IRE1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005783 endoplasmic reticulum	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for ER localization. IRE1 is a well-established ER-resident transmembrane protein (PMID:8358794). Supported by IDA and HDA evidence. Reason: ER localization is fundamental to IRE1 function as the ER stress sensor. Confirmed by IDA (PMID:8358794) and HDA (PMID:26928762). Supporting Evidence: file:yeast/IRE1/IRE1-deep-research-falcon.md Ire1 is an ER membrane protein with a luminal stress-sensing domain and cytosolic kinase/RNase module; it forms puncta/clusters on the ER membrane during stress, consistent with its role as a spatially organized RNA-processing hub.
GO:0036498 IRE1-mediated unfolded protein response	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for the IRE1-mediated UPR. IRE1 is the defining component of this pathway in yeast, sensing unfolded proteins and activating HAC1 mRNA splicing (PMID:8358794, PMID:9323131). Reason: This is the core biological process of IRE1. The gene is named after this pathway. Confirmed by IDA (PMID:19079236) and IMP (PMID:8358794, PMID:8513503). Supporting Evidence: file:yeast/IRE1/IRE1-deep-research-falcon.md The UniProt accession P32361 corresponds to *budding yeast (Saccharomyces cerevisiae* S288c) Ire1/Ern1 (YHR079C), an ER-resident single-pass (type I) transmembrane stress sensor with a cytosolic serine/threonine kinase domain and an endoribonuclease (RNase) domain that initiates the yeast unfolded protein response (UPR) by splicing HAC1 mRNA**. file:yeast/IRE1/IRE1-deep-research-falcon.md Yeast UPR is effectively a single-sensor, single-transcription-factor architecture (Ire1→Hac1), which enables unusually clean genetic epistasis and mechanistic dissection.
GO:0004521 RNA endonuclease activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for RNA endonuclease activity. IRE1 is a site-specific endonuclease that cleaves HAC1 pre-mRNA at two specific sites to initiate unconventional mRNA splicing (PMID:9323131, PMID:18191223). Reason: RNA endonuclease activity is a core molecular function of IRE1. Confirmed by IDA (PMID:9323131). The KEN domain (residues 983-1115) is the catalytic domain for this activity. Supporting Evidence: file:yeast/IRE1/IRE1-deep-research-falcon.md Reaction: Ire1's RNase performs site-specific endonucleolytic cleavage of HAC1u mRNA at both the 5′ and 3′ splice junctions, thereby removing an inhibitory intron and initiating spliceosome-independent splicing.
GO:0004674 protein serine/threonine kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for protein Ser/Thr kinase activity. IRE1 undergoes trans-autophosphorylation on Ser-840, Ser-841, and Thr-844, which is required for activation of the endoribonuclease domain (PMID:8663458, PMID:18191223). Reason: Kinase activity is a core molecular function of IRE1. Confirmed by IDA (PMID:8663458) and crystal structure (PMID:18191223). Kinase activation is required for RNase activation. Supporting Evidence: file:yeast/IRE1/IRE1-deep-research-falcon.md Ire1 has a Ser/Thr kinase domain that undergoes trans-autophosphorylation upon oligomerization, which is coupled to RNase activation in current models of UPR induction.
GO:0051082 unfolded protein binding	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: GO:0051082 is now formally obsolete. IRE1 does directly bind unfolded proteins via its lumenal domain (PMID:17923530), but it functions as a sensor/signaling molecule, not a chaperone. The binding triggers oligomerization and UPR activation, not protein folding. Reason: GO:0051082 "unfolded protein binding" is now formally obsolete. While IRE1 does bind unfolded proteins via its lumenal domain (PMID:17923530), this binding serves a signaling function (sensor), not a chaperone function. IRE1 does not assist protein folding. The unfolded protein binding by IRE1 is mechanistically part of its sensor function in the UPR, which is already captured by GO:0036498. There is currently no appropriate GO MF term for "unfolded protein sensor activity" to use as a replacement.
GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: IBA annotation for apoptotic signaling in response to ER stress. This is primarily a metazoan function (IRE1alpha/beta in mammals). Yeast does not have classical apoptosis, although programmed cell death mechanisms exist. The IBA inference from mammalian orthologs may not be fully appropriate for yeast. Reason: This annotation appears to be inferred from mammalian IRE1 orthologs where IRE1 contributes to apoptotic signaling under prolonged ER stress. S. cerevisiae does not have classical apoptosis. While yeast has programmed cell death pathways, this specific term is too metazoan-centric for yeast IRE1.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for nucleotide binding from UniProt keyword. IRE1 binds ATP/ADP in its kinase domain (PMID:18191223, crystal structure with ADP). Reason: Correct but very broad. IRE1 binds ATP for its kinase activity. Acceptable as an IEA.
GO:0003824 catalytic activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for catalytic activity from UniProt keyword. IRE1 has both kinase and endoribonuclease catalytic activities. Reason: Correct but extremely broad. Both kinase and RNase activities are catalytic. Acceptable as a broad IEA.
GO:0004521 RNA endonuclease activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for RNA endonuclease activity from combined automated methods. Consistent with IBA and IDA evidence. Reason: Correct. Consistent with experimental evidence (PMID:9323131, PMID:18191223).
GO:0004540 RNA nuclease activity	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for RNA nuclease activity from InterPro. Broader parent of RNA endonuclease activity. Reason: Correct but less specific than GO:0004521. Acceptable as a broad IEA.
GO:0004672 protein kinase activity	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for protein kinase activity from InterPro. Broader parent of protein serine/threonine kinase activity. Reason: Correct but less specific than GO:0004674. Acceptable as an IEA.
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for protein Ser/Thr kinase from combined automated methods. Consistent with IBA and IDA evidence. Reason: Correct. Consistent with experimental evidence (PMID:8663458, PMID:18191223).
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for ATP binding. IRE1 binds ATP in its kinase domain. Crystal structure shows ADP bound in the active site (PMID:18191223). Reason: Correct. ATP binding is essential for kinase activity and confirmed by crystal structure.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation for ER membrane from UniProt subcellular location. IRE1 is a type I transmembrane protein spanning the ER membrane. Reason: Correct. Confirmed by IDA (PMID:8358794) and topology studies.
GO:0006397 mRNA processing	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for mRNA processing from InterPro. IRE1 processes HAC1 mRNA through unconventional splicing. Reason: Correct. IRE1 endoribonuclease activity directly processes HAC1 pre-mRNA (PMID:9323131). Supporting Evidence: file:yeast/IRE1/IRE1-deep-research-falcon.md Reaction: Ire1's RNase performs site-specific endonucleolytic cleavage of HAC1u mRNA at both the 5′ and 3′ splice junctions, thereby removing an inhibitory intron and initiating spliceosome-independent splicing.
GO:0006986 response to unfolded protein	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for response to unfolded protein from UniProt keyword. IRE1 is the primary sensor and effector of the unfolded protein response in yeast. Reason: Correct. This is the core biological process of IRE1.
GO:0016301 kinase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for kinase activity from UniProt keyword. Broader parent of protein kinase activity. Reason: Correct but very broad. Acceptable as an IEA.
GO:0016740 transferase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for transferase activity from UniProt keyword. Very broad parent of kinase activity. Reason: Correct but extremely broad. Acceptable as an IEA.
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for hydrolase activity from UniProt keyword. Broad parent of RNA nuclease activity. Reason: Correct but extremely broad. Acceptable as an IEA.
GO:0030968 endoplasmic reticulum unfolded protein response	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for ER UPR from combined automated methods. Consistent with IMP evidence. Reason: Correct. IRE1 is the master regulator of the ER UPR in yeast.
GO:0031505 fungal-type cell wall organization	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: IEA annotation for fungal-type cell wall organization from ARBA. This is consistent with IMP and IGI evidence (PMID:18971375, PMID:8898193) showing IRE1 is required for cell wall integrity. Reason: Cell wall organization is a downstream consequence of IRE1's UPR signaling function. The UPR regulates expression of cell wall biosynthesis genes. Not a core function of IRE1 itself.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for metal ion binding from UniProt keyword. IRE1 kinase domain binds Mg2+ as a cofactor (PMID:18191223). Reason: Correct. Mg2+ is required as a cofactor for kinase activity. Confirmed by crystal structure (PMID:18191223).
