Affinage

ERN1

Serine/threonine-protein kinase/endoribonuclease IRE1 · UniProt O75460

Length
977 aa
Mass
109.7 kDa
Annotated
2026-06-09
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERN1/IRE1 is the central ER-transmembrane sensor of the unfolded protein response (UPR), coupling detection of ER protein-folding stress to transcriptional and post-transcriptional reprogramming of the secretory pathway (PMID:9637683, PMID:11779464). Its luminal MHC-like domain directly binds unfolded peptides with a characteristic amino-acid bias, an event that drives allosteric oligomerization; impairing the oligomerization interface decouples peptide binding from activation and abolishes IRE1 activity in cells (PMID:28971800). In the resting state IRE1 is held inactive by the ER chaperone BiP/Kar2p, which binds the luminal domain and is released upon stress, switching BiP from its chaperone cycle to a stress-sensor cycle and priming dissociation in an ATP-dependent manner (PMID:11118306, PMID:31695187). IRE1 is bifunctional: it is a Ser/Thr kinase that trans-autophosphorylates upon oligomerization, and a site-specific endoribonuclease (PMID:9323131, PMID:8670804, PMID:8663458). Activation-loop phosphorylation allosterically licenses the RNase domain, whose catalytic apparatus (general acid-base pair His1061/Tyr1043 with Asn1057/Arg1056 coordinating the scissile phosphate) executes two distinct cleavage programs (PMID:21729333, PMID:24704861): cooperative cleavage by oligomeric subunits performs the unconventional splicing of HAC1/XBP1 mRNA to generate the active transcription factor XBP1s, completed in vivo by tRNA/RNA ligase, while a non-cooperative single-subunit mode mediates regulated IRE1-dependent decay (RIDD) of ER-targeted mRNAs and pre-miRNAs (PMID:9323131, PMID:11779464, PMID:25437541, PMID:37946177). Through XBP1s the pathway supports oxidative protein folding, exemplified by its control of protein disulfide isomerases required for proinsulin folding in pancreatic β cells (PMID:29507125). Beyond RNase signaling, IRE1 kinase activity drives NF-κB-dependent inflammatory outputs and phosphorylates substrates including FMRP to control lipid homeostasis, and prevents ER membrane permeabilization by suppressing Bnip3 (PMID:33610548, PMID:35191199, PMID:26106220). The duration and balance of IRE1 signaling dictate cell fate, with sustained IRE1 activity promoting survival and proliferation while its RNase-mediated pre-miRNA decay and inflammatory programs can drive death or tumor progression (PMID:17991856, PMID:19137072, PMID:30111846, PMID:37946177). IRE1 output is tuned by multiple regulators: phosphatases Ptc2p and Dcr2 that dephosphorylate the activation loop, the kinase-domain inhibitor EI24, and BRCA1-mediated ubiquitination targeting IRE1 for proteasomal degradation (PMID:9528768, PMID:16990850, PMID:35005829, PMID:36471805).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Established that IRE1's cytoplasmic kinase activity depends on oligomerization-driven trans-phosphorylation, defining how an ER-resident sensor converts luminal stress into a catalytic signal.

    Evidence In vitro kinase assays, oligomerization assays, and deletion mutagenesis in yeast Ire1p

    PMID:8663458 PMID:8670804

    Open questions at the time
    • Did not identify physiological RNase substrates
    • Did not define the luminal stress-sensing mechanism
  2. 1997 High

    Resolved that IRE1 is a single bifunctional enzyme whose endoribonuclease cleaves HAC1 mRNA at both splice junctions, with ligation completing unconventional splicing — the founding mechanism of the UPR.

    Evidence In vitro reconstitution of HAC1 splicing from purified components plus site-specific endonuclease assay

    PMID:9323131

    Open questions at the time
    • Mammalian substrate unknown at this stage
    • Coupling between kinase and RNase domains not defined
  3. 1998 High

    Extended the mechanism to humans and showed IRE1 autoregulates its own expression in a kinase-dependent manner, while identifying the first negative regulator (phosphatase Ptc2p).

    Evidence Autophosphorylation/RNase assays, dominant-negative and reporter assays in human cells; in vitro dephosphorylation and genetics in yeast

    PMID:9528768 PMID:9637683

    Open questions at the time
    • Mammalian RNase substrate still unidentified
    • How phosphorylation state controls RNase activity not yet quantified
  4. 2000 High

    Identified BiP/Kar2p as the luminal-domain brake whose stress-induced dissociation triggers IRE1 activation, providing a model for stress detection.

    Evidence Direct binding, co-IP, and phosphorylation-state assays in yeast; later interface mapping (Q88) by mutagenesis

    PMID:11118306 PMID:17276461

    Open questions at the time
    • Whether BiP release alone is sufficient versus direct unfolded-protein sensing unresolved at this point
  5. 2001 High

    Defined the mammalian arm by identifying XBP1 mRNA as the conserved splicing substrate and placing IRE1-XBP1 downstream of ATF6, and showed IRE1 associates with stress-dependent RNA in vivo.

