term: id: GO:0030968 label: endoplasmic reticulum unfolded protein response evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: IRE-1 is one of three sensors mediating the ER-UPR in metazoans. This term captures the broader UPR pathway. action: ACCEPT reason: Core biological process annotation. IRE-1 is a major and highly conserved ER stress sensor that activates the UPR. The child term GO:0036498 (IRE1-mediated UPR) is more specific. supported_by: - reference_id: PMID:11779465 supporting_text: We have used C. elegans as a genetic model system to dissect UPR signaling in a multicellular organism - term: id: GO:0034976 label: response to endoplasmic reticulum stress evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: IRE-1 responds to and mediates the cellular response to ER stress. action: ACCEPT reason: Valid annotation capturing IRE-1's role in ER stress response. This is a parent of the more specific UPR terms. supported_by: - reference_id: PMID:11779465 supporting_text: C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress - term: id: GO:0080090 label: regulation of primary metabolic process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Very broad term that encompasses IRE-1's regulatory role in protein folding homeostasis. action: MARK_AS_OVER_ANNOTATED reason: While technically accurate as UPR affects protein and lipid metabolism, this term is too broad to be informative about IRE-1's specific function. More specific UPR-related terms are preferred. supported_by: [] - term: id: GO:0106310 label: protein serine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000116 qualifier: enables review: summary: IRE-1 autophosphorylates on serine residues. This is more specific than protein Ser/Thr kinase activity. action: ACCEPT reason: Valid annotation based on Rhea mapping. UniProt indicates autophosphorylation mainly on serine residues. supported_by: - reference_id: UniProt:Q09499 supporting_text: 'PTM: Autophosphorylated mainly on serine residues' - term: id: GO:0036498 label: IRE1-mediated unfolded protein response evidence_type: IMP original_reference_id: PMID:20733002 qualifier: involved_in review: summary: Mao & Crowder 2010 showed that IRE-1 is required for hypoxic preconditioning in C. elegans, linking UPR activation to adaptive protection. action: ACCEPT reason: Valid experimental evidence. The study demonstrated that non-lethal hypoxia activates the UPR through IRE-1, and this confers adaptive protection to subsequent hypoxia. supported_by: - reference_id: PMID:20733002 supporting_text: the pharmacological induction of misfolded proteins is itself sufficient to stimulate a delayed protective response to hypoxic injury that requires the UPR pathway proteins IRE-1, XBP-1, and ATF-6 - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: IMP original_reference_id: PMID:18216284 qualifier: involved_in review: summary: Uccelletti et al. 2008 showed that IRE-1 is required for transcriptional upregulation of apy-1 and other UPR target genes upon ER stress. action: KEEP_AS_NON_CORE reason: Valid annotation showing IRE-1's downstream effect on transcription through XBP-1s activation. However, this is an indirect effect of the core xbp-1 splicing function rather than a direct transcriptional role. supported_by: - reference_id: PMID:18216284 supporting_text: ER stress induced by tunicamycin or high temperature resulted in increased transcription of apy-1. This increase was not observed in C. elegans mutants defective in ire-1 or atf-6 - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: IGI original_reference_id: PMID:18216284 qualifier: involved_in review: summary: Same study showing genetic interaction for transcriptional regulation of UPR target genes. action: KEEP_AS_NON_CORE reason: Valid genetic interaction evidence. The G723R kinase-dead mutation prevents transcriptional upregulation of apy-1 upon ER stress. This demonstrates the role of IRE-1 in UPR gene induction. supported_by: - reference_id: UniProt:Q09499 supporting_text: 'G->R: In zc14; loss of adaptive protection conferred by non-lethal hypoxia treatment. Prevents transcriptional up-regulation of apy-1 upon ER stress' - term: id: GO:0036498 label: IRE1-mediated unfolded protein response evidence_type: IGI original_reference_id: PMID:22125500 qualifier: involved_in review: summary: Richardson et al. 2011 demonstrated genetic interactions between ire-1, xbp-1, pek-1, and atf-6 in UPR signaling during development and immunity. action: ACCEPT reason: Valid genetic interaction evidence showing functional IRE-1 pathway in physiological conditions. XBP-1 deficiency causes constitutive ER stress with elevated IRE-1 activity. supported_by: - reference_id: PMID:22125500 supporting_text: XBP-1 deficiency results