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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: UniProt:Q09499 SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:11779465}; Single-pass type I membrane protein {ECO:0000269|PubMed:11779465} file:worm/ire-1/ire-1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0036498 IRE1-mediated unfolded protein response | IBA GO_REF:0000033 | ACCEPT | 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). 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. Supporting Evidence: PMID:11779465 C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress PMID:11780124 Activation of the UPR causes IRE1-dependent splicing of a small intron from the XBP-1 mRNA both in C. elegans and mice |
| GO:0004521 RNA endonuclease activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:11780124 Purified mouse IRE1 accurately cleaved XBP-1 mRNA in vitro, indicating that XBP-1 mRNA is a direct target of IRE1 endonucleolytic activity file:worm/ire-1/ire-1-bioreason-rl-predictions.md 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 |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: UniProt:Q09499 The kinase domain is activated by trans- autophosphorylation. Kinase activity is required for activation of the endoribonuclease domain (By similarity) |
| GO:0051082 unfolded protein binding | IBA GO_REF:0000033 | REMOVE | 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. 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. Supporting Evidence: UniProt:Q09499 Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto- activation (PubMed:11779465) |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:25340700 This process is mediated by the ER stress response sensor IRE-1, but is independent of its canonical downstream target XBP-1 |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: IRE-1 binds ATP for its kinase activity. This is a parent term of ATP binding which is more specific. 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. Supporting Evidence: UniProt:Q09499 ATP-binding; Endoplasmic reticulum; Glycoprotein; Hydrolase; Kinase |
| GO:0003824 catalytic activity | IEA GO_REF:0000043 | ACCEPT | Summary: IRE-1 has dual catalytic activities - kinase and endoribonuclease. This is a very general parent term. 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. Supporting Evidence: UniProt:Q09499 RecName: Full=Serine/threonine-protein kinase; EC=2.7.11.1; Includes: RecName: Full=Endoribonuclease; EC=3.1.26.- |
| GO:0004521 RNA endonuclease activity | IEA GO_REF:0000002 | ACCEPT | Summary: Duplicate annotation of RNA endonuclease activity from InterPro mapping. Same as the IBA annotation above. 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. Supporting Evidence: UniProt:Q09499 InterPro; IPR010513; KEN_dom |
| GO:0004540 RNA nuclease activity | IEA GO_REF:0000002 | ACCEPT | Summary: Parent term of RNA endonuclease activity. IRE-1 cleaves RNA endonucleolytically, not exonucleolytically. 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. Supporting Evidence: UniProt:Q09499 Includes: RecName: Full=Endoribonuclease; EC=3.1.26.- |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: IRE-1 has protein kinase activity via its cytosolic kinase domain. This is a parent term of protein serine/threonine kinase activity. Reason: Accurate annotation from InterPro domain mapping. The Pkinase domain (PF00069) is present. More specific child term for Ser/Thr kinase is also annotated. Supporting Evidence: UniProt:Q09499 InterPro; IPR000719; Prot_kinase_dom |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate annotation of protein serine/threonine kinase activity from combined automated methods. Reason: Valid annotation consistent with the kinase domain function. The IBA annotation is also present. Duplicates from different evidence sources are acceptable. Supporting Evidence: UniProt:Q09499 GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:WormBase |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: IRE-1 kinase domain binds ATP as substrate for phosphotransfer reactions. Reason: Core molecular function required for kinase activity. ATP binding is essential for the trans-autophosphorylation that activates the RNase domain. Supporting Evidence: UniProt:Q09499 CATALYTIC ACTIVITY: Reaction=L-seryl |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IRE-1 is a type I single-pass ER transmembrane protein with luminal stress-sensing domain and cytosolic effector domains. 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. Supporting Evidence: UniProt:Q09499 SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:11779465}; Single-pass type I membrane protein {ECO:0000269|PubMed:11779465} |
| GO:0006397 mRNA processing | IEA GO_REF:0000002 | ACCEPT | Summary: IRE-1 processes xbp-1 mRNA through unconventional cytoplasmic splicing, removing a small intron to generate the active XBP-1s form. 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. Supporting Evidence: PMID:11780124 Activation of the UPR causes IRE1-dependent splicing of a small intron from the XBP-1 mRNA |