    Evidence XBP1 splicing identification, epistasis, reporter assays; in vivo UV crosslinking with domain mutants

    PMID:11590247 PMID:11779464

    Open questions at the time
    • Catalytic mechanism of cleavage not yet structurally defined
    • RIDD activity not yet recognized
  6. 2006 Medium

    Showed IRE1 must localize to the nucleus via an importin-recognized NLS for HAC1 splicing, and identified a second activation-loop phosphatase (Dcr2) tuning the response.

    Evidence GFP-NLS localization, importin binding, mutagenesis with HAC1 readout; in vitro dephosphorylation and phospho-mimetic Co-IP

    PMID:16990850 PMID:17035634

    Open questions at the time
    • Generality of nuclear localization requirement across species unclear
    • How dephosphorylation timing shapes signal duration not defined
  7. 2007 High

    Established that the duration of IRE1 signaling is a determinant of cell fate, with sustained activity favoring survival — linking UPR kinetics to apoptosis decisions.

    Evidence Analog-sensitive kinase chemical-genetics, viability assays, retinitis pigmentosa animal model

    PMID:17991856

    Open questions at the time
    • Molecular effectors converting signal duration into fate not identified here
  8. 2009 High

    Cleanly separated IRE1 from PERK, demonstrating opposite effects on proliferation and viability and clarifying UPR branch division of labor.

    Evidence Chemical-genetic individual activation of IRE1 versus PERK with proliferation/apoptosis readouts

    PMID:19137072

    Open questions at the time
    • Downstream targets driving proliferation versus death not delineated
  9. 2011 High

    Provided atomic-level assignment of the RNase active site, identifying the catalytic acid-base residues and the two-subunit RNA docking architecture.

    Evidence X-ray crystallography plus active-site mutagenesis with quantitative kinetics and in vitro RNase assays

    PMID:21729333

    Open questions at the time
    • How oligomeric state selects between substrate classes not yet resolved
  10. 2014 High

    Distinguished two RNase modes — cooperative oligomeric XBP1/HAC1 splicing versus single-subunit non-cooperative RIDD — and showed activation-loop phosphorylation licenses splicing activity, explaining how a single enzyme runs distinct programs.

    Evidence In vitro cleavage and complementation assays, oligomerization-interface mutants, RNase inhibitor; phospho-species isolation with cellular XBP1 splicing

    PMID:24704861 PMID:25437541

    Open questions at the time
    • In-cell determinants selecting splicing versus RIDD not fully defined
    • Full RIDD substrate repertoire not enumerated
  11. 2017 High

    Defined the luminal sensing mechanism directly: the MHC-like groove binds unfolded peptides and drives oligomerization required for activity, establishing peptide binding as the proximal trigger.

    Evidence Peptide binding assays, allostery characterization, oligomerization-interface mutagenesis, cell-based activity assays of human IRE1α LD

    PMID:28971800

    Open questions at the time
    • Relative contributions of direct peptide binding versus BiP release in cells not quantified
  12. 2019 High

    Reconstituted the human BiP-IRE1 cycle, showing BiP switches from chaperone to sensor mode at IRE1, and connected XBP1s output to a concrete folding function (PDI-dependent proinsulin folding).

    Evidence In vitro reconstitution with purified human components, ATPase/co-chaperone assays; β-cell conditional KO and pathway reconstitution

    PMID:29507125 PMID:31695187

    Open questions at the time
    • How sensor-mode switching is reversed during recovery not defined
  13. 2022 Medium

    Expanded IRE1 regulation and output: input kinases (AKT at S724), degradation control (BRCA1 ubiquitination), kinase-domain inhibition (EI24), output protection (Pumilio shielding spliced Xbp1 from RIDD), ligase regulation (RtcB phosphorylation), and kinase-driven inflammatory/lipid programs (FMRP, NF-κB).

    Evidence In vitro kinase/ubiquitination assays, Co-IP and domain mapping, phosphoproteomics, conditional KO mice, and in vivo disease models (atherosclerosis, adipose lipolysis)

    PMID:33610548 PMID:35005829 PMID:35191199 PMID:35193953 PMID:35332141 PMID:35863429 PMID:36471805

    Open questions at the time
    • Most regulators validated in single labs
    • Interplay among the multiple regulatory inputs in vivo not integrated
  14. 2023 Medium

    Demonstrated an XBP1s-independent pro-death output: IRE1 RNase degrades pre-miR-301a to derepress GADD45A and promote apoptosis, broadening the RIDD repertoire to pre-miRNAs.

