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 proposed for obsoletion. 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 proposed for obsoletion. 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...	UNDECIDED	Summary: IDA annotation for nuclear localization. This may reflect a minor population of IRE1 or a specific experimental condition. Reason: Unable to access PMID:17035634 to verify the nuclear localization claim. IRE1 is primarily an ER membrane protein, so nuclear localization would be unusual and requires verification.
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 proposed for obsoletion. 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 proposed for obsoletion. IRE1 binds unfolded proteins as a sensor, not a chaperone. The term does not accurately describe the functional role of this binding.

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.

Molecular Function:

protein serine/threonine kinase activity

Directly Involved In:

IRE1-mediated unfolded protein response endoplasmic reticulum unfolded protein response response to endoplasmic reticulum stress

Cellular Locations:

endoplasmic reticulum membrane

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.

Molecular Function:

RNA endonuclease activity

Directly Involved In:

mRNA processing IRE1-mediated unfolded protein response

Cellular Locations:

endoplasmic reticulum membrane

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:1625574

IRE1 encodes a putative protein kinase containing a membrane-spanning domain and is required for inositol phototrophy in Saccharomyces cerevisiae.

PMID:16319894

Global analysis of protein phosphorylation in yeast.

PMID:16365312

On the mechanism of sensing unfolded protein in the endoplasmic reticulum.

PMID:16990850

Dcr2 targets Ire1 and downregulates the unfolded protein response in Saccharomyces cerevisiae.

PMID:17035634

The unfolded protein response transducer Ire1p contains a nuclear localization sequence recognized by multiple beta importins.

PMID:17923530

Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins.

PMID:18191223

Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing.

PMID:18971375

The unfolded protein response is induced by the cell wall integrity mitogen-activated protein kinase signaling cascade and is required for cell wall integrity in Saccharomyces cerevisiae.

PMID:19079236

The unfolded protein response signals through high-order assembly of Ire1.

PMID:20625545

BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.

PMID:26928762

One library to make them all - streamlining the creation of yeast libraries via a SWAp-Tag strategy.

PMID:26966233

Unfolded protein response regulates yeast small GTPase Arl1p activation at late Golgi via phosphorylation of Arf GEF Syt1p.

PMID:8358794

A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus.

PMID:8513503

Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase.

PMID:8663458

The unfolded protein response pathway in Saccharomyces cerevisiae. Oligomerization and trans-phosphorylation of Ire1p (Ern1p) are required for kinase activation.

PMID:8670804

Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.

PMID:8898193

A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response.

PMID:9323131

The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response.

PMID:9528768

Protein serine/threonine phosphatase Ptc2p negatively regulates the unfolded-protein response by dephosphorylating Ire1p kinase.

Reactome:R-SCE-535524

Phosphorylated Ire1 Dimer Binds ADP

file:yeast/IRE1/IRE1-deep-research-falcon.md

Falcon deep research report on yeast IRE1 (P32361)

Yeast Ire1 is an ER-resident type I transmembrane stress sensor with a cytosolic Ser/Thr kinase domain and an endoribonuclease (RNase) domain that initiates the unfolded protein response by splicing HAC1 mRNA; HAC1 is the canonical RNA substrate in S. cerevisiae (whereas metazoan IRE1 splices XBP1).

"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**."
Ire1's RNase performs site-specific endonucleolytic cleavage of HAC1u mRNA at both the 5' and 3' splice junctions, removing an inhibitory intron and initiating spliceosome-independent (unconventional) splicing.

"**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."
Cleavage-site specificity is determined by splice-junction sequence determinants: point mutations of critical guanosines (e.g. G885C at the 5' junction) selectively block cleavage at that junction. In vitro cleavage requires an adenosine nucleotide cofactor (ATP required; ADP or AMP-PNP can substitute; GTP cannot).

"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... omission of ATP abolishes cleavage, while **ADP** or **AMP-PNP** can substitute; **GTP cannot**."
Purified Ire1 fragment together with purified tRNA ligase (Trl1/Rlg1) is sufficient to reconstitute correct HAC1 splicing in vitro; Trl1 ligates the exons after Ire1 cleavage.

"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."
Ire1 has a Ser/Thr kinase domain that undergoes trans-autophosphorylation upon oligomerization, which is coupled to activation of the RNase domain in current models of UPR induction.

"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."
Beyond enabling activation, kinase function is implicated in attenuation/homeostatic shutdown, contributing to disassembly of Ire1 oligomers and termination of signaling.

"Beyond enabling activation, kinase function is implicated in **attenuation/homeostatic shutdown**: mechanistic syntheses report kinase-dependent processes contributing to the disassembly of Ire1 oligomers and termination of signaling."
Ire1 is an ER membrane protein with a luminal stress-sensing domain and a cytosolic kinase/RNase module; under stress it forms puncta/clusters on the ER membrane, acting as a spatially organized RNA-processing hub, and HAC1u mRNA is recruited to these clusters for splicing.

"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... HAC1u mRNA is recruited to Ire1 puncta/clusters for splicing during ER stress."
Under non-stress conditions Kar2/BiP binding keeps Ire1 in a less self-associated state; ER stress promotes Kar2 dissociation and Ire1 self-association/activation. Ire1 activation can also involve direct engagement of unfolded proteins via its luminal domain, promoting oligomerization.

"Under non-stress conditions Kar2/BiP binding keeps Ire1 in a less self-associated state; ER stress promotes Kar2 dissociation and Ire1 self-association/activation... Ire1 activation can involve direct engagement of unfolded proteins via its luminal domain, which promotes oligomerization and signaling."
Ire1 can be activated not only by unfolded proteins but also by lipid bilayer stress, sensed via its transmembrane/amphipathic features; lipid bilayer stress favors dimeric rather than large oligomeric assemblies and elicits weaker RNase output.

"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. LBS tends to promote **dimeric** rather than large oligomeric Ire1 assemblies and can elicit **weaker RNase output** and a milder UPR."
Regulated Ire1-dependent decay (RIDD) of additional ER-associated mRNAs is absent (or not convincingly supported) in S. cerevisiae; HAC1 is effectively the predominant (possibly sole) physiologically relevant Ire1 RNase substrate in budding yeast.

"Authoritative 2023–2024 reviews state that **regulated Ire1-dependent decay (RIDD)**—Ire1 RNase cleavage of additional ER-associated mRNAs—is **absent (or not convincingly supported) in *S. cerevisiae***, in contrast to other organisms such as *S. pombe* and metazoans. The yeast literature summarized indicates that **HAC1 is effectively the predominant (possibly sole) physiologically relevant Ire1 RNase substrate** in budding yeast."
Yeast UPR is effectively a single-sensor, single-transcription-factor architecture (Ire1 -> Hac1), unlike metazoans which have additional sensors (PERK, ATF6).

"Yeast UPR is effectively a single-sensor, single-transcription-factor architecture (Ire1→Hac1), which enables unusually clean genetic epistasis and mechanistic dissection."
A 2023 preprint reports that the cell wall integrity MAPK Slt2 enhances both HAC1 mRNA splicing and translation, adding a regulatory layer that promotes adaptation to ER stress in S. cerevisiae.

"A 2023 bioRxiv preprint proposes that **MAPK Slt2** enhances both **HAC1 mRNA splicing and translation**, contributing to adaptation under ER stress."

Deep Research

Falcon

(IRE1-deep-research-falcon.md)

Research report: *Saccharomyces cerevisiae* IRE1 (UniProt P32361; gene IRE1/ERN1; locus YHR079C) Falcon Edison Scientific Literature 36 citations 2 artifacts 2026-05-30T10:35:55.788992

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000032 The schematic diagram from Figure 2 illustrates the yeast Ire1–Hac1 unfolded protein response (UPR) pathway. Under non-stress condi (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Saccharomyces cerevisiae IRE1 (UniProt P32361; gene IRE1/ERN1; locus YHR079C)

0) Identity verification (critical disambiguation)

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. This aligns with current yeast-focused reviews describing Ire1 as the central UPR sensor and effector in S. cerevisiae, and with the foundational biochemical demonstration that Ire1 is a bifunctional kinase/endoribonuclease cleaving HAC1 at two splice junctions. (ishiwatakimata2023fundamentalandapplicative pages 3-4, ishiwatakimata2023fundamentalandapplicative pages 4-6, sidrauski1997thetransmembranekinase pages 3-4)

A key species-level distinction is that yeast Ire1’s canonical RNA substrate is HAC1, whereas metazoan IRE1 splices XBP1; thus, mammalian IRE1α/β literature is not directly transferable for substrate specificity or pathway outputs. (fauzee2023endoplasmicstresssensor pages 1-2, bartoszewska2023dualrnaseactivity pages 3-5)

1) Key concepts and definitions (current understanding)

1.1 Unfolded Protein Response (UPR) in yeast

ER stress (insufficient folding capacity or ER dysfunction) triggers a protective gene-expression program termed the unfolded protein response (UPR). In S. cerevisiae, the UPR is primarily the Ire1–Hac1 axis, discovered and mechanistically characterized in yeast genetics and biochemistry. (ishiwatakimata2023fundamentalandapplicative pages 6-8, ishiwatakimata2023fundamentalandapplicative pages 3-4)

1.2 Ire1 as a bifunctional ER stress sensor and signal transducer

In budding yeast, Ire1 is an ER-located type I transmembrane protein. 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. (ishiwatakimata2023fundamentalandapplicative pages 4-6, ishiwatakimata2023fundamentalandapplicative pages 3-4)

1.3 The canonical yeast output: unconventional HAC1 mRNA splicing

The defining biochemical step in yeast UPR signaling is nonconventional splicing of unspliced HAC1 (HAC1u) mRNA. Ire1 cleaves HAC1 mRNA at both splice junctions, and then tRNA ligase (Trl1/Rlg1) ligates the exons to generate the spliced form (HAC1i), which is translated to the bZIP transcription factor Hac1 that activates UPR target genes (including ER chaperones and folding enzymes). (sidrauski1997thetransmembranekinase pages 4-6, ishiwatakimata2023fundamentalandapplicative pages 3-4)

2) Molecular function: enzymatic activities and substrate specificity

2.1 Endoribonuclease (RNase) activity: reaction and substrate specificity

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. (sidrauski1997thetransmembranekinase pages 3-4, sidrauski1997thetransmembranekinase pages 4-6)