in constitutive ER stress, reflected by increased basal levels of IRE-1 and PEK-1 activity under physiological conditions - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: ISS original_reference_id: PMID:11779465 qualifier: enables review: summary: Sequence similarity to mammalian IRE1 kinase domain supports Ser/Thr kinase activity annotation. action: ACCEPT reason: Valid ISS annotation based on conserved kinase domain. The protein kinase domain (aa 518-778) is well-conserved with mammalian IRE1. supported_by: - reference_id: UniProt:Q09499 supporting_text: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family - term: id: GO:0030968 label: endoplasmic reticulum unfolded protein response evidence_type: IMP original_reference_id: PMID:25340700 qualifier: involved_in review: summary: Levi-Ferber et al. 2014 demonstrated IRE-1 function in ER stress response including cell non-autonomous signaling from neurons to germline. action: ACCEPT reason: Valid IMP evidence. The study showed ire-1 mutants fail to respond to ER stress conditions that increase germline apoptosis in wild-type animals. supported_by: - reference_id: PMID:25340700 supporting_text: pharmacological or genetic induction of ER stress enhances germline apoptosis. This process is mediated by the ER stress response sensor IRE-1 - term: id: GO:0043025 label: neuronal cell body evidence_type: IMP original_reference_id: PMID:23791175 qualifier: is_active_in review: summary: Taylor & Dillin 2013 showed neuronal IRE-1/XBP-1 signaling with cell non-autonomous effects on stress resistance and longevity. action: KEEP_AS_NON_CORE reason: Valid annotation reflecting neuronal localization and function. IRE-1 in neurons mediates cell non-autonomous signaling. However, neuronal cell body is a specific subcellular localization within neurons; the primary localization is ER membrane. supported_by: - reference_id: PMID:23791175 supporting_text: Neuronally derived XBP-1s was sufficient to rescue stress resistance, increase longevity, and activate the UPR(ER) in distal, non-neuronal cell types through a cell-nonautonomous mechanism - term: id: GO:0004521 label: RNA endonuclease activity evidence_type: IMP original_reference_id: PMID:11779465 qualifier: enables review: summary: Shen et al. 2001 demonstrated that IRE-1 mediates xbp-1 mRNA splicing in C. elegans, establishing its endoribonuclease activity. action: ACCEPT reason: Primary experimental evidence for the core endoribonuclease function. ire-1 is required for xbp-1 mRNA splicing in C. elegans. supported_by: - reference_id: PMID:11779465 supporting_text: C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress - term: id: GO:0036498 label: IRE1-mediated unfolded protein response evidence_type: IMP original_reference_id: PMID:11779465 qualifier: involved_in review: summary: Foundational study demonstrating IRE-1's role in UPR signaling in C. elegans. action: ACCEPT reason: Core experimental evidence for the eponymous IRE1-mediated UPR pathway. This study established C. elegans as a model for UPR signaling. supported_by: - reference_id: PMID:11779465 supporting_text: We have used C. elegans as a genetic model system to dissect UPR signaling in a multicellular organism - term: id: GO:0030968 label: endoplasmic reticulum unfolded protein response evidence_type: IMP original_reference_id: PMID:11779465 qualifier: involved_in review: summary: Same foundational study showing IRE-1's essential role in ER-UPR. action: ACCEPT reason: Valid IMP evidence for IRE-1's role in the broader ER-UPR pathway. supported_by: - reference_id: PMID:11779465 supporting_text: We propose that UPR transcriptional activation by ire-1 as well as translational attenuation by pek-1 maintain ER homeostasis - term: id: GO:0030968 label: endoplasmic reticulum unfolded protein response evidence_type: IGI original_reference_id: PMID:11779465 qualifier: involved_in review: summary: Genetic interaction evidence showing ire-1 and pek-1 act in complementary UPR pathways essential for development. action: ACCEPT reason: Valid IGI evidence demonstrating that ire-1/xbp-1 and pek-1 act in complementary pathways essential for worm development and survival. supported_by: - reference_id: PMID:11779465 supporting_text: ire-1/xbp-1 acts with pek-1, a protein kinase that mediates translation attenuation, in complementary pathways that are essential for worm development and survival - term: id: GO:0030968 label: endoplasmic reticulum unfolded protein response evidence_type: IMP original_reference_id: PMID:11780124 qualifier: involved_in review: summary: Calfon et al. 2002 (Nature) demonstrated that ire-1 and xbp-1 mutations abolish the UPR in C. elegans. action: ACCEPT reason: Key experimental evidence from Nature paper establishing