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	ACCEPT	Summary: IEA annotation for protein serine kinase activity from Rhea mapping. IRE1 autophosphorylates on serine residues (Ser-840, Ser-841). Reason: Correct. Serine autophosphorylation is confirmed (PMID:18191223, PMID:8670804).
GO:0005515 protein binding	IPI PMID:16990850 Dcr2 targets Ire1 and downregulates the unfolded protein res...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding showing interaction with DCR2 (Q05924). Reason: Protein binding is uninformative. The specific interaction with DCR2 may be relevant to IRE1 regulation but is not captured by the generic term.
GO:0042802 identical protein binding	IPI PMID:18191223 Structure of the dual enzyme Ire1 reveals the basis for cata...	ACCEPT	Summary: IPI annotation for identical protein binding (homodimerization). IRE1 homodimerizes upon ER stress, and dimerization is essential for both kinase trans-autophosphorylation and RNase activation (PMID:18191223, PMID:8663458). Reason: Homodimerization is functionally critical for IRE1 activation. Crystal structures confirm the dimer interface (PMID:18191223, PMID:16365312). Supporting Evidence: file:yeast/IRE1/IRE1-deep-research-falcon.md Under ER stress, Ire1 becomes activated through self-association (dimerization and higher-order oligomerization), autophosphorylation via its Ser/Thr kinase domain, and activation of its cytosolic RNase domain.
GO:0042802 identical protein binding	IPI PMID:19079236 The unfolded protein response signals through high-order ass...	ACCEPT	Summary: IPI annotation for identical protein binding. Additional evidence for IRE1 homodimerization. Reason: Consistent with other evidence for functionally important homodimerization.
GO:0042802 identical protein binding	IPI PMID:20625545 BiP binding to the ER-stress sensor Ire1 tunes the homeostat...	ACCEPT	Summary: IPI annotation for identical protein binding from study of BiP binding to IRE1 and its regulation of UPR homeostasis. Reason: Additional evidence for IRE1 homodimerization, studied in the context of BiP regulation.
GO:0005789 endoplasmic reticulum membrane	NAS PMID:17923530 Two regulatory steps of ER-stress sensor Ire1 involving its ...	ACCEPT	Summary: NAS annotation for ER membrane from ComplexPortal. Consistent with IDA evidence. Reason: Correct. Consistent with IDA (PMID:8358794) and topology studies.
GO:0036498 IRE1-mediated unfolded protein response	IDA PMID:19079236 The unfolded protein response signals through high-order ass...	ACCEPT	Summary: IDA annotation for IRE1-mediated UPR from ComplexPortal. Reason: Core biological process of IRE1. Experimentally demonstrated.
GO:0005789 endoplasmic reticulum membrane	IDA PMID:8358794 A transmembrane protein with a cdc2+/CDC28-related kinase ac...	ACCEPT	Summary: IDA annotation for ER membrane localization from the founding paper on IRE1 (PMID:8358794). IRE1 is a transmembrane protein with lumenal and cytoplasmic domains. Reason: Primary experimental evidence for ER membrane localization from the original characterization. Supporting Evidence: file:yeast/IRE1/IRE1-deep-research-falcon.md Ire1 is an ER membrane protein with a luminal stress-sensing domain and cytosolic kinase/RNase module; it forms puncta/clusters on the ER membrane during stress, consistent with its role as a spatially organized RNA-processing hub.
GO:0004521 RNA endonuclease activity	IDA PMID:9323131 The transmembrane kinase Ire1p is a site-specific endonuclea...	ACCEPT	Summary: IDA annotation for RNA endonuclease activity. IRE1 is a site-specific endonuclease that cleaves HAC1 pre-mRNA at two specific positions (PMID:9323131). Reason: Core molecular function demonstrated by direct assay. This is the key enzymatic activity that mediates UPR signaling. Supporting Evidence: file:yeast/IRE1/IRE1-deep-research-falcon.md Point mutations in critical guanosine residues at splice junctions (e.g., G885C at the 5′ junction) selectively block cleavage at that junction in vivo and in vitro, demonstrating that Ire1 recognizes specific splice-junction determinants in HAC1. file:yeast/IRE1/IRE1-deep-research-falcon.md Sidrauski & Walter reconstituted the full splicing reaction in vitro with purified Ire1 fragment + purified tRNA ligase, showing that these components are sufficient to produce correctly spliced HAC1.