    Evidence NGS, IRE1 inhibitor, fractionation, miRNA target protector, XBP1s overexpression, cell death assays

    PMID:37946177

    Open questions at the time
    • Single-lab finding
    • Generality of pre-miRNA decay across cell types not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the combined inputs (peptide sensing, BiP release, activation-loop phosphorylation, kinase inputs, and degradation) are quantitatively integrated to set the splicing-versus-RIDD balance and ultimately the survival-versus-death decision in vivo remains unresolved.
  • No unified model linking signal strength/duration to RNase mode selection
  • In vivo substrate hierarchies for RIDD largely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0003723 RNA binding 2 GO:0016787 hydrolase activity 2 GO:0140299 molecular sensor activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005634 nucleus 1 GO:0005635 nuclear envelope 1
Pathway
R-HSA-8953897 Cellular responses to stimuli 5 R-HSA-8953854 Metabolism of RNA 4 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-392499 Metabolism of proteins 2
Partners
BIP/KAR2BRCA1DCR2EI24FMRPPTC2RTCBXBP1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Ire1p is a bifunctional enzyme with both kinase and site-specific endoribonuclease activities; it cleaves HAC1 mRNA specifically at both splice junctions to initiate unconventional mRNA splicing, and addition of purified tRNA ligase completes splicing in vitro from purified components. In vitro reconstitution of HAC1 mRNA splicing from purified components; site-specific endonuclease assay Cell High 9323131
1996 Ire1p oligomerizes in response to ER stress and undergoes trans-autophosphorylation as a result of oligomerization; both oligomerization and a C-terminal tail domain beyond the kinase domain are required for UPR induction. Molecular genetics and biochemical studies; in vivo and in vitro oligomerization assays; kinase activity assays The EMBO journal High 8670804
1996 The cytoplasmic domain of yeast Ire1p (Ern1p) has intrinsic Ser/Thr kinase activity; oligomerization of cytoplasmic domains is required for trans-phosphorylation and kinase activation; the last 130 amino acids mediate oligomerization but are dispensable for in vitro kinase activity. In vitro kinase activity assay; in vivo and in vitro oligomerization assays; deletion mutagenesis The Journal of biological chemistry High 8663458
1998 Human IRE1 (hIre1p) is a type I ER transmembrane protein with intrinsic autophosphorylation activity and endoribonuclease activity that cleaves the 5' splice site of yeast HAC1 mRNA; overexpressed hIre1p localizes to the ER with concentration around the nuclear envelope; a catalytically inactive kinase mutant acts as a dominant-negative to block BiP promoter activation; Ire1p mRNA autoregulation requires functional kinase activity. Autophosphorylation assay; endoribonuclease activity assay; immunofluorescence localization; dominant-negative overexpression; reporter gene (BiP promoter) assay Genes & development High 9637683
2001 In mammalian cells, IRE1 splices XBP1 mRNA unconventionally in response to ER stress (analogous to yeast HAC1 splicing), producing an active transcription factor; XBP1 is a direct target of ATF6, placing IRE1-dependent XBP1 splicing downstream of ATF6 in the mammalian UPR. Identification of XBP1 mRNA splicing by IRE1; reporter assays; epistasis analysis placing ATF6 upstream of XBP1 Cell High 11779464
2000 The yeast ER chaperone Kar2p/BiP directly binds the luminal domain of Ire1p and keeps Ire1p in an inactive, unphosphorylated state; ER stress causes Kar2p to dissociate from Ire1p, triggering Ire1p activation. Direct protein interaction assay; co-immunoprecipitation; demonstration of Kar2p-dependent Ire1p phosphorylation state Biochemical and biophysical research communications High 11118306
1998 The serine/threonine phosphatase Ptc2p directly dephosphorylates Ire1p in an Mg2+-dependent manner; the Ptc2p–Ire1p interaction is specific, direct, phosphorylation-dependent, and mediated through a kinase interaction domain in Ptc2p; Ptc2p negatively regulates the UPR by downregulating HAC1 splicing. In vitro dephosphorylation assay; two-hybrid and direct interaction assays; genetic deletion/overexpression with HAC1 splicing readout Molecular and cellular biology High 9528768
2001 Mammalian IRE1 is intimately associated with RNA in vivo (detected by UV crosslinking); the IRE1-associated RNA fragments are different in stressed vs. unstressed cells and shorter in stressed cells; complex formation requires both the kinase and endonuclease domains of IRE1. In vivo UV crosslinking; domain mutant analysis Journal of cell science Medium 11590247
2006 The phosphatase Dcr2 physically interacts with phosphorylated Ire1 (mimicked by Ire1-S840E/S841E) and dephosphorylates Ire1 in vitro; Dcr2 overexpression delays HAC1 splicing and sensitizes cells to ER stress in a phosphatase-activity-dependent manner. In vitro dephosphorylation assay; in vivo co-immunoprecipitation; genetic overexpression/deletion with HAC1 splicing readout EMBO reports High 16990850
2007 The ATP-bound conformation of Kar2p/BiP (substrate-free) interacts with Ire1p via lobe IB of its ATPase domain (around residue Q88); substitution Q88E abolishes the Kar2p–Ire1p interaction, identifying the binding interface. Oligosaccharide-shielding mapping; site-directed mutagenesis; co-immunoprecipitation Journal of molecular biology Medium 17276461