IRE-1-XBP-1 pathway conservation in metazoans. supported_by: - reference_id: PMID:11780124 supporting_text: mutations in either ire-1 or the transcription-factor-encoding xbp-1 gene abolished the UPR in Caenorhabditis elegans - term: id: GO:0004521 label: RNA endonuclease activity evidence_type: ISS original_reference_id: PMID:11779465 qualifier: enables review: summary: Sequence similarity evidence for RNA endonuclease activity based on conserved KEN domain. action: ACCEPT reason: Valid ISS annotation. The KEN domain is conserved with mammalian IRE1 which has been shown to directly cleave XBP-1 mRNA. supported_by: - reference_id: PMID:11780124 supporting_text: Purified mouse IRE1 accurately cleaved XBP-1 mRNA in vitro - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: ISS original_reference_id: PMID:11779465 qualifier: located_in review: summary: Sequence similarity evidence for ER membrane localization based on conserved topology and transmembrane domain. action: ACCEPT reason: Valid ISS annotation. The protein has a conserved type I transmembrane topology with luminal sensor domain and cytosolic effector domains. supported_by: - reference_id: UniProt:Q09499 supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:11779465}; Single-pass type I membrane protein' - term: id: GO:0035966 label: response to topologically incorrect protein evidence_type: IMP original_reference_id: PMID:23335331 qualifier: involved_in review: summary: Schipanski et al. 2013 showed that UPR pathways including IRE-1 modulate protein aggregation in a neuroserpin disease model. action: KEEP_AS_NON_CORE reason: Valid annotation showing IRE-1's role in responding to misfolded/aggregated proteins. This is related to but distinct from the canonical unfolded protein response. supported_by: - reference_id: PMID:23335331 supporting_text: downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation - term: id: GO:0035966 label: response to topologically incorrect protein evidence_type: IGI original_reference_id: PMID:23335331 qualifier: involved_in review: summary: Genetic interaction evidence for IRE-1 in protein conformational disease model. action: KEEP_AS_NON_CORE reason: Valid IGI evidence showing genetic interaction between UPR components and protein aggregation pathways. supported_by: - reference_id: PMID:23335331 supporting_text: perturbations of proteostasis through impairment of the heat shock response or altered UPR signaling enhance neuroserpin accumulation in vivo - term: id: GO:0002119 label: nematode larval development evidence_type: IGI original_reference_id: PMID:11779465 qualifier: involved_in review: summary: Shen et al. 2001 showed that ire-1 and pek-1 are redundant genes essential for larval development. action: KEEP_AS_NON_CORE reason: Valid developmental phenotype annotation. Single mutants are viable but double mutants (ire-1 with pek-1 or atf-6) arrest at early larval stages. This is a downstream consequence of UPR function rather than a direct developmental regulatory role. supported_by: - reference_id: UniProt:Q09499 supporting_text: In combination with RNAi-mediated knockdown of atf-6, causes sluggish movement, arrested development at the L2 larval stage, and lethality soon thereafter references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000043 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping findings: [] - id: GO_REF:0000116 title: Automatic Gene Ontology annotation based on Rhea mapping findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:11779465 title: Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. findings: - statement: IRE-1 mediates xbp-1 mRNA splicing for UPR transcriptional activation supporting_text: C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress - statement: ire-1 and pek-1 act in complementary pathways essential for development supporting_text: ire-1/xbp-1 acts with pek-1, a protein kinase that mediates translation attenuation, in complementary pathways that are essential for worm development and survival - statement: C. elegans requires ire-1 for survival upon ER stress supporting_text: C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress - id: PMID:11780124 title: IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. findings: - statement: IRE1-dependent splicing of xbp-1 mRNA conserved in C. elegans and mammals supporting_text: Activation of the UPR causes IRE1-dependent splicing of a small intron from the XBP-1 mRNA both in C. elegans and mice - statement: Mutations in ire-1 or xbp-1 abolish UPR in C. elegans supporting_text: mutations in either ire-1 or the transcription-factor-encoding xbp-1 gene abolished the UPR in Caenorhabditis elegans - statement: IRE1 directly cleaves XBP-1 mRNA supporting_text: Purified mouse IRE1 