GO:0005783 endoplasmic reticulum	HDA PMID:26928762 One library to make them all - streamlining the creation of ...	ACCEPT	Summary: HDA annotation for ER localization from large-scale yeast library analysis. Reason: Consistent with IDA and IBA evidence for ER localization.
GO:0004672 protein kinase activity	HDA PMID:16319894 Global analysis of protein phosphorylation in yeast.	ACCEPT	Summary: HDA annotation for protein kinase activity from global phosphorylation analysis in yeast. Reason: Consistent with IDA evidence for kinase activity (PMID:8663458).
GO:0034067 protein localization to Golgi apparatus	IMP PMID:26966233 Unfolded protein response regulates yeast small GTPase Arl1p...	KEEP AS NON CORE	Summary: IMP annotation for protein localization to Golgi apparatus. IRE1 influences protein sorting and Golgi function through UPR target gene regulation. Reason: Protein localization to Golgi is a downstream effect of IRE1's UPR signaling function, not a direct function of IRE1.
GO:0034976 response to endoplasmic reticulum stress	IMP PMID:26966233 Unfolded protein response regulates yeast small GTPase Arl1p...	ACCEPT	Summary: IMP annotation for response to ER stress. IRE1 is the primary ER stress sensor and signaling molecule in yeast. Reason: Core biological process. IRE1 is the defining component of the ER stress response in yeast. Supporting Evidence: file:yeast/IRE1/IRE1-deep-research-falcon.md Recent yeast-focused syntheses emphasize that Ire1 can be activated not only by unfolded proteins but also by lipid bilayer stress, sensed via Ire1's transmembrane/amphipathic features.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-SCE-535524	ACCEPT	Summary: TAS annotation for ER membrane from Reactome pathway. Reason: Correct. Consistent with IDA evidence.
GO:0004674 protein serine/threonine kinase activity	IDA PMID:8663458 The unfolded protein response pathway in Saccharomyces cerev...	ACCEPT	Summary: IDA annotation for protein Ser/Thr kinase activity. IRE1 undergoes trans-autophosphorylation requiring oligomerization (PMID:8663458). K702A mutation abolishes autophosphorylation. Reason: Core molecular function demonstrated by direct assay. Trans-autophosphorylation is essential for activating the endoribonuclease domain. Supporting Evidence: file:yeast/IRE1/IRE1-deep-research-falcon.md Ire1 has a Ser/Thr kinase domain that undergoes trans-autophosphorylation upon oligomerization, which is coupled to RNase activation in current models of UPR induction.
GO:0005634 nucleus	IDA PMID:17035634 The unfolded protein response transducer Ire1p contains a nu...	KEEP AS NON CORE	Summary: IDA annotation for nuclear localization. PMID:17035634 (Goffin et al. 2006) directly demonstrates that Ire1p contains a functional 18-residue nuclear localization sequence (NLS) in its cytoplasmic linker region, recognized by both importin alpha (Kap60p) and multiple importin beta homologues, and that this NLS targets Ire1p (or an NLS-GFP fusion) to the yeast nucleus in a Ran-GTPase-dependent process in vivo. Reason: The cached abstract for PMID:17035634 is available in this repository and directly supports nuclear localization: it reports a validated NLS that targets Ire1p to the nucleus, and shows that point mutations disrupting this NLS impair ER-stress-induced HAC1 mRNA splicing and UPR signaling. This is genuine experimental (IDA) evidence for a nuclear pool of Ire1p, not an artifact, so the annotation should not be left UNDECIDED. It is kept as non-core because IRE1's core, best-established catalytic functions (kinase trans-autophosphorylation and HAC1 RNase splicing) occur at the ER membrane; the nuclear-import step described here is a regulatory/signaling-trafficking aspect rather than the site of the defining enzymatic activities. Supporting Evidence: PMID:17035634 The Ire1p transmembrane receptor kinase/endonuclease transduces the unfolded protein response (UPR) from the endoplasmic reticulum (ER) to the nucleus in Saccharomyces cerevisiae. PMID:17035634 This 18-residue sequence is capable of targeting green fluorescent protein to the nucleus of yeast cells in a process requiring proteins involved in the Ran GTPase cycle that facilitates nuclear import. PMID:17035634 The NLS-dependent nuclear localization of Ire1p would thus seem to be central to its role in UPR signaling.