2006 Yeast Ire1p contains a nuclear localization sequence (NLS) in its linker region (residues ~642–657) recognized by importin-alpha (classical NLS) and multiple importin-beta homologues; NLS-dependent nuclear localization of Ire1p is required for ER stress-induced HAC1 mRNA splicing and UPR signaling. GFP-NLS fusion localization; importin binding studies (kinetic data); site-directed mutagenesis of NLS; UPR reporter and HAC1 splicing assays Molecular biology of the cell Medium 17035634
2007 Sustained IRE1 signaling during persistent ER stress promotes cell survival, whereas attenuation of IRE1 (and ATF6) activity while PERK signaling is maintained correlates with apoptosis; artificial sustaining of IRE1 activity enhanced cell survival, establishing a causal link between IRE1 signaling duration and cell fate. Chemical-genetic activation of IRE1 (analog-sensitive kinase allele); cell viability/apoptosis assays; animal model (retinitis pigmentosa) Science (New York, N.Y.) High 17991856
2009 Sustained IRE1 signaling (uncoupled from ER stress by chemical-genetic strategy) enhances cell proliferation without promoting apoptosis, whereas equivalent PERK signaling impairs proliferation and promotes apoptosis; IRE1 and PERK thus have opposite effects on cell viability. Chemical-genetic individual activation of IRE1 or PERK; cell proliferation and apoptosis assays PloS one High 19137072
2011 Crystal structures of Ire1 RNase domain define the active site: H1061 and Y1043 act as general acid-base pair (contributing ≥7.6 and 1.4 kcal/mol to transition state stabilization respectively), with N1057 and R1056 coordinating the scissile phosphate; two RNase subunits contribute to RNA stem-loop docking while each monomer contains a separate catalytic apparatus; Ire1 can also cleave anticodon stem-loops of tRNA. X-ray crystallography (two new structures); active-site mutagenesis with quantitative kinetic analysis; in vitro RNase assays BMC biology High 21729333
2014 IRE1 uses two mechanistically distinct modes of RNA cleavage: XBP1/HAC1 intron excision requires cooperative action of IRE1 subunits within oligomers, whereas RIDD cleavage is performed by a single IRE1 subunit without cooperativity; these activities can be separated by mutations at oligomerization interfaces or by complementation with catalytically inactive RNase mutants. In vitro IRE1 cleavage assays; complementation with RNase-inactive mutants; oligomerization interface mutations; IRE1 RNase inhibitor (STF-083010) Cell reports High 25437541
2014 Phosphorylation within the kinase activation loop of Ire1 significantly increases RNase splicing activity in vitro; Ire1 mutants that cannot be phosphorylated on the activation loop show decreased XBP1 and promiscuous RNase splicing activity in cells, coupling kinase phosphorylation to RNase activation. Isolation of distinct phosphorylated Ire1 species; in vitro RNase splicing assays; activation-loop phosphorylation-deficient mutants; in-cell XBP1 splicing assay Nature communications High 24704861
2017 Human IRE1α luminal domain (hIRE1α LD) directly binds peptides with characteristic amino acid bias via an MHC-like groove; unfolded protein/peptide binding induces allosteric changes that drive oligomerization; mutation of a hydrophobic patch at the oligomerization interface decouples peptide binding from oligomerization; impairing oligomerization abolishes IRE1 activity in living cells. Peptide binding assays; NMR/biochemical characterization of allosteric changes; site-directed mutagenesis of oligomerization interface; cell-based IRE1 activity assays eLife High 28971800
2019 Reconstitution of human UPR components reveals that BiP binding to the luminal domains of IRE1 (and PERK) switches BiP from its chaperone cycle to an ER stress sensor cycle by preventing co-chaperone binding and abolishing ATPase stimulation; misfolded protein-dependent dissociation of BiP from IRE1 is primed by ATP but not ADP. In vitro reconstitution with purified human UPR and chaperone components; ATPase assays; co-chaperone binding assays Nature structural & molecular biology High 31695187
2022 AKT directly phosphorylates IRE1 at serine 724 in response to insulin, promoting XBP1u mRNA splicing and generation of XBP1s in liver, linking insulin signaling to IRE1-dependent lipogenesis. In vitro kinase assay (AKT phosphorylating IRE1 S724); mutagenesis; hepatocyte and mouse liver experiments with XBP1 isoform measurement The Journal of biological chemistry Medium 35863429
2022 BRCA1 acts as an E3 ubiquitin ligase that ubiquitinates IRE1 (and PERK) in the ER, targeting them for proteasome-mediated degradation; BRCA1 deficiency leads to elevated IRE1 protein levels and constitutively activated UPR. Co-immunoprecipitation; ubiquitination assays; proteasome inhibition; BRCA1 knockdown/depletion with IRE1 protein level measurement iScience Medium 36471805
2022 ER transmembrane protein EI24 binds to the kinase domain of IRE1 under non-stressed conditions to inhibit its activation; upon ER stress, EI24 dissociates from IRE1 to permit UPR activation. Co-immunoprecipitation; domain mapping; EI24 knockout with IRE1 activation readout EMBO reports Medium 35005829
2022 The RNA ligase RtcB is tyrosine-phosphorylated by c-Abl and dephosphorylated by PTP1B; phosphorylation of RtcB at Y306 perturbs its interaction with IRE1α and attenuates XBP1 mRNA splicing, providing a mechanism that tunes adaptive vs. pro-death IRE1 outputs. Phosphoproteomics; co-immunoprecipitation; site-directed mutagenesis (Y306); kinase/phosphatase inhibitor treatments; XBP1 splicing assays Life science alliance Medium 35193953
2021 IRE1 kinase activity (but not RNase activity) is required for inflammation-induced adipocyte lipolysis; IRE1 kinase-mediated NF-κB activation and IL-6 secretion are part of this inflammatory lipolytic program; IRE1 kinase activity is dispensable for adrenergic/cAMP-induced lipolysis; adipocyte-specific IRE1 knockout mice confirmed IRE1 is required for endotoxin-induced blood triglyceride increase. IRE1 kinase inhibitors; IRE1 RNase inhibitors; adiponectin-Cre IRE1 conditional knockout mice; adipose tissue explants; in vivo endotoxin challenge The Journal of biological chemistry High 33610548