accurately cleaved XBP-1 mRNA in vitro, indicating that XBP-1 mRNA is a direct target of IRE1 endonucleolytic activity - id: PMID:18216284 title: APY-1, a novel Caenorhabditis elegans apyrase involved in unfolded protein response signalling and stress responses. findings: - statement: ire-1 required for transcriptional upregulation of apy-1 upon ER stress supporting_text: ER stress induced by tunicamycin or high temperature resulted in increased transcription of apy-1. This increase was not observed in C. elegans mutants defective in ire-1 or atf-6 - id: PMID:20733002 title: Protein misfolding induces hypoxic preconditioning via a subset of the unfolded protein response machinery. findings: - statement: IRE-1 required for hypoxic preconditioning supporting_text: the pharmacological induction of misfolded proteins is itself sufficient to stimulate a delayed protective response to hypoxic injury that requires the UPR pathway proteins IRE-1, XBP-1, and ATF-6 - id: PMID:22125500 title: Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabditis elegans larval development and immunity. findings: - statement: XBP-1 deficiency causes constitutive ER stress with elevated IRE-1 activity supporting_text: XBP-1 deficiency results in constitutive ER stress, reflected by increased basal levels of IRE-1 and PEK-1 activity under physiological conditions - id: PMID:23335331 title: A novel interaction between aging and ER overload in a protein conformational dementia. findings: - statement: UPR pathways modulate protein aggregation supporting_text: downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation - id: PMID:23791175 title: XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. findings: - statement: Neuronal XBP-1s activates UPR in distal cells non-autonomously supporting_text: Neuronally derived XBP-1s was sufficient to rescue stress resistance, increase longevity, and activate the UPR(ER) in distal, non-neuronal cell types through a cell-nonautonomous mechanism - id: PMID:25340700 title: "It's all in your mind: determining germ cell fate by neuronal IRE-1 in\ \ C. elegans." findings: - statement: IRE-1 mediates ER stress-induced germline apoptosis independently of XBP-1 supporting_text: This process is mediated by the ER stress response sensor IRE-1, but is independent of its canonical downstream target XBP-1 - statement: Neuronal (ASI) IRE-1 activation sufficient to induce germline apoptosis supporting_text: activation of ire-1, specifically in the ASI neurons, but not in germ cells, is sufficient to induce apoptosis in the germline - id: ire-1-deep-research-falcon.md title: Deep research report on C. elegans ire-1 gene function findings: - statement: IRE-1 executes RIDD of daf-7 mRNA in ASI neurons supporting_text: In C. elegans, recent work identifies daf-7 (a TGFbeta family ligand expressed in ASI neurons) as a physiological RIDD substrate - id: file:worm/ire-1/ire-1-deep-research-falcon.md title: Deep research report on ire-1 findings: [] - id: PMID:23149939 title: A specific set of exon junction complex subunits is required for the nuclear retention of unspliced RNAs in Caenorhabditis elegans. findings: - statement: In Y14-depleted animals, unspliced tra-2 RNA leaks to the cytoplasm and is then aberrantly spliced, possibly by IRE-1; IRE-1 itself is not required for the export or retention step supporting_text: 3A ), indicating that IRE-1 is not involved in the premature export of unspliced tra-2 RNA per se . - statement: The aberrant cytoplasmic splicing of leaked tra-2 RNA depends on IRE-1 supporting_text: This aberrant cytoplasmic splicing seems to be catalyzed by IRE-1, because production of tra-2s RNA was suppressed by depletion of IRE-1 reference_review: relevance: LOW correctness: VERIFIED review_notes: Full text cached; title matches the PMID cited by UniProt. The nuclear retention machinery here is the exon junction complex (Y14, MAG-1, eIF4AIII, UAP56) together with splicing factors. IRE-1 enters only as the probable enzyme that splices tra-2 RNA after it has leaked to the cytoplasm. ire-1(RNAi) alone has no germline sex-determination defect. The paper therefore does not support a role for IRE-1 in nuclear retention. The cytoplasmic splicing of mislocalized tra-2 RNA is a non-physiological consequence of EJC depletion and is not annotated. - id: file:worm/ire-1/ire-1-uniprot.txt title: UniProt entry Q09499 (IRE1_CAEEL) findings: [] reference_review: relevance: MEDIUM correctness: DISPUTED review_notes: UniProt FUNCTION comment. ER stress sensing, xbp-1 splicing, the complementary PEK-1 pathway and hypoxic preconditioning agree with the review (PMID:11779465, PMID:18216284, PMID:20733002). The final sentence, "Plays a role in the nuclear retention of unspliced mRNAs (PubMed:23149939)", is contradicted by the cited paper, which concludes that IRE-1 is not involved in the export of unspliced RNA. source_defects: - defect_type: WRONG_STATEMENT resource: UNIPROT record: UniProtKB:Q09499 slot: CC:FUNCTION requested_change: CHECK asserted_value: "Plays a role in the nuclear retention of unspliced mRNAs (PubMed:23149939)" confidence: CONFIRMED explanation: The FUNCTION comment of Q09499 says ire-1 "Plays a role in the nuclear retention of unspliced mRNAs (PubMed:23149939)". In that paper nuclear retention depends on exon junction complex subunits and splicing factors. IRE-1 acts only after unspliced tra-2 RNA has leaked to the cytoplasm of Y14-depleted animals, where it probably splices that RNA aberrantly. The authors state that IRE-1 is not involved in the premature export of unspliced tra-2 RNA. The sentence should be removed, or reworded to say that IRE-1 can splice mislocalized cytoplasmic tra-2 RNA when the exon junction complex is depleted. supported_by: - reference_id: PMID:23149939 supporting_text: 3A ), indicating that IRE-1 is not involved in the premature export of unspliced tra-2 RNA per se . - reference_id: PMID:23149939 supporting_text: This aberrant cytoplasmic splicing seems to be catalyzed by IRE-1, because production of tra-2s RNA was suppressed by depletion of IRE-1 - id: file:worm/ire-1/ire-1-deep-research-wormbase.md title: WormBase gene description for ire-1 (worm) findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: WormBase curated description. The claims checked are correct. The kinase/endoribonuclease identity, the UPR requirement and the xbp-1 mRNA cleavage that produces active XBP-1 agree with PMID:11779465 and PMID:11780124. core_functions: - molecular_function: id: GO:0004521 label: RNA endonuclease activity description: IRE-1 cleaves xbp-1 mRNA in an unconventional cytoplasmic splicing reaction, removing a 23-nucleotide intron to generate the active XBP-1s transcription factor. The RNase domain also executes RIDD (Regulated IRE1-Dependent Decay) of select mRNAs including daf-7. directly_involved_in: - id: GO:0036498 label: IRE1-mediated unfolded protein response locations: - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: PMID:11780124 supporting_text: Purified mouse IRE1 accurately cleaved XBP-1 mRNA in vitro, indicating that XBP-1 mRNA is a direct target of IRE1 endonucleolytic activity - molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity description: The cytosolic kinase domain undergoes trans-autophosphorylation upon ER stress, which is required for activation of the endoribonuclease domain. Kinase-dead mutations (G723R) abolish both xbp-1 splicing and RIDD. directly_involved_in: - id: GO:0036498 label: IRE1-mediated unfolded protein response locations: - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: UniProt:Q09499 supporting_text: The kinase domain is activated by trans- autophosphorylation. Kinase activity is required for activation of the endoribonuclease domain (By similarity) - description: The luminal N-terminal domain senses accumulation of unfolded proteins in the ER lumen, triggering IRE-1 oligomerization and activation of cytosolic effector domains. No molecular-function term is asserted for sensing. GO:0051082 is obsolete (and the IBA annotation to it is removed in this review), and the signalling output is captured by the kinase and endoribonuclease core functions. directly_involved_in: - id: GO:0006986 label: response to unfolded protein locations: - id: GO:0005783 label: endoplasmic reticulum supported_by: - reference_id: UniProt:Q09499 supporting_text: Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto- activation (PubMed:11779465) proposed_new_terms: [] suggested_questions: - question: What are the specific RIDD substrates beyond daf-7 in C. elegans, and how does RIDD contribute to tissue-specific IRE-1 functions? Recent work identified daf-7 as a neuronal RIDD substrate, but the full spectrum of RIDD targets in different tissues remains to be characterized. - question: How does IRE-1 achieve different activation thresholds for xbp-1 splicing versus RIDD? Studies show RIDD can occur at lower stress levels than xbp-1 splicing, suggesting distinct regulatory mechanisms. suggested_experiments: - description: RNA-seq or CLIP-seq to identify IRE-1 RIDD substrates in different C. elegans tissues under varying stress conditions. This would reveal the full complement of RIDD targets and tissue-specific regulation. - description: Structure-function analysis of IRE-1 domains required for cell non-autonomous signaling versus canonical UPR. This would help distinguish the molecular requirements for neuronal IRE-1 signaling to germline versus canonical xbp-1-dependent UPR. tags: [caeel-upr-stress]