GO:0006020 inositol metabolic process	IMP PMID:1625574 IRE1 encodes a putative protein kinase containing a membrane...	KEEP AS NON CORE	Summary: IMP annotation for inositol metabolic process. IRE1 was originally identified as required for inositol prototrophy (PMID:1625574). The UPR regulates inositol biosynthesis genes. Reason: Inositol metabolism is regulated by the UPR pathway. IRE1 influences inositol levels through transcriptional regulation of biosynthetic genes, but this is a downstream consequence of UPR signaling.
GO:0030968 endoplasmic reticulum unfolded protein response	IMP PMID:8358794 A transmembrane protein with a cdc2+/CDC28-related kinase ac...	ACCEPT	Summary: IMP annotation for ER UPR from the founding paper on IRE1 signaling (PMID:8358794). IRE1 is required for signaling from the ER to the nucleus. Reason: Core biological process. This is the defining function of IRE1.
GO:0030968 endoplasmic reticulum unfolded protein response	IMP PMID:8513503 Transcriptional induction of genes encoding endoplasmic reti...	ACCEPT	Summary: IMP annotation for ER UPR from additional evidence. Reason: Additional experimental evidence for the core biological process.
GO:0031505 fungal-type cell wall organization	IMP PMID:18971375 The unfolded protein response is induced by the cell wall in...	KEEP AS NON CORE	Summary: IMP annotation for fungal-type cell wall organization. IRE1 mutants have cell wall defects. Reason: Cell wall organization is a downstream consequence of UPR signaling. The UPR regulates genes involved in cell wall biosynthesis.
GO:0031505 fungal-type cell wall organization	IGI PMID:18971375 The unfolded protein response is induced by the cell wall in...	KEEP AS NON CORE	Summary: IGI annotation for fungal-type cell wall organization based on genetic interaction data. Reason: Same as above - downstream consequence of UPR signaling.
GO:0031505 fungal-type cell wall organization	IMP PMID:8898193 A novel mechanism for regulating activity of a transcription...	KEEP AS NON CORE	Summary: IMP annotation for fungal-type cell wall organization from earlier study. Reason: Downstream consequence of UPR signaling. Not a core function of IRE1.
GO:0051082 unfolded protein binding	IDA PMID:17923530 Two regulatory steps of ER-stress sensor Ire1 involving its ...	MARK AS OVER ANNOTATED	Summary: IDA annotation for unfolded protein binding based on direct demonstration that IRE1 lumenal domain directly interacts with unfolded proteins (PMID:17923530). This paper showed two regulatory steps: cluster formation and direct interaction with unfolded proteins. Reason: GO:0051082 is now formally obsolete. While the experimental evidence is solid that IRE1 binds unfolded proteins (PMID:17923530), the function of this binding is as a sensor/signal transducer, not as a chaperone. IRE1 does not assist protein folding. The binding triggers oligomerization and UPR activation. There is currently no appropriate GO MF term for "unfolded protein sensor activity." The sensing function is best captured at the BP level by GO:0030968 and GO:0036498. Falcon deep research corroborates that luminal binding of unfolded proteins serves to promote oligomerization and signaling (a sensor role), not folding. Supporting Evidence: file:yeast/IRE1/IRE1-deep-research-falcon.md Ire1 activation can involve direct engagement of unfolded proteins via its luminal domain, which promotes oligomerization and signaling.
GO:0051082 unfolded protein binding	IMP PMID:17923530 Two regulatory steps of ER-stress sensor Ire1 involving its ...	MARK AS OVER ANNOTATED	Summary: IMP annotation for unfolded protein binding. Same study as the IDA annotation above (PMID:17923530). Reason: Same reasoning as the IDA annotation. GO:0051082 is now formally obsolete. IRE1 binds unfolded proteins as a sensor, not a chaperone. The term does not accurately describe the functional role of this binding.

Gene Description

Existing Annotations Review

Core Functions

Protein serine/threonine kinase that undergoes trans-autophosphorylation upon ER stress-induced oligomerization, activating the endoribonuclease domain to splice HAC1 mRNA and trigger the unfolded protein response.

RNA endonuclease that cleaves HAC1 pre-mRNA at two specific sites to initiate unconventional mRNA splicing, producing mature HAC1 mRNA encoding the UPR transcription factor.

References

Deep Research

Falcon

📚 Additional Documentation

Notes

Bioreason Rl Predictions

Bioreason Rl Review

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