2022 ER stress-induced activation of IRE1 kinase leads to phosphorylation of FMRP (Fragile X Mental Retardation Protein), suppressing macrophage cholesterol efflux and efferocytosis; pharmacological IRE1 kinase inhibition or FMRP deficiency enhances efflux and reduces atherosclerosis in mice. Mass spectrometry (phosphoproteomics); co-immunoprecipitation; IRE1 kinase inhibitors; FMRP knockout mice; atherosclerosis in vivo model EMBO molecular medicine High 35191199
2015 IRE1 kinase signaling prevents ER membrane permeabilization by suppressing accumulation of the BH3-domain protein Bnip3; without IRE1, Bnip3 accumulates, triggering Bax/Bak oligomerization in the ER membrane, ER membrane permeabilization, mitochondrial calcium accumulation, cytosolic oxidative stress, and cell death. IRE1 kinase inhibition; IRE1 knockout/knockdown; Bnip3 overexpression/knockdown; Bax/Bak oligomerization assay; ER calcium leak measurement Science signaling Medium 26106220
2018 Constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic cytokines (IL-6, IL-8, CXCL1, GM-CSF, TGFβ2) in triple-negative breast cancer cells; paclitaxel enhances IRE1 RNase activity and expands tumor-initiating cells via this pathway; IRE1 RNase inhibition increases paclitaxel efficacy in xenograft models. IRE1 RNase inhibitor; IRE1 knockdown; xenograft mouse model; cytokine measurements Nature communications Medium 30111846
2018 MYC directly controls IRE1 transcription by binding to its promoter and enhancer; MYC forms a transcriptional complex with XBP1 and enhances XBP1 transcriptional activity; XBP1 is a synthetic lethal partner of MYC hyperactivation. ChIP (MYC binding to IRE1 promoter/enhancer); co-IP (MYC-XBP1 complex); siRNA knockdown; in vivo xenograft and GEMM models The Journal of clinical investigation Medium 29480818
2023 IRE1 endoribonuclease activity degrades pre-miR-301a during ER stress; loss of pre-miR-301a elevates GADD45A mRNA (a proapoptotic factor targeted by miR-301a-3p), promoting apoptosis; this is XBP1s-independent, identifying IRE1 RNase-mediated pre-miRNA decay as a distinct pro-death output. Next-generation sequencing; IRE1 inhibitor; nuclear-cytosolic fractionation; miRNA target protector; XBP1s overexpression; cell death assays Cell communication and signaling : CCS Medium 37946177
2018 IRE1 RNase signaling in glioblastoma controls expression of UBE2D3 (a ubiquitin-conjugating E2 enzyme) through both XBP1s and RIDD; UBE2D3 activates the NF-κB pathway, resulting in chemokine production and myeloid cell infiltration into tumors. Genetic and pharmacological IRE1 invalidation; RNA-seq; pathway reporter assays; xenograft mouse models; human GBM dataset analysis Neuro-oncology Medium 38153426
2019 IRE1α deletion in mouse pancreatic β cells reduces expression of five protein disulfide isomerases (PDI, PDIR, P5, ERp44, ERp46) and impairs oxidative folding of proinsulin; reconstitution of the IRE1α-XBP1 pathway restores PDI expression, proinsulin/insulin content, and insulin secretion. β cell-specific Ire1α conditional knockout mice; Ire1α-deleted insulinoma cell lines; reconstitution of IRE1α-XBP1 pathway; insulin secretion assays; protein disulfide isomerase expression analysis The Journal of cell biology High 29507125
2022 IRE1 signaling (via XBP1s) cross-talks with PERK to sustain PERK expression during prolonged ER stress, providing a mechanism for UPR branch coordination during chronic stress. IRE1 and XBP1s inhibitors; XBP1s overexpression; PERK protein/mRNA quantification under ER stress; genetic epistasis Cell death & disease Medium 38637497
2022 Pumilio, an RNA-binding protein, is phosphorylated by hIRE1 kinase during ER stress; phosphorylated Pumilio protects spliced Xbp1 mRNA from RIDD degradation, providing a mechanism for selective Xbp1 mRNA sparing. In vitro phosphorylation assay (hIRE1 phosphorylating Pumilio); Pumilio phosphorylation-site mutagenesis; RNA immunoprecipitation; Xbp1 mRNA stability assays in Drosophila eye Nature communications Medium 35332141
1997 Yeast Ire1p interacts with the transcriptional coactivator Gcn5p (Ada4p); the Gcn5/Ada complex is selectively required for the UPR but not the heat shock response, suggesting Ire1p recruits this histone acetyltransferase complex to activate UPR target genes. Two-hybrid and co-immunoprecipitation; genetic requirement analysis (ada/gcn5 mutants vs. UPR and heat shock reporters) Proceedings of the National Academy of Sciences of the United States of America Medium 9113982
2001 RNase L and Ire1p have mutually exclusive RNA substrate specificities despite being in the same superfamily; comparison of conserved active-site residues by mutagenesis identifies overlapping but not identical requirements, establishing functional distinctions between family members. In vitro RNA cleavage assays with wild-type and mutant RNase L and Ire1p; comparative mutagenesis of conserved nuclease domain residues RNA (New York, N.Y.) Medium 11333017
2022 In the context of alveolar type 2 cell ER stress, IRE1α signaling (via XBP1) drives a cell-autonomous reprogrammed cell state and promotes granulocyte recruitment; an IRE1α inhibitor reduces the reprogrammed state, granulocyte recruitment, alveolitis, and lung injury. Single-cell RNA sequencing; organoid-based modeling; IRE1α inhibitor treatment; in vivo SP-C mutation mouse models Proceedings of the National Academy of Sciences of the United States of America Medium 36252035