Cleavage-site specificity: 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. Cleavage at the two junctions can occur independently (no obligate order). (sidrauski1997thetransmembranekinase pages 3-4, sidrauski1997thetransmembranekinase pages 4-6)

Cofactor/nucleotide dependence: In vitro cleavage requires an adenosine nucleotide cofactor: omission of ATP abolishes cleavage, while ADP or AMP-PNP can substitute; GTP cannot. This supports a conformational/ligand role for adenine nucleotide binding in RNase activation rather than requiring phosphoryl transfer. (sidrauski1997thetransmembranekinase pages 2-3)

Completion of splicing: 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. (sidrauski1997thetransmembranekinase pages 4-6)

2.2 tRNA ligase (Trl1/Rlg1) and RNA end-chemistry

Yeast HAC1 splicing is mechanistically analogous to tRNA splicing chemistry: Ire1 cleavage produces characteristic RNA ends (described in mechanistic summaries), and Trl1/Rlg1 performs the ligation steps needed to generate the spliced HAC1 product. (rubio2010activatingeventsof pages 19-24)

2.3 Kinase activity: role in activation and attenuation

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. (ishiwatakimata2023fundamentalandapplicative pages 4-6, ishiwatakimata2023fundamentalandapplicative pages 3-4)

Beyond enabling activation, kinase function is implicated in attenuation/homeostatic shutdown: mechanistic syntheses report kinase-dependent processes contributing to the disassembly of Ire1 oligomers and termination of signaling. (rubio2010activatingeventsof pages 24-31, ishiwatakimata2023fundamentalandapplicative pages 12-13)

3) Cellular localization and interacting partners

3.1 Localization

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. (ishiwatakimata2023fundamentalandapplicative pages 3-4, ishiwatakimata2023fundamentalandapplicative pages 4-6)

A schematic depiction of this localization and pathway logic (Ire1 repression by Kar2/BiP, stress-induced clustering, HAC1 splicing, Hac1-driven transcriptional response) is shown here: (ishiwatakimata2023fundamentalandapplicative media d2ed78d3)

3.2 Key interaction partners and regulators

Kar2/BiP (ER Hsp70 chaperone): Under non-stress conditions Kar2/BiP binding keeps Ire1 in a less self-associated state; ER stress promotes Kar2 dissociation and Ire1 self-association/activation. However, Kar2 dissociation alone is not sufficient for full activation, and mutants defective in Kar2 binding can still respond to stress, supporting multilayer regulation. (ishiwatakimata2023fundamentalandapplicative pages 4-6, ishiwatakimata2023fundamentalandapplicative pages 3-4)
Unfolded client proteins: Ire1 activation can involve direct engagement of unfolded proteins via its luminal domain, which promotes oligomerization and signaling. (ishiwatakimata2023fundamentalandapplicative pages 4-6)
HAC1 mRNA: HAC1u mRNA is recruited to Ire1 puncta/clusters for splicing during ER stress. (ishiwatakimata2023fundamentalandapplicative pages 3-4)
Trl1/Rlg1: Ligates the exon fragments after Ire1 cleavage to complete HAC1 splicing. (ishiwatakimata2023fundamentalandapplicative pages 3-4, sidrauski1997thetransmembranekinase pages 4-6)

4) Pathway role and outputs

4.1 Core pathway steps (yeast Ire1–Hac1 branch)

ER stress increases unfolded protein burden and/or perturbs ER membrane homeostasis.
Ire1 transitions from repressed state (Kar2/BiP-associated) to an active state via dimerization/oligomerization and autophosphorylation.
Activated Ire1 RNase cleaves HAC1u mRNA at both splice junctions.
Trl1/Rlg1 ligates exons to produce HAC1i.
HAC1i is translated to Hac1 transcription factor, which induces UPR target genes (chaperones, folding enzymes, ERAD components; and, in broader UPR framing, lipid biosynthesis genes). (ishiwatakimata2023fundamentalandapplicative pages 4-6, ernst2024endoplasmicreticulummembrane pages 4-6)

4.2 Proteotoxic stress vs lipid bilayer stress (LBS)

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. LBS tends to promote dimeric rather than large oligomeric Ire1 assemblies and can elicit weaker RNase output and a milder UPR. (ishiwatakimata2023fundamentalandapplicative pages 4-6, ernst2024endoplasmicreticulummembrane pages 6-7)

5) Recent developments (prioritizing 2023–2024)

5.1 2023 yeast UPR synthesis: expanded regulation layers

A 2023 yeast-focused review consolidates “canonical” and updated mechanistic insights, including: (i) multilayer control of Ire1 by Kar2/BiP and intrinsic disordered segments; (ii) stress-specific activation by unfolded proteins vs membrane stress; and (iii) multiple attenuation routes, including Ire1 dephosphorylation and HAC1 mRNA handling. (ishiwatakimata2023fundamentalandapplicative pages 4-6, ishiwatakimata2023fundamentalandapplicative pages 13-14)

5.2 2024 review focus: membrane homeostasis and lipid-induced UPR

A 2024 Cold Spring Harbor Perspectives review situates Ire1 within ER membrane homeostasis, explicitly linking UPR induction to aberrant lipid metabolism (lipid bilayer stress) and emphasizing oligomeric-state control of Ire1 activation. (ernst2024endoplasmicreticulummembrane pages 4-6, ernst2024endoplasmicreticulummembrane pages 6-7)

5.3 New regulatory input (2023 preprint): MAPK Slt2 modulates HAC1 splicing/translation

A 2023 bioRxiv preprint proposes that MAPK Slt2 enhances both HAC1 mRNA splicing and translation, contributing to adaptation under ER stress. It reports quantitative kinetics under DTT stress (5 mM): Hac1 protein is detectable by ~1 h but reduced at 6–8 h; Slt2 phosphorylation exhibits strong late activation (reported up to ~19-fold at ≥4 h) consistent with multi-phase adaptation. (uppala2023adaptationtoer pages 11-15)

6) RIDD and non-canonical RNase outputs: what applies to S. cerevisiae?

Authoritative 2023–2024 reviews state that regulated Ire1-dependent decay (RIDD)—Ire1 RNase cleavage of additional ER-associated mRNAs—is absent (or not convincingly supported) in S. cerevisiae, in contrast to other organisms such as S. pombe and metazoans. The yeast literature summarized indicates that HAC1 is effectively the predominant (possibly sole) physiologically relevant Ire1 RNase substrate in budding yeast; genome-wide analyses did not identify additional targets beyond HAC1, and reports of other cleavage events were not reproducible. (ernst2024endoplasmicreticulummembrane pages 4-6, ishiwatakimata2023fundamentalandapplicative pages 6-8, fauzee2023endoplasmicstresssensor pages 1-2)

7) Current applications and real-world implementations

7.1 Yeast biotechnology: improving secretion and ER capacity

Manipulating the Ire1/Hac1 axis (often by HAC1/Hac1 overexpression or constitutive UPR induction) is used to increase secretory capacity and can drive ER expansion. However, strong or constitutive UPR activation can impose growth defects in S. cerevisiae, motivating strategies that tune UPR strength or combine factors (e.g., co-overexpression with other stress-response transcription factors). (ishiwatakimata2023fundamentalandapplicative pages 10-12, ishiwatakimata2023fundamentalandapplicative pages 1-3)

7.2 Fungal biotechnology (industry): quantitative yield increases from UPR activation

A 2024 applied review summarizes that constitutive/activated HacA/Hac1 strategies have delivered substantial increases in secreted-product yields in industrial fungi, including up to sevenfold higher laccase production and ~2.8-fold higher bovine preprochymosin in reported implementations. These examples illustrate how the Ire1/Hac1-style transcriptional UPR program can be leveraged to expand folding/secretion capacity. (jadhav2024proteinsecretionand pages 6-7)

7.3 Crop protection / antifungal strategies: targeting IRE1-dependent hac1 splicing

A 2023 Journal of Agricultural and Food Chemistry study developed a cell-based reporter screening platform (using transformed S. cerevisiae where DTT-induced UPR/hac1 splicing drives a GFP signal) to identify natural products that inhibit fungal IRE1-dependent hac1 splicing. The work reports dose–response inhibition (IC50 determination) and extends to plant-pathogen assays in which subtoxic doses of active inhibitors significantly reduced necrosis in infected leaves (Wilcoxon tests, p < 0.05 to < 0.001). This is a concrete translational use of Ire1/Hac1 pathway biology in an applied setting. (charpentier2023naturalproductstargeting pages 13-17)

8) Expert synthesis and authoritative interpretation (what leading sources emphasize)

Centrality of Ire1/Hac1 in budding yeast UPR: Yeast UPR is effectively a single-sensor, single-transcription-factor architecture (Ire1→Hac1), which enables unusually clean genetic epistasis and mechanistic dissection; reviews emphasize this as a strength of yeast as a model for ER stress biology. (ishiwatakimata2023fundamentalandapplicative pages 6-8, fauzee2023endoplasmicstresssensor pages 1-2)
Two-input sensing (proteotoxic vs membrane stress): 2023–2024 sources emphasize the physiological importance of lipid bilayer stress as a distinct trigger of Ire1 activation, integrating ER proteostasis with membrane homeostasis. (ishiwatakimata2023fundamentalandapplicative pages 4-6, ernst2024endoplasmicreticulummembrane pages 4-6)
Likely absence of RIDD in S. cerevisiae: Recent authoritative reviews treat RIDD as absent in budding yeast, reinforcing a functional annotation in which HAC1 splicing is Ire1’s key RNase output in this organism. (ernst2024endoplasmicreticulummembrane pages 4-6, ishiwatakimata2023fundamentalandapplicative pages 6-8)

9) Recent data/statistics from studies (selected examples)

Enzymology (foundational quantitative/biochemical constraints): Ire1 RNase activity requires an adenosine nucleotide cofactor (ATP required; ADP or AMP-PNP can substitute; GTP cannot), and single-nucleotide changes at splice junctions block cleavage at that junction—quantitative constraints critical for mechanistic and engineering interpretation. (sidrauski1997thetransmembranekinase pages 2-3, sidrauski1997thetransmembranekinase pages 4-6)
Stress adaptation signaling kinetics (2023 preprint): Under DTT (5 mM), Slt2 phosphorylation shows time-dependent fold changes (reported ~2.5-fold at 2 h in WT and up to ~19-fold activation at ≥4 h), and Hac1 protein is detectable early (~1 h) but reduced at later times (6–8 h), indicating dynamic control of the Ire1/Hac1 output during prolonged stress. (uppala2023adaptationtoer pages 11-15)
Biotechnology outcomes (reviewed implementations): Up to 7-fold higher laccase yield and ~2.8-fold higher bovine preprochymosin yield reported from UPR activation strategies in filamentous fungi (reviewed 2024). (jadhav2024proteinsecretionand pages 6-7)
Crop protection assay statistics (2023 primary): Inhibitors targeting IRE1-dependent hac1 splicing reduced necrosis area with reported statistical significance (p < 0.05 to < 0.001) and were characterized via IC50/MIG50 dose–response frameworks. (charpentier2023naturalproductstargeting pages 13-17)

10) Evidence map (curated key sources)

The following table summarizes the highest-value sources used for functional annotation and recent developments.