| GO:0006986 response to unfolded protein | IEA GO_REF:0000043 | ACCEPT | Summary: IRE-1 is a primary sensor and responder to unfolded proteins in the ER lumen. Reason: Core biological process annotation. IRE-1 detects unfolded proteins via its luminal domain and activates the UPR to restore ER homeostasis. Supporting Evidence: PMID:11779465 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) |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000117 | ACCEPT | Summary: IRE-1 regulates gene expression by activating XBP-1s transcription factor through xbp-1 mRNA splicing. 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. Supporting Evidence: UniProt:Q09499 The active endoribonuclease domain splices xbp-1 precursor mRNA to produce the mature form which then induces transcription of UPR target genes (PubMed:11779465) |
| GO:0016301 kinase activity | IEA GO_REF:0000043 | ACCEPT | Summary: General parent term for the kinase activity of IRE-1. Reason: Valid but general annotation. More specific child terms for protein Ser/Thr kinase activity are also present. Supporting Evidence: UniProt:Q09499 Belongs to the protein kinase superfamily. Ser/Thr protein kinase family |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | ACCEPT | Summary: Very general parent term capturing the phosphotransferase function of the kinase domain. Reason: Valid but extremely general annotation. More specific terms are preferred. Supporting Evidence: UniProt:Q09499 Serine/threonine-protein kinase; EC=2.7.11.1 |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | ACCEPT | Summary: General parent term for the endoribonuclease activity which hydrolyzes phosphodiester bonds in RNA. Reason: Valid but general annotation. More specific RNA nuclease terms are preferred. Supporting Evidence: UniProt:Q09499 Endoribonuclease; EC=3.1.26.- |
| GO:0030968 endoplasmic reticulum unfolded protein response | IEA GO_REF:0000002 | ACCEPT | Summary: IRE-1 is one of three sensors mediating the ER-UPR in metazoans. This term captures the broader UPR pathway. 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. Supporting Evidence: PMID:11779465 We have used C. elegans as a genetic model system to dissect UPR signaling in a multicellular organism |
| GO:0034976 response to endoplasmic reticulum stress | IEA GO_REF:0000117 | ACCEPT | Summary: IRE-1 responds to and mediates the cellular response to ER stress. Reason: Valid annotation capturing IRE-1's role in ER stress response. This is a parent of the more specific UPR terms. 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:0080090 regulation of primary metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Very broad term that encompasses IRE-1's regulatory role in protein folding homeostasis. 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. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: IRE-1 autophosphorylates on serine residues. This is more specific than protein Ser/Thr kinase activity. Reason: Valid annotation based on Rhea mapping. UniProt indicates autophosphorylation mainly on serine residues. Supporting Evidence: UniProt:Q09499 PTM: Autophosphorylated mainly on serine residues |
| GO:0036498 IRE1-mediated unfolded protein response | IMP PMID:20733002 Protein misfolding induces hypoxic preconditioning via a sub... | ACCEPT | Summary: Mao & Crowder 2010 showed that IRE-1 is required for hypoxic preconditioning in C. elegans, linking UPR activation to adaptive protection. 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. Supporting Evidence: PMID:20733002 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 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:18216284 APY-1, a novel Caenorhabditis elegans apyrase involved in un... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:18216284 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 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:18216284 APY-1, a novel Caenorhabditis elegans apyrase involved in un... | KEEP AS NON CORE | Summary: Same study showing genetic interaction for transcriptional regulation of UPR target genes. 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. Supporting Evidence: UniProt:Q09499 G->R: In zc14; loss of adaptive protection conferred by non-lethal hypoxia treatment. Prevents transcriptional up-regulation of apy-1 upon ER stress |
| GO:0036498 IRE1-mediated unfolded protein response | IGI PMID:22125500 Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabdi... | ACCEPT | 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. 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. Supporting Evidence: PMID:22125500 XBP-1 deficiency results in constitutive ER stress, reflected by increased basal levels of IRE-1 and PEK-1 activity under physiological conditions |
| GO:0004674 protein serine/threonine kinase activity | ISS PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | ACCEPT | Summary: Sequence similarity to mammalian IRE1 kinase domain supports Ser/Thr kinase activity annotation. Reason: Valid ISS annotation based on conserved kinase domain. The protein kinase domain (aa 518-778) is well-conserved with mammalian IRE1. Supporting Evidence: UniProt:Q09499 Belongs to the protein kinase superfamily. Ser/Thr protein kinase family |
| GO:0030968 endoplasmic reticulum unfolded protein response | IMP PMID:25340700 It's all in your mind: determining germ cell fate by neurona... | ACCEPT | Summary: Levi-Ferber et al. 2014 demonstrated IRE-1 function in ER stress response including cell non-autonomous signaling from neurons to germline. 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. Supporting Evidence: PMID:25340700 pharmacological or genetic induction of ER stress enhances germline apoptosis. This process is mediated by the ER stress response sensor IRE-1 |