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 3335 11779464
2007 IRE1 signaling affects cell fate during the unfolded protein response. Science (New York, N.Y.) 1179 17991856
1998 A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes & development 762 9637683
1997 The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 709 9323131
2014 Getting RIDD of RNA: IRE1 in cell fate regulation. Trends in biochemical sciences 488 24657016
2013 IRE1: ER stress sensor and cell fate executor. Trends in cell biology 461 23880584
1996 Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. The EMBO journal 438 8670804
2019 Structure and Molecular Mechanism of ER Stress Signaling by the Unfolded Protein Response Signal Activator IRE1. Frontiers in molecular biosciences 413 30931312
2019 UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor. Nature structural & molecular biology 333 31695187
2009 Divergent effects of PERK and IRE1 signaling on cell viability. PloS one 267 19137072
2000 Dissociation of Kar2p/BiP from an ER sensory molecule, Ire1p, triggers the unfolded protein response in yeast. Biochemical and biophysical research communications 238 11118306
2018 Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nature communications 236 30111846
2000 IRE1 and efferent signaling from the endoplasmic reticulum. Journal of cell science 221 11034898
2008 How IRE1 reacts to ER stress. Cell 196 18191217
2018 Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. The Journal of clinical investigation 193 29480818
2017 An unfolded protein-induced conformational switch activates mammalian IRE1. eLife 179 28971800
2017 IRE1 signaling exacerbates Alzheimer's disease pathogenesis. Acta neuropathologica 172 28341998
2017 Targeting IRE1 with small molecules counteracts progression of atherosclerosis. Proceedings of the National Academy of Sciences of the United States of America 163 28137856
2014 Ire1 has distinct catalytic mechanisms for XBP1/HAC1 splicing and RIDD. Cell reports 154 25437541
1996 The unfolded protein response pathway in Saccharomyces cerevisiae. Oligomerization and trans-phosphorylation of Ire1p (Ern1p) are required for kinase activation. The Journal of biological chemistry 149 8663458
2020 Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming. Nature chemical biology 143 32690944
2021 The Structure, Activation and Signaling of IRE1 and Its Role in Determining Cell Fate. Biomedicines 139 33562589
2018 Dual IRE1 RNase functions dictate glioblastoma development. EMBO molecular medicine 137 29311133
2014 Phosphoregulation of Ire1 RNase splicing activity. Nature communications 111 24704861
2020 Pharmacological Targeting of IRE1 in Cancer. Trends in cancer 108 32861679
2018 IRE1-XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells. The Journal of cell biology 102 29507125
1998 Protein serine/threonine phosphatase Ptc2p negatively regulates the unfolded-protein response by dephosphorylating Ire1p kinase. Molecular and cellular biology 97 9528768
2014 Physiological roles of regulated Ire1 dependent decay. Frontiers in genetics 96 24795742
2001 Basis for regulated RNA cleavage by functional analysis of RNase L and Ire1p. RNA (New York, N.Y.) 89 11333017
2023 Melatonin Ameliorates Hepatic Ferroptosis in NAFLD by Inhibiting ER Stress via the MT2/cAMP/PKA/IRE1 Signaling Pathway. International journal of biological sciences 83 37564204
2022 Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity. Nature communications 83 35105890
2014 Cab45S inhibits the ER stress-induced IRE1-JNK pathway and apoptosis via GRP78/BiP. Cell death & disease 78 24810055
2017 The ERN1 transcription factor gene is a target of the CCaMK/CYCLOPS complex and controls rhizobial infection in Lotus japonicus. The New phytologist 76 28503742
2004 Discordance of UPR signaling by ATF6 and Ire1p-XBP1 with levels of target transcripts. Biochemical and biophysical research communications 73 15063770
2020 The molecular mechanism and functional diversity of UPR signaling sensor IRE1. Life sciences 68 33188833
2019 Radiation induces EIF2AK3/PERK and ERN1/IRE1 mediated pro-survival autophagy. Autophagy 67 30773986
2024 IRE1 signaling increases PERK expression during chronic ER stress. Cell death & disease 65 38637497
2021 IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis. Journal of cellular physiology 65 34297411