Year	Citation (first author/journal)	URL/DOI	Evidence type	Main contribution for Ire1 function	Quantitative/statistical data highlighted (if any)
1997	Sidrauski & Walter, Cell	https://doi.org/10.1016/S0092-8674(00)80369-4	Primary	Foundational demonstration that S. cerevisiae Ire1p is an ER/inner nuclear membrane transmembrane kinase and site-specific endoribonuclease; cleaves HAC1 mRNA at both splice junctions; together with tRNA ligase reconstitutes nonconventional splicing in vitro; establishes core Ire1→Hac1 UPR pathway and substrate specificity for HAC1 over control RNAs (sidrauski1997thetransmembranekinase pages 3-4, sidrauski1997thetransmembranekinase pages 6-7, sidrauski1997thetransmembranekinase pages 4-6, sidrauski1997thetransmembranekinase pages 2-3)	Cell paper cited as having 1201 citations; splice-site point mutations selectively block cleavage; purified Ire1 + tRNA ligase sufficient for splicing; ATP/ADP/AMP-PNP support cleavage whereas GTP does not (sidrauski1997thetransmembranekinase pages 3-4, sidrauski1997thetransmembranekinase pages 6-7, sidrauski1997thetransmembranekinase pages 2-3)
2023	Ishiwata-Kimata & Kimata, Journal of Fungi	https://doi.org/10.3390/jof9100989	Review	Best current yeast-focused synthesis: confirms Ire1 as ER type I transmembrane stress sensor with cytosolic kinase/RNase; activation by unfolded proteins and lipid bilayer stress; Kar2/BiP repression and release; oligomerization/puncta; predominant substrate is HAC1u in S. cerevisiae; attenuation via dephosphorylation/BiP re-binding; discusses industrial exploitation of constitutive UPR/Hac1 for secretion and ER expansion (ishiwatakimata2023fundamentalandapplicative pages 4-6, ishiwatakimata2023fundamentalandapplicative pages 6-8, ishiwatakimata2023fundamentalandapplicative pages 13-14, ishiwatakimata2023fundamentalandapplicative pages 3-4, ishiwatakimata2023fundamentalandapplicative pages 10-12, ishiwatakimata2023fundamentalandapplicative pages 1-3)	Notes milder RNase output under lipid bilayer stress with dimeric vs oligomeric Ire1; reports constitutive/enforced UPR can enlarge ER and improve secretion, but may retard growth in S. cerevisiae (ishiwatakimata2023fundamentalandapplicative pages 4-6, ishiwatakimata2023fundamentalandapplicative pages 10-12, ishiwatakimata2023fundamentalandapplicative pages 1-3)
2024	Ernst et al., Cold Spring Harbor Perspectives in Biology	https://doi.org/10.1101/cshperspect.a041400	Review	Authoritative 2024 review on ER membrane homeostasis/UPR; frames ScIre1 as integrating proteotoxic and lipid bilayer stress; emphasizes oligomeric-state control, signaling clusters/filaments, TMD-based membrane sensing, and absence of robust RIDD in S. cerevisiae compared with other systems (ernst2024endoplasmicreticulummembrane pages 6-7, ernst2024endoplasmicreticulummembrane pages 4-6)	No yeast-specific numeric dataset extracted in evidence, but highlights structurally distinct activation modes and broad transcriptional regulation of hundreds of UPR targets through spliced HAC1 (ernst2024endoplasmicreticulummembrane pages 4-6)
2023	Bartoszewska et al., Journal of Cell Communication and Signaling	https://doi.org/10.1007/s12079-023-00784-5	Review	Comparative review useful for distinguishing yeast Ire1 from mammalian IRE1α: confirms yeast Ire1 as original UPR sensor that cleaves HAC1 at two sites to produce active Hac1; also summarizes conserved dual kinase/RNase architecture across eukaryotes (bartoszewska2023dualrnaseactivity pages 3-5)	Article noted as having 23 citations; includes mammalian autophosphorylation residues S724/S726/S729 for comparison, underscoring species differences in downstream substrates (HAC1 vs XBP1) (bartoszewska2023dualrnaseactivity pages 3-5)
2023	Uppala et al., bioRxiv	https://doi.org/10.1101/2023.11.19.567283	Preprint / primary	Provides recent mechanistic evidence that MAPK Slt2 promotes adaptation to ER stress by enhancing both HAC1 mRNA splicing and translation, adding a regulatory layer upstream/parallel to canonical Ire1–Hac1 signaling in budding yeast (uppala2023adaptationtoer pages 11-15, uppala2023adaptationtoer pages 1-4)	DTT 5 mM time course (1–8 h); Hac1 detectable by 1 h then reduced at 6–8 h; Slt2 phosphorylation ~2.5-fold at 2 h in WT, ~4-fold for Flag-Slt2 at 2 h, and ~19-fold at ≥4 h; truncation mapping identified residues 1–400/1–440 as functional but 1–355 nonfunctional (uppala2023adaptationtoer pages 11-15)
2024	Jadhav et al., Applied Microbiology and Biotechnology	https://doi.org/10.1007/s00253-023-12985-4	Review	Application-focused review showing how Ire1/Hac1-like UPR manipulation is implemented in fungal biotechnology to improve secretory capacity; useful for real-world relevance of yeast UPR knowledge to enzyme/recombinant protein production (jadhav2024proteinsecretionand pages 6-7)	Reports activated HacA/Hac1 strategies increasing T. versicolor laccase up to 7-fold and bovine preprochymosin up to 2.8-fold; disruption of aoatg15 in A. oryzae gave ~3-fold higher bovine chymosin secretion (jadhav2024proteinsecretionand pages 6-7)

Table: This table summarizes core literature for functional annotation of budding yeast Ire1/ERN1/YHR079C, spanning foundational mechanism, current reviews, recent regulatory studies, and applied biotechnology relevance. It is useful for quickly linking each source to specific evidence on activation, enzymatic function, substrate specificity, pathway role, localization, and practical implementation.

References (URLs and publication dates from retrieved sources)

Sidrauski C, Walter P. Cell (1997-09). “The Transmembrane Kinase Ire1p Is a Site-Specific Endonuclease That Initiates mRNA Splicing in the Unfolded Protein Response.” https://doi.org/10.1016/S0092-8674(00)80369-4 (sidrauski1997thetransmembranekinase pages 3-4)
Ishiwata-Kimata Y, Kimata Y. Journal of Fungi (2023-10). “Fundamental and Applicative Aspects of the Unfolded Protein Response in Yeasts.” https://doi.org/10.3390/jof9100989 (ishiwatakimata2023fundamentalandapplicative pages 4-6)
Ernst R, Renne MF, Jain A, von der Malsburg A. Cold Spring Harbor Perspectives in Biology (2024-01). “Endoplasmic Reticulum Membrane Homeostasis and the Unfolded Protein Response.” https://doi.org/10.1101/cshperspect.a041400 (ernst2024endoplasmicreticulummembrane pages 4-6)
Charpentier T et al. Journal of Agricultural and Food Chemistry (2023-09). “Natural Products Targeting the Fungal Unfolded Protein Response as an Alternative Crop Protection Strategy.” https://doi.org/10.1021/acs.jafc.3c03602 (charpentier2023naturalproductstargeting pages 13-17)
Uppala JK et al. bioRxiv (2023-11). “Adaptation to ER Stress by Slt2 … via Enhancing Splicing and Translation of HAC1 mRNA in Saccharomyces cerevisiae.” https://doi.org/10.1101/2023.11.19.567283 (uppala2023adaptationtoer pages 11-15)
Jadhav R, Mach RL, Mach-Aigner AR. Applied Microbiology and Biotechnology (2024-01). “Protein secretion and associated stress in industrially employed filamentous fungi.” https://doi.org/10.1007/s00253-023-12985-4 (jadhav2024proteinsecretionand pages 6-7)