| GO:0043025 neuronal cell body | IMP PMID:23791175 XBP-1 is a cell-nonautonomous regulator of stress resistance... | KEEP AS NON CORE | Summary: Taylor & Dillin 2013 showed neuronal IRE-1/XBP-1 signaling with cell non-autonomous effects on stress resistance and longevity. 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. Supporting Evidence: PMID:23791175 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 |
| GO:0004521 RNA endonuclease activity | IMP PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | ACCEPT | Summary: Shen et al. 2001 demonstrated that IRE-1 mediates xbp-1 mRNA splicing in C. elegans, establishing its endoribonuclease activity. Reason: Primary experimental evidence for the core endoribonuclease function. ire-1 is required for xbp-1 mRNA splicing in C. elegans. 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 | IMP PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | ACCEPT | Summary: Foundational study demonstrating IRE-1's role in UPR signaling in C. elegans. Reason: Core experimental evidence for the eponymous IRE1-mediated UPR pathway. This study established C. elegans as a model for UPR signaling. Supporting Evidence: PMID:11779465 We have used C. elegans as a genetic model system to dissect UPR signaling in a multicellular organism |
| GO:0030968 endoplasmic reticulum unfolded protein response | IMP PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | ACCEPT | Summary: Same foundational study showing IRE-1's essential role in ER-UPR. Reason: Valid IMP evidence for IRE-1's role in the broader ER-UPR pathway. Supporting Evidence: PMID:11779465 We propose that UPR transcriptional activation by ire-1 as well as translational attenuation by pek-1 maintain ER homeostasis |
| GO:0030968 endoplasmic reticulum unfolded protein response | IGI PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | ACCEPT | Summary: Genetic interaction evidence showing ire-1 and pek-1 act in complementary UPR pathways essential for development. Reason: Valid IGI evidence demonstrating that ire-1/xbp-1 and pek-1 act in complementary pathways essential for worm development and survival. Supporting Evidence: PMID:11779465 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 |
| GO:0030968 endoplasmic reticulum unfolded protein response | IMP PMID:11780124 IRE1 couples endoplasmic reticulum load to secretory capacit... | ACCEPT | Summary: Calfon et al. 2002 (Nature) demonstrated that ire-1 and xbp-1 mutations abolish the UPR in C. elegans. Reason: Key experimental evidence from Nature paper establishing IRE-1-XBP-1 pathway conservation in metazoans. Supporting Evidence: PMID:11780124 mutations in either ire-1 or the transcription-factor-encoding xbp-1 gene abolished the UPR in Caenorhabditis elegans |
| GO:0004521 RNA endonuclease activity | ISS PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | ACCEPT | Summary: Sequence similarity evidence for RNA endonuclease activity based on conserved KEN domain. Reason: Valid ISS annotation. The KEN domain is conserved with mammalian IRE1 which has been shown to directly cleave XBP-1 mRNA. Supporting Evidence: PMID:11780124 Purified mouse IRE1 accurately cleaved XBP-1 mRNA in vitro |
| GO:0005789 endoplasmic reticulum membrane | ISS PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | ACCEPT | Summary: Sequence similarity evidence for ER membrane localization based on conserved topology and transmembrane domain. Reason: Valid ISS annotation. The protein has a conserved type I transmembrane topology with luminal sensor domain and cytosolic effector domains. Supporting Evidence: UniProt:Q09499 SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:11779465}; Single-pass type I membrane protein |
| GO:0035966 response to topologically incorrect protein | IMP PMID:23335331 A novel interaction between aging and ER overload in a prote... | KEEP AS NON CORE | Summary: Schipanski et al. 2013 showed that UPR pathways including IRE-1 modulate protein aggregation in a neuroserpin disease model. 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. Supporting Evidence: PMID:23335331 downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation |
| GO:0035966 response to topologically incorrect protein | IGI PMID:23335331 A novel interaction between aging and ER overload in a prote... | KEEP AS NON CORE | Summary: Genetic interaction evidence for IRE-1 in protein conformational disease model. Reason: Valid IGI evidence showing genetic interaction between UPR components and protein aggregation pathways. Supporting Evidence: PMID:23335331 perturbations of proteostasis through impairment of the heat shock response or altered UPR signaling enhance neuroserpin accumulation in vivo |
| GO:0002119 nematode larval development | IGI PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | KEEP AS NON CORE | Summary: Shen et al. 2001 showed that ire-1 and pek-1 are redundant genes essential for larval development. 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. Supporting Evidence: UniProt:Q09499 In combination with RNAi-mediated knockdown of atf-6, causes sluggish movement, arrested development at the L2 larval stage, and lethality soon thereafter |
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Download this section (compressed HTML)Q: 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.
Q: 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.
Experiment: 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.
Experiment: 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.
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