2022 Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging. The EMBO journal 64 36314651
2011 Structural and functional basis for RNA cleavage by Ire1. BMC biology 59 21729333
2021 Inflammation promotes adipocyte lipolysis via IRE1 kinase. The Journal of biological chemistry 52 33610548
2020 Targeting the IRE1-XBP1 axis to overcome endocrine resistance in breast cancer: Opportunities and challenges. Cancer letters 51 32446861
1997 Gene induction in response to unfolded protein in the endoplasmic reticulum is mediated through Ire1p kinase interaction with a transcriptional coactivator complex containing Ada5p. Proceedings of the National Academy of Sciences of the United States of America 49 9113982
2015 Fumonisin B1 induces autophagic cell death via activation of ERN1-MAPK8/9/10 pathway in monkey kidney MARC-145 cells. Archives of toxicology 48 25925693
2016 Divergence and Conservation of the Major UPR Branch IRE1-bZIP Signaling Pathway across Eukaryotes. Scientific reports 45 27256815
2015 Innate immunity at mucosal surfaces: the IRE1-RIDD-RIG-I pathway. Trends in immunology 45 26093676
2014 ERβ decreases breast cancer cell survival by regulating the IRE1/XBP-1 pathway. Oncogene 43 25347741
2015 IRE1 prevents endoplasmic reticulum membrane permeabilization and cell death under pathological conditions. Science signaling 41 26106220
2017 The requirement of IRE1 and XBP1 in resolving physiological stress during Drosophila development. Journal of cell science 38 28775151
2020 Cholesterol induced autophagy via IRE1/JNK pathway promotes autophagic cell death in heart tissue. Metabolism: clinical and experimental 37 32184090
2018 A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers. Genome medicine 37 30482246
2014 Metabolic respiration induces AMPK- and Ire1p-dependent activation of the p38-Type HOG MAPK pathway. PLoS genetics 36 25356552
2021 Genome-wide mRNA profiling identifies X-box-binding protein 1 (XBP1) as an IRE1 and PUMA repressor. Cellular and molecular life sciences : CMLS 35 34636989
2019 Knockdown of IRE1ɑ suppresses metastatic potential of colon cancer cells through inhibiting FN1-Src/FAK-GTPases signaling. The international journal of biochemistry & cell biology 35 31326465
2021 Exome-wide age-of-onset analysis reveals exonic variants in ERN1 and SPPL2C associated with Alzheimer's disease. Translational psychiatry 34 33637690
2022 Disruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 32 36252035
2023 A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment. iScience 31 37216120
2021 The protein kinase Ire1 impacts pathogenicity of Candida albicans by regulating homeostatic adaptation to endoplasmic reticulum stress. Cellular microbiology 31 33403715
2022 Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression. EMBO molecular medicine 30 35191199
2019 VceC Mediated IRE1 Pathway and Inhibited CHOP-induced Apoptosis to Support Brucella Replication in Goat Trophoblast Cells. International journal of molecular sciences 28 31443507
2006 Dcr2 targets Ire1 and downregulates the unfolded protein response in Saccharomyces cerevisiae. EMBO reports 27 16990850
2020 The IRE1 and PERK arms of the unfolded protein response promote survival of rhabdomyosarcoma cells. Cancer letters 26 32679165
2007 Lobe IB of the ATPase domain of Kar2p/BiP interacts with Ire1p to negatively regulate the unfolded protein response in Saccharomyces cerevisiae. Journal of molecular biology 26 17276461
2022 PCV2 and PRV Coinfection Induces Endoplasmic Reticulum Stress via PERK-eIF2α-ATF4-CHOP and IRE1-XBP1-EDEM Pathways. International journal of molecular sciences 25 35562870
2020 Expression of IDE and PITRM1 genes in ERN1 knockdown U87 glioma cells: effect of hypoxia and glucose deprivation. Endocrine regulations 24 32857715
2017 Opposite Roles of RNase and Kinase Activities of Inositol-Requiring Enzyme 1 (IRE1) on HSV-1 Replication. Viruses 24 28832521
2022 EI24 promotes cell adaption to ER stress by coordinating IRE1 signaling and calcium homeostasis. EMBO reports 23 35005829
2022 The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans. PLoS pathogens 23 35108336
2022 Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay. Nature communications 23 35332141
2020 Peptidomimetic-based identification of FDA-approved compounds inhibiting IRE1 activity. The FEBS journal 23 32446294