References

(ishiwatakimata2023fundamentalandapplicative pages 3-4): Yuki Ishiwata-Kimata and Yukio Kimata. Fundamental and applicative aspects of the unfolded protein response in yeasts. Journal of Fungi, 9:989, Oct 2023. URL: https://doi.org/10.3390/jof9100989, doi:10.3390/jof9100989. This article has 21 citations.
(ishiwatakimata2023fundamentalandapplicative pages 4-6): Yuki Ishiwata-Kimata and Yukio Kimata. Fundamental and applicative aspects of the unfolded protein response in yeasts. Journal of Fungi, 9:989, Oct 2023. URL: https://doi.org/10.3390/jof9100989, doi:10.3390/jof9100989. This article has 21 citations.
(sidrauski1997thetransmembranekinase pages 3-4): Carmela Sidrauski and Peter Walter. The transmembrane kinase ire1p is a site-specific endonuclease that initiates mrna splicing in the unfolded protein response. Cell, 90:1031-1039, Sep 1997. URL: https://doi.org/10.1016/s0092-8674(00)80369-4, doi:10.1016/s0092-8674(00)80369-4. This article has 1201 citations and is from a highest quality peer-reviewed journal.
(fauzee2023endoplasmicstresssensor pages 1-2): Yasmin Nabilah Binti Mohd Fauzee, Yuki Yoshida, and Yukio Kimata. Endoplasmic stress sensor ire1 is involved in cytosolic/nuclear protein quality control in pichia pastoris cells independent of hac1. Frontiers in Microbiology, Jun 2023. URL: https://doi.org/10.3389/fmicb.2023.1157146, doi:10.3389/fmicb.2023.1157146. This article has 10 citations and is from a peer-reviewed journal.
(bartoszewska2023dualrnaseactivity pages 3-5): Sylwia Bartoszewska, Jakub Sławski, James F. Collawn, and Rafał Bartoszewski. Dual rnase activity of ire1 as a target for anticancer therapies. Journal of Cell Communication and Signaling, 17:1145-1161, Sep 2023. URL: https://doi.org/10.1007/s12079-023-00784-5, doi:10.1007/s12079-023-00784-5. This article has 23 citations and is from a peer-reviewed journal.
(ishiwatakimata2023fundamentalandapplicative pages 6-8): Yuki Ishiwata-Kimata and Yukio Kimata. Fundamental and applicative aspects of the unfolded protein response in yeasts. Journal of Fungi, 9:989, Oct 2023. URL: https://doi.org/10.3390/jof9100989, doi:10.3390/jof9100989. This article has 21 citations.
(sidrauski1997thetransmembranekinase pages 4-6): Carmela Sidrauski and Peter Walter. The transmembrane kinase ire1p is a site-specific endonuclease that initiates mrna splicing in the unfolded protein response. Cell, 90:1031-1039, Sep 1997. URL: https://doi.org/10.1016/s0092-8674(00)80369-4, doi:10.1016/s0092-8674(00)80369-4. This article has 1201 citations and is from a highest quality peer-reviewed journal.
(sidrauski1997thetransmembranekinase pages 2-3): Carmela Sidrauski and Peter Walter. The transmembrane kinase ire1p is a site-specific endonuclease that initiates mrna splicing in the unfolded protein response. Cell, 90:1031-1039, Sep 1997. URL: https://doi.org/10.1016/s0092-8674(00)80369-4, doi:10.1016/s0092-8674(00)80369-4. This article has 1201 citations and is from a highest quality peer-reviewed journal.
(rubio2010activatingeventsof pages 19-24): CAD Rubio. Activating events of the unfolded protein response in saccharomyces cerevisiae. Unknown journal, 2010.
(rubio2010activatingeventsof pages 24-31): CAD Rubio. Activating events of the unfolded protein response in saccharomyces cerevisiae. Unknown journal, 2010.
(ishiwatakimata2023fundamentalandapplicative pages 12-13): Yuki Ishiwata-Kimata and Yukio Kimata. Fundamental and applicative aspects of the unfolded protein response in yeasts. Journal of Fungi, 9:989, Oct 2023. URL: https://doi.org/10.3390/jof9100989, doi:10.3390/jof9100989. This article has 21 citations.
(ishiwatakimata2023fundamentalandapplicative media d2ed78d3): Yuki Ishiwata-Kimata and Yukio Kimata. Fundamental and applicative aspects of the unfolded protein response in yeasts. Journal of Fungi, 9:989, Oct 2023. URL: https://doi.org/10.3390/jof9100989, doi:10.3390/jof9100989. This article has 21 citations.
(ernst2024endoplasmicreticulummembrane pages 4-6): Robert Ernst, Mike F. Renne, Aamna Jain, and Alexander von der Malsburg. Endoplasmic reticulum membrane homeostasis and the unfolded protein response. Cold Spring Harbor perspectives in biology, 16:a041400, Jan 2024. URL: https://doi.org/10.1101/cshperspect.a041400, doi:10.1101/cshperspect.a041400. This article has 24 citations and is from a peer-reviewed journal.
(ernst2024endoplasmicreticulummembrane pages 6-7): Robert Ernst, Mike F. Renne, Aamna Jain, and Alexander von der Malsburg. Endoplasmic reticulum membrane homeostasis and the unfolded protein response. Cold Spring Harbor perspectives in biology, 16:a041400, Jan 2024. URL: https://doi.org/10.1101/cshperspect.a041400, doi:10.1101/cshperspect.a041400. This article has 24 citations and is from a peer-reviewed journal.
(ishiwatakimata2023fundamentalandapplicative pages 13-14): Yuki Ishiwata-Kimata and Yukio Kimata. Fundamental and applicative aspects of the unfolded protein response in yeasts. Journal of Fungi, 9:989, Oct 2023. URL: https://doi.org/10.3390/jof9100989, doi:10.3390/jof9100989. This article has 21 citations.
(uppala2023adaptationtoer pages 11-15): Jagadeesh Kumar Uppala, Anish Chakraborty, Jasmine George, Kimberly Ann Mayer, Chandrima Ghosh, Ritisha Dey, Pradeep Chaluvally-Raghavan, and Madhusudan Dey. Adaptation to er stress by slt2, counterpart of human map kinase erk1/2, via enhancing splicing and translation of hac1 mrna in saccharomyces cerevisiae. bioRxiv, Nov 2023. URL: https://doi.org/10.1101/2023.11.19.567283, doi:10.1101/2023.11.19.567283. This article has 1 citations.
(ishiwatakimata2023fundamentalandapplicative pages 10-12): Yuki Ishiwata-Kimata and Yukio Kimata. Fundamental and applicative aspects of the unfolded protein response in yeasts. Journal of Fungi, 9:989, Oct 2023. URL: https://doi.org/10.3390/jof9100989, doi:10.3390/jof9100989. This article has 21 citations.
(ishiwatakimata2023fundamentalandapplicative pages 1-3): Yuki Ishiwata-Kimata and Yukio Kimata. Fundamental and applicative aspects of the unfolded protein response in yeasts. Journal of Fungi, 9:989, Oct 2023. URL: https://doi.org/10.3390/jof9100989, doi:10.3390/jof9100989. This article has 21 citations.
(jadhav2024proteinsecretionand pages 6-7): Reshma Jadhav, Robert L Mach, and Astrid R Mach-Aigner. Protein secretion and associated stress in industrially employed filamentous fungi. Applied Microbiology and Biotechnology, Jan 2024. URL: https://doi.org/10.1007/s00253-023-12985-4, doi:10.1007/s00253-023-12985-4. This article has 28 citations and is from a domain leading peer-reviewed journal.
(charpentier2023naturalproductstargeting pages 13-17): Thomas Charpentier, Guillaume Viault, Anne-Marie Le Ray, Nelly Bataillé-Simoneau, Jean-Jacques Helesbeux, Nadège Blon, Franck Bastide, Muriel Marchi, Sophie Aligon, Antoine Bruguière, Chau Phi Dinh, Zahia Benbelkacem, Jean-Felix Dallery, Philippe Simoneau, Pascal Richomme, and Thomas Guillemette. Natural products targeting the fungal unfolded protein response as an alternative crop protection strategy. Journal of agricultural and food chemistry, 71:13706-13716, Sep 2023. URL: https://doi.org/10.1021/acs.jafc.3c03602, doi:10.1021/acs.jafc.3c03602. This article has 11 citations and is from a highest quality peer-reviewed journal.
(sidrauski1997thetransmembranekinase pages 6-7): Carmela Sidrauski and Peter Walter. The transmembrane kinase ire1p is a site-specific endonuclease that initiates mrna splicing in the unfolded protein response. Cell, 90:1031-1039, Sep 1997. URL: https://doi.org/10.1016/s0092-8674(00)80369-4, doi:10.1016/s0092-8674(00)80369-4. This article has 1201 citations and is from a highest quality peer-reviewed journal.
(uppala2023adaptationtoer pages 1-4): Jagadeesh Kumar Uppala, Anish Chakraborty, Jasmine George, Kimberly Ann Mayer, Chandrima Ghosh, Ritisha Dey, Pradeep Chaluvally-Raghavan, and Madhusudan Dey. Adaptation to er stress by slt2, counterpart of human map kinase erk1/2, via enhancing splicing and translation of hac1 mrna in saccharomyces cerevisiae. bioRxiv, Nov 2023. URL: https://doi.org/10.1101/2023.11.19.567283, doi:10.1101/2023.11.19.567283. This article has 1 citations.

Artifacts

Edison artifact artifact-00

Citations

sidrauski1997thetransmembranekinase pages 2-3
sidrauski1997thetransmembranekinase pages 4-6
rubio2010activatingeventsof pages 19-24
ishiwatakimata2023fundamentalandapplicative pages 4-6
ishiwatakimata2023fundamentalandapplicative pages 3-4
uppala2023adaptationtoer pages 11-15
jadhav2024proteinsecretionand pages 6-7
charpentier2023naturalproductstargeting pages 13-17
ernst2024endoplasmicreticulummembrane pages 4-6
bartoszewska2023dualrnaseactivity pages 3-5
sidrauski1997thetransmembranekinase pages 3-4
fauzee2023endoplasmicstresssensor pages 1-2
ishiwatakimata2023fundamentalandapplicative pages 6-8
rubio2010activatingeventsof pages 24-31
ishiwatakimata2023fundamentalandapplicative pages 12-13
ernst2024endoplasmicreticulummembrane pages 6-7
ishiwatakimata2023fundamentalandapplicative pages 13-14
ishiwatakimata2023fundamentalandapplicative pages 10-12
ishiwatakimata2023fundamentalandapplicative pages 1-3
sidrauski1997thetransmembranekinase pages 6-7
uppala2023adaptationtoer pages 1-4
https://doi.org/10.1016/S0092-8674(00
https://doi.org/10.3390/jof9100989
https://doi.org/10.1101/cshperspect.a041400
https://doi.org/10.1007/s12079-023-00784-5
https://doi.org/10.1101/2023.11.19.567283
https://doi.org/10.1007/s00253-023-12985-4
https://doi.org/10.1021/acs.jafc.3c03602
https://doi.org/10.3390/jof9100989,
https://doi.org/10.1016/s0092-8674(00
https://doi.org/10.3389/fmicb.2023.1157146,
https://doi.org/10.1007/s12079-023-00784-5,
https://doi.org/10.1101/cshperspect.a041400,
https://doi.org/10.1101/2023.11.19.567283,
https://doi.org/10.1007/s00253-023-12985-4,
https://doi.org/10.1021/acs.jafc.3c03602,

📚 Additional Documentation

Bioreason Rl Predictions

(IRE1-bioreason-rl-predictions.md)

BioReason Chat Export

Exported on March 22, 2026 at 02:03 AM

Organism: Saccharomyces cerevisiae

Sequence:

MRLLRRNMLVLTLLVCVFSSIISCSIPLSSRTSRRQIVEDEVASTKKLNFNYGVDKNINSPIPAPRTTEGLPNMKLSSYPTPNLLNTADNRRANKKGRRAANSISVPYLENRSLNELSLSDILIAADVEGGLHAVDRRNGHIIWSIEPENFQPLIEIQEPSRLETYETLIIEPFGDGNIYYFNAHQGLQKLPLSIRQLVSTSPLHLKTNIVVNDSGKIVEDEKVYTGSMRTIMYTINMLNGEIISAFGPGSKNGYFGSQSVDCSPEEKIKLQECENMIVIGKTIFELGIHSYDGASYNVTYSTWQQNVLDVPLALQNTFSKDGMCIAPFRDKSLLASDLDFRIARWVSPTFPGIIVGLFDVFNDLRTNENILVPHPFNPGDHESISSNKVYLDQTSNLSWFALSSQNFPSLVESAPISRYASSDRWRVSSIFEDETLFKNAIMGVHQIYNNEYDHLYENYEKTNSLDTTHKYPPLMIDSSVDTTDLHQNNEMNSLKEYMSPEDLEAYRKKIHEQISRELDEKNQNSLLLKFGSLVYRIIETGVFLLLFLIFCAILQRFKILPPLYVLLSKIGFMPEKEIPIVESKSLNCPSSSENVTKPFDMKSGKQVVFEGAVNDGSLKSEKDNDDADEDDEKSLDLTTEKKKRKRGSRGGKKGRKSRIANIPNFEQSLKNLVVSEKILGYGSSGTVVFQGSFQGRPVAVKRMLIDFCDIALMEIKLLTESDDHPNVIRYYCSETTDRFLYIALELCNLNLQDLVESKNVSDENLKLQKEYNPISLLRQIASGVAHLHSLKIIHRDLKPQNILVSTSSRFTADQQTGAENLRILISDFGLCKKLDSGQSSFRTNLNNPSGTSGWRAPELLEESNNLQCQVETEHSSSRHTVVSSDSFYDPFTKRRLTRSIDIFSMGCVFYYILSKGKHPFGDKYSRESNIIRGIFSLDEMKCLHDRSLIAEATDLISQMIDHDPLKRPTAMKVLRHPLFWPKSKKLEFLLKVSDRLEIENRDPPSALLMKFDAGSDFVIPSGDWTVKFDKTFMDNLERYRKYHSSKLMDLLRALRNKYHHFMDLPEDIAELMGPVPDGFYDYFTKRFPNLLIGVYMIVKENLSDDQILREFLYS

Thinking Trace

I begin by dissecting the InterPro architecture and its order along the sequence. The N-terminal half is dominated by beta-propeller-like modules: IPR015943 (WD40/YVTN repeat-like-containing domain superfamily, residues 105–283), IPR018391 (Pyrrolo-quinoline quinone beta-propeller repeat, residues 116–349), and IPR011047 (Quinoprotein alcohol dehydrogenase-like superfamily, residues 121–337). These overlapping signatures collectively define a multi-bladed beta-propeller scaffold that forms a rigid interaction platform. In soluble quinoprotein dehydrogenases this fold binds cofactors, but here—especially in conjunction with the absence of catalytic motifs and the presence of downstream signaling domains—this propeller functions primarily as an assembly and sensing module rather than an enzyme active site. Immediately downstream, the architecture transitions into the hallmark IRE1/2-like sensor-effector core: IPR045133 (Serine/threonine-protein kinase/endoribonuclease IRE1/2-like family, residues 295–1112), which encodes a bifunctional signaling machine that couples RNA-responsive sensing to phosphorylation and endoribonuclease activities.

The central catalytic module is IPR000719 (Protein kinase domain, residues 674–980), reinforced by IPR011009 (Protein kinase-like domain superfamily, residues 677–992) and an embedded catalytic signature IPR008271 (Serine/threonine-protein kinase, active site, residues 793–805). This arrangement establishes a bona fide serine/threonine kinase core capable of autophosphorylation and substrate phosphorylation. C-terminal to the kinase, IPR010513 (KEN domain, residues 983–1115) and its superfamily IPR038357 (KEN domain superfamily, residues 983–1115) specify an RNA endonuclease module. The juxtaposition of the kinase and KEN domains is diagnostic of the IRE1/2 lineage: kinase-driven conformational switching exposes and activates the KEN RNase. Together, the N-terminal beta-propeller scaffold, the IRE1/2-like signaling core, and the C-terminal KEN RNase causally define a bifunctional signaling enzyme that senses signals via oligomerization, phosphorylates itself and targets, and cleaves RNA.

From this architecture, the molecular function resolves into two coupled chemistries. The protein kinase domain with its active-site motif (IPR000719; IPR008271; IPR011009) imposes ATP-dependent serine/threonine phosphorylation. The KEN domain imposes endoribonuclease activity toward RNA substrates. Thus, the most parsimonious functional set includes ATP binding and protein serine/threonine kinase activity, alongside endoribonuclease activity that is conditional and signal-gated.

These activities position the protein squarely in stress-adaptive pathways. The IRE1/2-like family (IPR045133) is specialized for integrating environmental and translational cues; the beta-propeller platform and KEN RNase support regulated RNA processing, while the kinase core propagates phosphorylation cascades. In yeast, such bifunctional signaling enzymes orchestrate responses to heat, nutrient limitation, and oxidative stress by coordinating mRNA cleavage and translational control. Consequently, the biological process is best captured by stress-adaptive signaling culminating in RNA processing and translational reprogramming.

Cellular location follows from the soluble beta-propeller and cytosolic kinase/RNase composition, together with the absence of transmembrane segments. The soluble nature and assembly-prone N-terminal propeller argue for a cytoplasmic residency, consistent with a role in RNA handling and phosphorylation within cytoplasmic ribonucleoprotein hubs.

Mechanistically, I hypothesize that the N-terminal beta-propeller nucleates higher-order assemblies that sense cytoplasmic stress and drive oligomerization. Oligomerization allosterically activates the internal serine/threonine kinase (IPR000719), which then autophosphorylates to stabilize an active conformation that exposes the KEN RNase (IPR010513). The RNase cleaves target RNA(s), tuning mRNA pools and enabling broader stress-adaptive programs. Likely interaction partners include cytoplasmic RNA-binding factors and ribosome-associated assemblies that deliver substrates and scaffold the signaling complex.

Functional Summary

A cytoplasmic bifunctional signaling enzyme that assembles via an N-terminal beta‑propeller scaffold, activates an internal serine/threonine kinase core, and couples this switching mechanism to a C‑terminal endoribonuclease. By integrating phosphorylation with regulated RNA cleavage, it coordinates stress-adaptive signaling and translational reprogramming in the cytoplasm, likely responding to environmental cues by oligomerizing, autophosphorylating, and cleaving RNA to remodel mRNA pools.

UniProt Summary

Probable serine/threonine-protein kinase.

InterPro Domains

WD40/YVTN repeat-like-containing domain superfamily (IPR015943, homologous_superfamily) — residues 105-283
Pyrrolo-quinoline quinone beta-propeller repeat (IPR018391, repeat) — residues 116-349
Quinoprotein alcohol dehydrogenase-like superfamily (IPR011047, homologous_superfamily) — residues 121-337
Serine/threonine-protein kinase/endoribonuclease IRE1/2-like (IPR045133, family) — residues 295-1112
Protein kinase domain (IPR000719, domain) — residues 674-980
Protein kinase-like domain superfamily (IPR011009, homologous_superfamily) — residues 677-992
Serine/threonine-protein kinase, active site (IPR008271, active_site) — residues 793-805
KEN domain (IPR010513, domain) — residues 983-1115
KEN domain superfamily (IPR038357, homologous_superfamily) — residues 983-1115

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), catalytic activity (GO:0003824), transferase activity (GO:0016740), hydrolase activity (GO:0016787), catalytic activity, acting on a nucleic acid (GO:0140640), catalytic activity, acting on a protein (GO:0140096), protein binding (GO:0005515), catalytic activity, acting on RNA (GO:0140098), hydrolase activity, acting on ester bonds (GO:0016788), unfolded protein binding (GO:0051082), transferase activity, transferring phosphorus-containing groups (GO:0016772), protein kinase activity (GO:0004672), identical protein binding (GO:0042802), protein serine/threonine kinase activity (GO:0004674), kinase activity (GO:0016301), nuclease activity (GO:0004518), phosphotransferase activity, alcohol group as acceptor (GO:0016773), ribonuclease activity (GO:0004540), RNA endonuclease activity (GO:0004521), endoribonuclease activity (GO:0004519)