2022 Activation of the canonical ER stress IRE1-XBP1 pathway by insulin regulates glucose and lipid metabolism. The Journal of biological chemistry 22 35863429
2022 IRE1/XBP1 and endoplasmic reticulum signaling - from basic to translational research for cardiovascular disease. Current opinion in physiology 22 37207249
2020 IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells. Biomolecules 22 32545307
2019 IRE1-XBP1 Pathway of the Unfolded Protein Response Is Required during Early Differentiation of C2C12 Myoblasts. International journal of molecular sciences 22 31888027
2018 The Role of IRE1 Signaling in the Central Nervous System Diseases. Current neuropharmacology 22 29663887
2018 Reshaping the Immune Tumor Microenvironment Through IRE1 Signaling. Trends in molecular medicine 22 29804923
2022 Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation. Proceedings of the National Academy of Sciences of the United States of America 21 36215479
2019 ERN1 and CYCLOPS coordinately activate NIN signaling to promote infection thread formation in Lotus japonicus. Journal of plant research 21 31313020
2016 ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer. Oncotarget 21 27829216
2006 The unfolded protein response transducer Ire1p contains a nuclear localization sequence recognized by multiple beta importins. Molecular biology of the cell 21 17035634
2024 Astrocyte PERK and IRE1 Signaling Contributes to Morphine Tolerance and Hyperalgesia through Upregulation of Lipocalin-2 and NLRP3 Inflammasome in the Rodent Spinal Cord. Anesthesiology 20 38079113
2020 Palmitate-Induced IRE1-XBP1-ZEB Signaling Represses Desmoplakin Expression and Promotes Cancer Cell Migration. Molecular cancer research : MCR 20 33106375
2020 Review: The two faces of IRE1 and their role in protecting plants from stress. Plant science : an international journal of experimental plant biology 19 33487343
2019 Effect of glucose deprivation on the expression of genes encoding glucocorticoid receptor and some related factors in ERN1-knockdown U87 glioma cells. Endocrine regulations 19 31734653
2022 GPx8 regulates apoptosis and autophagy in esophageal squamous cell carcinoma through the IRE1/JNK pathway. Cellular signalling 18 35288240
2001 Alterations in an IRE1-RNA complex in the mammalian unfolded protein response. Journal of cell science 18 11590247
2024 Short-chain fatty acid butyrate against TMAO activating endoplasmic-reticulum stress and PERK/IRE1-axis with reducing atrial arrhythmia. Journal of advanced research 17 39111622
2023 An IRE1-proteasome system signalling cohort controls cell fate determination in unresolved proteotoxic stress of the plant endoplasmic reticulum. Nature plants 17 37563456
2022 RNA sequencing identifies novel regulated IRE1-dependent decay targets that affect multiple myeloma survival and proliferation. Experimental hematology & oncology 17 35361260
2020 The Unfolded Protein Response Modulates a Phosphoinositide-Binding Protein through the IRE1-bZIP60 Pathway. Plant physiology 17 32205450
2023 Dual RNase activity of IRE1 as a target for anticancer therapies. Journal of cell communication and signaling 16 37721642
2023 IRE1-mediated degradation of pre-miR-301a promotes apoptosis through upregulation of GADD45A. Cell communication and signaling : CCS 16 37946177
2021 IRE1 and PERK signaling regulates inflammatory responses in a murine model of contact hypersensitivity. Allergy 16 34314538
2016 Structural Insights into IRE1 Functions in the Unfolded Protein Response. Current medicinal chemistry 16 27686654
2024 IRE1 endoribonuclease signaling promotes myeloid cell infiltration in glioblastoma. Neuro-oncology 15 38153426
2024 GRP78/IRE1 and cGAS/STING pathway crosstalk through CHOP facilitates iodoacetic acid-mediated testosterone decline. Journal of hazardous materials 15 39002476
2022 Stress-induced tyrosine phosphorylation of RtcB modulates IRE1 activity and signaling outputs. Life science alliance 15 35193953
2022 BRCA1 mediates protein homeostasis through the ubiquitination of PERK and IRE1. iScience 15 36471805
2021 Structural and molecular bases to IRE1 activity modulation. The Biochemical journal 15 34375386
2020 CCDC170 affects breast cancer apoptosis through IRE1 pathway. Aging 14 33291081

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