Biological Process: biological_process (GO:0008150), metabolic process (GO:0008152), localization (GO:0051179), regulation of biological process (GO:0050789), signaling (GO:0023052), biological regulation (GO:0065007), response to stimulus (GO:0050896), cellular process (GO:0009987), cellular localization (GO:0051641), response to chemical (GO:0042221), regulation of metabolic process (GO:0019222), nitrogen compound metabolic process (GO:0006807), cellular component organization or biogenesis (GO:0071840), organic substance metabolic process (GO:0071704), macromolecule localization (GO:0033036), cellular metabolic process (GO:0044237), small molecule metabolic process (GO:0044281), cell wall organization or biogenesis (GO:0071554), regulation of cellular process (GO:0050794), cellular response to stimulus (GO:0051716), response to stress (GO:0006950), cell communication (GO:0007154), signal transduction (GO:0007165), primary metabolic process (GO:0044238), organic hydroxy compound metabolic process (GO:1901615), organonitrogen compound metabolic process (GO:1901564), heterocycle metabolic process (GO:0046483), protein metabolic process (GO:0019538), regulation of macromolecule metabolic process (GO:0060255), alcohol metabolic process (GO:0006066), cellular aromatic compound metabolic process (GO:0006725), carbohydrate metabolic process (GO:0005975), cellular nitrogen compound metabolic process (GO:0034641), macromolecule metabolic process (GO:0043170), response to organic substance (GO:0010033), phosphorus metabolic process (GO:0006793), fungal-type cell wall organization or biogenesis (GO:0071852), organic cyclic compound metabolic process (GO:1901360), endoplasmic reticulum unfolded protein response (GO:0030968), nucleobase-containing compound metabolic process (GO:0006139), cellular response to chemical stimulus (GO:0070887), cellular response to stress (GO:0033554), regulation of biosynthetic process (GO:0009889), response to topologically incorrect protein (GO:0035966), regulation of nitrogen compound metabolic process (GO:0051171), cellular macromolecule localization (GO:0070727), cellular component organization (GO:0016043), regulation of cellular metabolic process (GO:0031323), regulation of primary metabolic process (GO:0080090), cell wall organization (GO:0071555), cellular carbohydrate metabolic process (GO:0044262), fungal-type cell wall organization (GO:0031505), inositol metabolic process (GO:0006020), regulation of macromolecule biosynthetic process (GO:0010556), cellular response to organic substance (GO:0071310), phosphate-containing compound metabolic process (GO:0006796), external encapsulating structure organization (GO:0045229), regulation of gene expression (GO:0010468), protein modification process (GO:0036211), response to endoplasmic reticulum stress (GO:0034976), cellular response to topologically incorrect protein (GO:0035967), macromolecule modification (GO:0043412), nucleic acid metabolic process (GO:0090304), polyol metabolic process (GO:0019751), regulation of DNA-templated transcription in response to stress (GO:0043620), regulation of cellular biosynthetic process (GO:0031326), regulation of nucleobase-containing compound metabolic process (GO:0019219), response to unfolded protein (GO:0006986), protein localization (GO:0008104), regulation of RNA metabolic process (GO:0051252), gene expression (GO:0010467), protein localization to organelle (GO:0033365), RNA metabolic process (GO:0016070), nucleic acid phosphodiester bond hydrolysis (GO:0090305), regulation of RNA biosynthetic process (GO:2001141), protein phosphorylation (GO:0006468), cellular response to unfolded protein (GO:0034620), regulation of DNA-templated transcription (GO:0006355), RNA processing (GO:0006396), phosphorylation (GO:0016310), RNA phosphodiester bond hydrolysis (GO:0090501), mRNA processing (GO:0006397), mRNA metabolic process (GO:0016071), protein localization to Golgi apparatus (GO:0034067), regulation of nucleic acid-templated transcription (GO:1903506), protein autophosphorylation (GO:0046777), mRNA cleavage (GO:0006379), mRNA cleavage involved in mRNA processing (GO:0098787)

Cellular Component: cellular_component (GO:0005575), protein-containing complex (GO:0032991), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), endoplasmic reticulum protein-containing complex (GO:0140534), membrane (GO:0016020), membrane protein complex (GO:0098796), organelle subcompartment (GO:0031984), intracellular protein-containing complex (GO:0140535), catalytic complex (GO:1902494), cytoplasm (GO:0005737), endomembrane system (GO:0012505), organelle membrane (GO:0031090), transferase complex (GO:1990234), intracellular organelle (GO:0043229), endonuclease complex (GO:1905348), endoplasmic reticulum subcompartment (GO:0098827), nuclear outer membrane-endoplasmic reticulum membrane network (GO:0042175), endoplasmic reticulum (GO:0005783), membrane-bounded organelle (GO:0043227), intracellular membrane-bounded organelle (GO:0043231), transferase complex, transferring phosphorus-containing groups (GO:0061695), endoplasmic reticulum membrane (GO:0005789), endoribonuclease complex (GO:1902555), nucleus (GO:0005634), protein kinase complex (GO:1902911), serine/threonine protein kinase complex (GO:1902554)

Generated by BioReason

Bioreason Rl Review

(IRE1-bioreason-rl-review.md)

BioReason-Pro RL Review: IRE1 (S. cerevisiae)

Source: IRE1-bioreason-rl-predictions.md

Correctness: 3/5
Completeness: 3/5

Functional Summary Review

The BioReason summary states:

A cytoplasmic bifunctional signaling enzyme that assembles via an N-terminal beta-propeller scaffold, activates an internal serine/threonine kinase core, and couples this switching mechanism to a C-terminal endoribonuclease.

The identification of the bifunctional kinase/endoribonuclease is correct and well-supported. The curated review confirms both protein serine/threonine kinase activity (GO:0004674) and RNA endonuclease activity (GO:0004521) as core molecular functions. The coupling of kinase activation to RNase activation is also correctly described.

However, the localization as "cytoplasmic" is a significant error. IRE1 is a type I transmembrane protein of the ER membrane (GO:0005789). The curated review explicitly states: "IRE1 is a type I transmembrane serine/threonine-protein kinase and endoribonuclease... contains an N-terminal lumenal domain (residues 19-526) that senses unfolded proteins in the ER, a single transmembrane helix, and a cytoplasmic portion." Multiple IDA annotations confirm ER membrane localization (PMID:8358794).

The description of the N-terminal region as a "beta-propeller scaffold" is misleading. While InterPro matches beta-propeller superfamily signatures (IPR015943, IPR018391) for this region, the curated review identifies it as the ER lumenal sensor domain that binds unfolded proteins. BioReason interprets these domains as a generic "assembly and sensing module" but misses that this is the ER stress sensor.

By integrating phosphorylation with regulated RNA cleavage, it coordinates stress-adaptive signaling and translational reprogramming in the cytoplasm, likely responding to environmental cues by oligomerizing, autophosphorylating, and cleaving RNA to remodel mRNA pools.

The mechanistic description of oligomerization -> autophosphorylation -> RNase activation is correct in outline. But the summary completely misses the specific biological context: the unfolded protein response (UPR), HAC1 mRNA splicing, ER stress sensing, and the fact that IRE1 is the sole UPR sensor in yeast. The phrase "stress-adaptive signaling and translational reprogramming" is too vague to be useful when the specific pathway (GO:0036498 IRE1-mediated unfolded protein response; GO:0030968 ER UPR) is one of the best-characterized stress signaling pathways in yeast.

Comparison with interpro2go:

The interpro2go annotations (GO_REF:0000002) contribute RNA nuclease activity (GO:0004540), protein kinase activity (GO:0004672), mRNA processing (GO:0006397), and signal transduction (GO:0007165). BioReason's functional summary captures the kinase and RNase activities, which overlaps with interpro2go. Neither interpro2go nor BioReason reaches the specific UPR pathway terms -- those come from IBA and experimental evidence. BioReason does not meaningfully improve on interpro2go here; the ER membrane localization error is a regression from interpro2go's CC predictions, which include ER terms.

Notes on thinking trace

The trace misinterprets the N-terminal lumenal domain as a cytoplasmic beta-propeller. The reasoning states "the absence of transmembrane segments" -- but the protein has a transmembrane helix (residues ~527-549). The thinking trace appears to have missed the transmembrane segment or given it insufficient weight, leading to the cytoplasmic localization error. The model's strong prior for "soluble = cytosolic" overrides structural evidence for membrane anchoring.

📄 View Raw YAML

id: P32361
gene_symbol: IRE1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: >-
  IRE1 (also known as ERN1) is a type I transmembrane serine/threonine-protein kinase
  and endoribonuclease that serves as the primary ER stress sensor in S. cerevisiae.
  It contains an N-terminal lumenal domain (residues 19-526) that senses unfolded proteins
  in the ER, a single transmembrane helix, and a cytoplasmic portion with both kinase
  (residues 674-980) and KEN/endoribonuclease (residues 983-1115) domains. Upon ER stress,
  unfolded proteins bind the lumenal domain, triggering oligomerization and trans-
  autophosphorylation, which activates the endoribonuclease domain. The RNase domain
  then splices HAC1 precursor mRNA to produce mature HAC1 mRNA encoding a transcription
  factor that induces UPR target genes. IRE1 is the sole UPR sensor in yeast, unlike
  metazoans which have additional sensors (PERK, ATF6).
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for ER localization. IRE1 is a well-established ER-resident
      transmembrane protein (PMID:8358794). Supported by IDA and HDA evidence.
    action: ACCEPT
    reason: >-
      ER localization is fundamental to IRE1 function as the ER stress sensor.
      Confirmed by IDA (PMID:8358794) and HDA (PMID:26928762).
    additional_reference_ids:
    - file:yeast/IRE1/IRE1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        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.
- term:
    id: GO:0036498
    label: IRE1-mediated unfolded protein response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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).
    additional_reference_ids:
    - file:yeast/IRE1/IRE1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        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**.
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        Yeast UPR is effectively a single-sensor, single-transcription-factor architecture (Ire1→Hac1), which enables unusually clean genetic epistasis and mechanistic dissection.
- term:
    id: GO:0004521
    label: RNA endonuclease activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    additional_reference_ids:
    - file:yeast/IRE1/IRE1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        **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.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    additional_reference_ids:
    - file:yeast/IRE1/IRE1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        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.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0051082 is proposed for obsoletion. 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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0051082 "unfolded protein binding" is proposed for obsoletion. 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.
- term:
    id: GO:0070059
    label: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum
      stress
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for nucleotide binding from UniProt keyword. IRE1 binds
      ATP/ADP in its kinase domain (PMID:18191223, crystal structure with ADP).
    action: ACCEPT
    reason: >-
      Correct but very broad. IRE1 binds ATP for its kinase activity. Acceptable
      as an IEA.
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for catalytic activity from UniProt keyword. IRE1 has both
      kinase and endoribonuclease catalytic activities.
    action: ACCEPT
    reason: >-
      Correct but extremely broad. Both kinase and RNase activities are catalytic.
      Acceptable as a broad IEA.
- term:
    id: GO:0004521
    label: RNA endonuclease activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for RNA endonuclease activity from combined automated methods.
      Consistent with IBA and IDA evidence.
    action: ACCEPT
    reason: >-
      Correct. Consistent with experimental evidence (PMID:9323131, PMID:18191223).
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for RNA nuclease activity from InterPro. Broader parent of
      RNA endonuclease activity.
    action: ACCEPT
    reason: >-
      Correct but less specific than GO:0004521. Acceptable as a broad IEA.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for protein kinase activity from InterPro. Broader parent
      of protein serine/threonine kinase activity.
    action: ACCEPT
    reason: >-
      Correct but less specific than GO:0004674. Acceptable as an IEA.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for protein Ser/Thr kinase from combined automated methods.
      Consistent with IBA and IDA evidence.
    action: ACCEPT
    reason: >-
      Correct. Consistent with experimental evidence (PMID:8663458, PMID:18191223).
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for ATP binding. IRE1 binds ATP in its kinase domain. Crystal
      structure shows ADP bound in the active site (PMID:18191223).
    action: ACCEPT
    reason: >-
      Correct. ATP binding is essential for kinase activity and confirmed by
      crystal structure.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for ER membrane from UniProt subcellular location. IRE1 is
      a type I transmembrane protein spanning the ER membrane.
    action: ACCEPT
    reason: >-
      Correct. Confirmed by IDA (PMID:8358794) and topology studies.
- term:
    id: GO:0006397
    label: mRNA processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for mRNA processing from InterPro. IRE1 processes HAC1 mRNA
      through unconventional splicing.
    action: ACCEPT
    reason: >-
      Correct. IRE1 endoribonuclease activity directly processes HAC1 pre-mRNA
      (PMID:9323131).
    additional_reference_ids:
    - file:yeast/IRE1/IRE1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        **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.
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct. This is the core biological process of IRE1.
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for kinase activity from UniProt keyword. Broader parent of
      protein kinase activity.
    action: ACCEPT
    reason: >-
      Correct but very broad. Acceptable as an IEA.
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for transferase activity from UniProt keyword. Very broad
      parent of kinase activity.
    action: ACCEPT
    reason: >-
      Correct but extremely broad. Acceptable as an IEA.
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for hydrolase activity from UniProt keyword. Broad parent
      of RNA nuclease activity.
    action: ACCEPT
    reason: >-
      Correct but extremely broad. Acceptable as an IEA.
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for ER UPR from combined automated methods. Consistent with
      IMP evidence.
    action: ACCEPT
    reason: >-
      Correct. IRE1 is the master regulator of the ER UPR in yeast.
- term:
    id: GO:0031505
    label: fungal-type cell wall organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for metal ion binding from UniProt keyword. IRE1 kinase
      domain binds Mg2+ as a cofactor (PMID:18191223).
    action: ACCEPT
    reason: >-
      Correct. Mg2+ is required as a cofactor for kinase activity. Confirmed by
      crystal structure (PMID:18191223).
- term:
    id: GO:0106310
    label: protein serine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  review:
    summary: >-
      IEA annotation for protein serine kinase activity from Rhea mapping. IRE1
      autophosphorylates on serine residues (Ser-840, Ser-841).
    action: ACCEPT
    reason: >-
      Correct. Serine autophosphorylation is confirmed (PMID:18191223, PMID:8670804).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16990850
  review:
    summary: >-
      IPI annotation for protein binding showing interaction with DCR2 (Q05924).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative. The specific interaction with DCR2 may be
      relevant to IRE1 regulation but is not captured by the generic term.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18191223
  review:
    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).
    action: ACCEPT
    reason: >-
      Homodimerization is functionally critical for IRE1 activation. Crystal
      structures confirm the dimer interface (PMID:18191223, PMID:16365312).
    additional_reference_ids:
    - file:yeast/IRE1/IRE1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        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**.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19079236
  review:
    summary: >-
      IPI annotation for identical protein binding. Additional evidence for
      IRE1 homodimerization.
    action: ACCEPT
    reason: >-
      Consistent with other evidence for functionally important homodimerization.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:20625545
  review:
    summary: >-
      IPI annotation for identical protein binding from study of BiP binding
      to IRE1 and its regulation of UPR homeostasis.
    action: ACCEPT
    reason: >-
      Additional evidence for IRE1 homodimerization, studied in the context of
      BiP regulation.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:17923530
  review:
    summary: >-
      NAS annotation for ER membrane from ComplexPortal. Consistent with IDA
      evidence.
    action: ACCEPT
    reason: >-
      Correct. Consistent with IDA (PMID:8358794) and topology studies.
- term:
    id: GO:0036498
    label: IRE1-mediated unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:19079236
  review:
    summary: >-
      IDA annotation for IRE1-mediated UPR from ComplexPortal.
    action: ACCEPT
    reason: >-
      Core biological process of IRE1. Experimentally demonstrated.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:8358794
  review:
    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.
    action: ACCEPT
    reason: >-
      Primary experimental evidence for ER membrane localization from the
      original characterization.
    additional_reference_ids:
    - file:yeast/IRE1/IRE1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        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.
- term:
    id: GO:0004521
    label: RNA endonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:9323131
  review:
    summary: >-
      IDA annotation for RNA endonuclease activity. IRE1 is a site-specific
      endonuclease that cleaves HAC1 pre-mRNA at two specific positions
      (PMID:9323131).
    action: ACCEPT
    reason: >-
      Core molecular function demonstrated by direct assay. This is the key
      enzymatic activity that mediates UPR signaling.
    additional_reference_ids:
    - file:yeast/IRE1/IRE1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        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.
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        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.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: HDA
  original_reference_id: PMID:26928762
  review:
    summary: >-
      HDA annotation for ER localization from large-scale yeast library analysis.
    action: ACCEPT
    reason: >-
      Consistent with IDA and IBA evidence for ER localization.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: HDA
  original_reference_id: PMID:16319894
  review:
    summary: >-
      HDA annotation for protein kinase activity from global phosphorylation
      analysis in yeast.
    action: ACCEPT
    reason: >-
      Consistent with IDA evidence for kinase activity (PMID:8663458).
- term:
    id: GO:0034067
    label: protein localization to Golgi apparatus
  evidence_type: IMP
  original_reference_id: PMID:26966233
  review:
    summary: >-
      IMP annotation for protein localization to Golgi apparatus. IRE1 influences
      protein sorting and Golgi function through UPR target gene regulation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Protein localization to Golgi is a downstream effect of IRE1's UPR
      signaling function, not a direct function of IRE1.
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IMP
  original_reference_id: PMID:26966233
  review:
    summary: >-
      IMP annotation for response to ER stress. IRE1 is the primary ER stress
      sensor and signaling molecule in yeast.
    action: ACCEPT
    reason: >-
      Core biological process. IRE1 is the defining component of the ER stress
      response in yeast.
    additional_reference_ids:
    - file:yeast/IRE1/IRE1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        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.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-SCE-535524
  review:
    summary: >-
      TAS annotation for ER membrane from Reactome pathway.
    action: ACCEPT
    reason: >-
      Correct. Consistent with IDA evidence.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:8663458
  review:
    summary: >-
      IDA annotation for protein Ser/Thr kinase activity. IRE1 undergoes
      trans-autophosphorylation requiring oligomerization (PMID:8663458).
      K702A mutation abolishes autophosphorylation.
    action: ACCEPT
    reason: >-
      Core molecular function demonstrated by direct assay. Trans-autophosphorylation
      is essential for activating the endoribonuclease domain.
    additional_reference_ids:
    - file:yeast/IRE1/IRE1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        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.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17035634
  review:
    summary: >-
      IDA annotation for nuclear localization. This may reflect a minor
      population of IRE1 or a specific experimental condition.
    action: UNDECIDED
    reason: >-
      Unable to access PMID:17035634 to verify the nuclear localization claim.
      IRE1 is primarily an ER membrane protein, so nuclear localization would
      be unusual and requires verification.
- term:
    id: GO:0006020
    label: inositol metabolic process
  evidence_type: IMP
  original_reference_id: PMID:1625574
  review:
    summary: >-
      IMP annotation for inositol metabolic process. IRE1 was originally
      identified as required for inositol prototrophy (PMID:1625574). The
      UPR regulates inositol biosynthesis genes.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:8358794
  review:
    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.
    action: ACCEPT
    reason: >-
      Core biological process. This is the defining function of IRE1.
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:8513503
  review:
    summary: >-
      IMP annotation for ER UPR from additional evidence.
    action: ACCEPT
    reason: >-
      Additional experimental evidence for the core biological process.
- term:
    id: GO:0031505
    label: fungal-type cell wall organization
  evidence_type: IMP
  original_reference_id: PMID:18971375
  review:
    summary: >-
      IMP annotation for fungal-type cell wall organization. IRE1 mutants
      have cell wall defects.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cell wall organization is a downstream consequence of UPR signaling.
      The UPR regulates genes involved in cell wall biosynthesis.
- term:
    id: GO:0031505
    label: fungal-type cell wall organization
  evidence_type: IGI
  original_reference_id: PMID:18971375
  review:
    summary: >-
      IGI annotation for fungal-type cell wall organization based on genetic
      interaction data.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same as above - downstream consequence of UPR signaling.
- term:
    id: GO:0031505
    label: fungal-type cell wall organization
  evidence_type: IMP
  original_reference_id: PMID:8898193
  review:
    summary: >-
      IMP annotation for fungal-type cell wall organization from earlier study.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream consequence of UPR signaling. Not a core function of IRE1.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:17923530
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0051082 is proposed for obsoletion. 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.
    additional_reference_ids:
    - file:yeast/IRE1/IRE1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/IRE1/IRE1-deep-research-falcon.md
      supporting_text: |-
        Ire1 activation can involve direct engagement of unfolded proteins via its luminal domain, which promotes oligomerization and signaling.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IMP
  original_reference_id: PMID:17923530
  review:
    summary: >-
      IMP annotation for unfolded protein binding. Same study as the IDA
      annotation above (PMID:17923530).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Same reasoning as the IDA annotation. GO:0051082 is proposed for obsoletion.
      IRE1 binds unfolded proteins as a sensor, not a chaperone. The term does not
      accurately describe the functional role of this binding.
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, accompanied by conservative changes to GO terms applied by UniProt
  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:1625574
  title: IRE1 encodes a putative protein kinase containing a membrane-spanning domain and is required for inositol phototrophy in Saccharomyces cerevisiae.
  findings: []
- id: PMID:16319894
  title: Global analysis of protein phosphorylation in yeast.
  findings: []
- id: PMID:16365312
  title: On the mechanism of sensing unfolded protein in the endoplasmic reticulum.
  findings: []
- id: PMID:16990850
  title: Dcr2 targets Ire1 and downregulates the unfolded protein response in Saccharomyces cerevisiae.
  findings: []
- id: PMID:17035634
  title: The unfolded protein response transducer Ire1p contains a nuclear localization sequence recognized by multiple beta importins.
  findings: []
- id: PMID:17923530
  title: Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins.
  findings: []
- id: PMID:18191223
  title: Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing.
  findings: []
- id: PMID:18971375
  title: The unfolded protein response is induced by the cell wall integrity mitogen-activated protein kinase signaling cascade and is required for cell wall integrity in Saccharomyces cerevisiae.
  findings: []
- id: PMID:19079236
  title: The unfolded protein response signals through high-order assembly of Ire1.
  findings: []
- id: PMID:20625545
  title: BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.
  findings: []
- id: PMID:26928762
  title: One library to make them all - streamlining the creation of yeast libraries via a SWAp-Tag strategy.
  findings: []
- id: PMID:26966233
  title: Unfolded protein response regulates yeast small GTPase Arl1p activation at late Golgi via phosphorylation of Arf GEF Syt1p.
  findings: []
- id: PMID:8358794
  title: A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus.
  findings: []
- id: PMID:8513503
  title: Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase.
  findings: []
- id: PMID:8663458
  title: The unfolded protein response pathway in Saccharomyces cerevisiae. Oligomerization and trans-phosphorylation of Ire1p (Ern1p) are required for kinase activation.
  findings: []
- id: PMID:8670804
  title: Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.
  findings: []
- id: PMID:8898193
  title: A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response.
  findings: []
- id: PMID:9323131
  title: The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response.
  findings: []
- id: PMID:9528768
  title: Protein serine/threonine phosphatase Ptc2p negatively regulates the unfolded-protein response by dephosphorylating Ire1p kinase.
  findings: []
- id: Reactome:R-SCE-535524
  title: Phosphorylated Ire1 Dimer Binds ADP
  findings: []
- id: file:yeast/IRE1/IRE1-deep-research-falcon.md
  title: Falcon deep research report on yeast IRE1 (P32361)
  findings:
  - statement: |
      Yeast Ire1 is an ER-resident type I transmembrane stress sensor with a cytosolic
      Ser/Thr kinase domain and an endoribonuclease (RNase) domain that initiates the
      unfolded protein response by splicing HAC1 mRNA; HAC1 is the canonical RNA substrate
      in S. cerevisiae (whereas metazoan IRE1 splices XBP1).
    supporting_text: |-
      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**.
    reference_section_type: RESULTS
  - statement: |
      Ire1's RNase performs site-specific endonucleolytic cleavage of HAC1u mRNA at both
      the 5' and 3' splice junctions, removing an inhibitory intron and initiating
      spliceosome-independent (unconventional) splicing.
    supporting_text: |-
      **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.
    reference_section_type: RESULTS
  - statement: |
      Cleavage-site specificity is determined by splice-junction sequence determinants:
      point mutations of critical guanosines (e.g. G885C at the 5' junction) selectively
      block cleavage at that junction. In vitro cleavage requires an adenosine nucleotide
      cofactor (ATP required; ADP or AMP-PNP can substitute; GTP cannot).
    supporting_text: |-
      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... omission of ATP abolishes cleavage, while **ADP** or **AMP-PNP** can substitute; **GTP cannot**.
    reference_section_type: RESULTS
  - statement: |
      Purified Ire1 fragment together with purified tRNA ligase (Trl1/Rlg1) is sufficient
      to reconstitute correct HAC1 splicing in vitro; Trl1 ligates the exons after Ire1
      cleavage.
    supporting_text: |-
      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.
    reference_section_type: RESULTS
  - statement: |
      Ire1 has a Ser/Thr kinase domain that undergoes trans-autophosphorylation upon
      oligomerization, which is coupled to activation of the RNase domain in current
      models of UPR induction.
    supporting_text: |-
      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.
    reference_section_type: RESULTS
  - statement: |
      Beyond enabling activation, kinase function is implicated in attenuation/homeostatic
      shutdown, contributing to disassembly of Ire1 oligomers and termination of signaling.
    supporting_text: |-
      Beyond enabling activation, kinase function is implicated in **attenuation/homeostatic shutdown**: mechanistic syntheses report kinase-dependent processes contributing to the disassembly of Ire1 oligomers and termination of signaling.
    reference_section_type: RESULTS
  - statement: |
      Ire1 is an ER membrane protein with a luminal stress-sensing domain and a cytosolic
      kinase/RNase module; under stress it forms puncta/clusters on the ER membrane,
      acting as a spatially organized RNA-processing hub, and HAC1u mRNA is recruited to
      these clusters for splicing.
    supporting_text: |-
      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... HAC1u mRNA is recruited to Ire1 puncta/clusters for splicing during ER stress.
    reference_section_type: RESULTS
  - statement: |
      Under non-stress conditions Kar2/BiP binding keeps Ire1 in a less self-associated
      state; ER stress promotes Kar2 dissociation and Ire1 self-association/activation.
      Ire1 activation can also involve direct engagement of unfolded proteins via its
      luminal domain, promoting oligomerization.
    supporting_text: |-
      Under non-stress conditions Kar2/BiP binding keeps Ire1 in a less self-associated state; ER stress promotes Kar2 dissociation and Ire1 self-association/activation... Ire1 activation can involve direct engagement of unfolded proteins via its luminal domain, which promotes oligomerization and signaling.
    reference_section_type: RESULTS
  - statement: |
      Ire1 can be activated not only by unfolded proteins but also by lipid bilayer stress,
      sensed via its transmembrane/amphipathic features; lipid bilayer stress favors dimeric
      rather than large oligomeric assemblies and elicits weaker RNase output.
    supporting_text: |-
      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. LBS tends to promote **dimeric** rather than large oligomeric Ire1 assemblies and can elicit **weaker RNase output** and a milder UPR.
    reference_section_type: RESULTS
  - statement: |
      Regulated Ire1-dependent decay (RIDD) of additional ER-associated mRNAs is absent
      (or not convincingly supported) in S. cerevisiae; HAC1 is effectively the predominant
      (possibly sole) physiologically relevant Ire1 RNase substrate in budding yeast.
    supporting_text: |-
      Authoritative 2023–2024 reviews state that **regulated Ire1-dependent decay (RIDD)**—Ire1 RNase cleavage of additional ER-associated mRNAs—is **absent (or not convincingly supported) in *S. cerevisiae***, in contrast to other organisms such as *S. pombe* and metazoans. The yeast literature summarized indicates that **HAC1 is effectively the predominant (possibly sole) physiologically relevant Ire1 RNase substrate** in budding yeast.
    reference_section_type: DISCUSSION
  - statement: |
      Yeast UPR is effectively a single-sensor, single-transcription-factor architecture
      (Ire1 -> Hac1), unlike metazoans which have additional sensors (PERK, ATF6).
    supporting_text: |-
      Yeast UPR is effectively a single-sensor, single-transcription-factor architecture (Ire1→Hac1), which enables unusually clean genetic epistasis and mechanistic dissection.
    reference_section_type: DISCUSSION
  - statement: |
      A 2023 preprint reports that the cell wall integrity MAPK Slt2 enhances both HAC1
      mRNA splicing and translation, adding a regulatory layer that promotes adaptation
      to ER stress in S. cerevisiae.
    supporting_text: |-
      A 2023 bioRxiv preprint proposes that **MAPK Slt2** enhances both **HAC1 mRNA splicing and translation**, contributing to adaptation under ER stress.
    reference_section_type: RESULTS
core_functions:
- description: >-
    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.
  molecular_function:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  directly_involved_in:
  - id: GO:0036498
    label: IRE1-mediated unfolded protein response
  - id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  - id: GO:0034976
    label: response to endoplasmic reticulum stress
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
- description: >-
    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.
  molecular_function:
    id: GO:0004521
    label: RNA endonuclease activity
  directly_involved_in:
  - id: GO:0006397
    label: mRNA processing
  - id: GO:0036498
    label: IRE1-mediated unfolded protein response
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane

IRE1

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

Research report: Saccharomyces cerevisiae IRE1 (UniProt P32361; gene IRE1/ERN1; locus YHR079C)

0) Identity verification (critical disambiguation)

1) Key concepts and definitions (current understanding)

1.1 Unfolded Protein Response (UPR) in yeast

1.2 Ire1 as a bifunctional ER stress sensor and signal transducer

1.3 The canonical yeast output: unconventional HAC1 mRNA splicing

2) Molecular function: enzymatic activities and substrate specificity

2.1 Endoribonuclease (RNase) activity: reaction and substrate specificity

2.2 tRNA ligase (Trl1/Rlg1) and RNA end-chemistry

2.3 Kinase activity: role in activation and attenuation

3) Cellular localization and interacting partners

3.1 Localization

3.2 Key interaction partners and regulators

4) Pathway role and outputs

4.1 Core pathway steps (yeast Ire1–Hac1 branch)

4.2 Proteotoxic stress vs lipid bilayer stress (LBS)

5) Recent developments (prioritizing 2023–2024)

5.1 2023 yeast UPR synthesis: expanded regulation layers

5.2 2024 review focus: membrane homeostasis and lipid-induced UPR

5.3 New regulatory input (2023 preprint): MAPK Slt2 modulates HAC1 splicing/translation

6) RIDD and non-canonical RNase outputs: what applies to S. cerevisiae?

7) Current applications and real-world implementations

7.1 Yeast biotechnology: improving secretion and ER capacity

7.2 Fungal biotechnology (industry): quantitative yield increases from UPR activation

7.3 Crop protection / antifungal strategies: targeting IRE1-dependent hac1 splicing

8) Expert synthesis and authoritative interpretation (what leading sources emphasize)

9) Recent data/statistics from studies (selected examples)

10) Evidence map (curated key sources)

References (URLs and publication dates from retrieved sources)

Artifacts

Citations

📚 Additional Documentation

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Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Bioreason Rl Review

BioReason-Pro RL Review: IRE1 (S. cerevisiae)

Functional Summary Review

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