Affinage

ERN1

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

Length
977 aa
Mass
109.7 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERN1 (IRE1α) is the principal ER stress sensor and effector of the unfolded protein response, integrating luminal protein-folding status with cytoplasmic transcriptional and mRNA-decay programs to determine cell fate. Its luminal domain directly binds unfolded peptides via an MHC-like groove to drive oligomerization, while dissociation of the inhibitory chaperone BiP/GRP78 provides a complementary activation mechanism; oligomerization triggers trans-autophosphorylation of the cytoplasmic kinase domain, which allosterically activates a C-terminal endoribonuclease that cooperatively splices XBP1 mRNA within oligomers to produce a UPR transcription factor, or acts as a monomer to degrade ER-localized mRNAs via RIDD (PMID:9323131, PMID:11779464, PMID:25437541, PMID:28971800, PMID:11118306). The kinase domain also phosphorylates non-RNA substrates including FMRP and Pumilio, expanding IRE1 signaling beyond RNA processing to regulate cholesterol efflux and mRNA protection, while activation-loop phosphorylation state—controlled by upstream kinases (AKT) and phosphatases (Dcr2)—tunes the balance between adaptive XBP1 splicing and pro-death RIDD (PMID:35191199, PMID:35332141, PMID:35863429, PMID:16990850, PMID:24704861). IRE1 kinase activity independently of RNase function suppresses ER membrane permeabilization, modulates NF-κB–dependent inflammatory lipolysis in adipocytes, and confers resistance to MEK inhibition in KRAS-mutant cancers, underscoring context-dependent roles extending well beyond canonical UPR transcription (PMID:26106220, PMID:33610548, PMID:30482246).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 High

    Establishing that Ire1p oligomerizes in response to ER stress and undergoes trans-autophosphorylation answered how a single-pass transmembrane kinase transduces a luminal signal to its cytoplasmic effector domain.

    Evidence Biochemical autophosphorylation assays and dominant-negative/deletion mutant analysis in yeast

    PMID:8670804

    Open questions at the time
    • No structural basis for oligomerization interface
    • C-terminal tail function beyond the kinase domain uncharacterized
    • Mechanism of luminal sensing not addressed
  2. 1997 High

    Reconstituting HAC1 mRNA splicing from purified Ire1p and tRNA ligase proved that Ire1p is itself the site-specific endoribonuclease and that splicing requires only two components, establishing the direct enzymatic output of the UPR sensor.

    Evidence In vitro reconstitution with purified yeast Ire1p and tRNA ligase

    PMID:9323131

    Open questions at the time
    • Mammalian substrate unknown
    • Catalytic residues not yet identified
    • Whether kinase activity is required for RNase activity unclear
  3. 2000 High

    Demonstrating that Kar2p/BiP binds and inhibits Ire1p under basal conditions and dissociates during ER stress identified the first negative regulatory mechanism for Ire1p activation, answering how the sensor is kept silent in unstressed cells.

    Evidence Co-immunoprecipitation and phosphorylation-state analysis in yeast

    PMID:11118306

    Open questions at the time
    • Whether BiP dissociation is sufficient or whether direct unfolded-protein binding also contributes
    • Structural basis of BiP–Ire1p interaction unknown
    • Mammalian BiP–IRE1 interaction not yet characterized
  4. 2001 High

    Identifying XBP1 mRNA as the mammalian splicing substrate of IRE1 and showing that only the spliced form activates UPR target genes extended the yeast paradigm to mammals and defined the key transcription factor downstream of IRE1.

    Evidence XBP1 splicing assay, reporter assays, and IRE1 knockout MEFs

    PMID:11779464

    Open questions at the time
    • Whether IRE1 has non-XBP1 RNA substrates in mammals
    • How spliced XBP1 coordinates with ATF6-generated XBP1 mRNA
    • RNase substrate specificity determinants unknown
  5. 2006 High

    Identifying Dcr2 phosphatase as a direct Ire1p interactor that dephosphorylates Ire1p to attenuate HAC1 splicing answered how UPR signaling is shut off, establishing phosphatase-mediated deactivation as a critical regulatory mechanism.

    Evidence In vitro dephosphorylation of Ire1p by Dcr2; HAC1 splicing delay upon Dcr2 overexpression in yeast

    PMID:16990850

    Open questions at the time
    • Mammalian phosphatase(s) for IRE1 not identified
    • Whether dephosphorylation precedes or follows oligomer disassembly
  6. 2010 High

    Genome-wide identification of IRE1α cleavage targets at a consensus stem-loop/CUGCAG motif established that IRE1 degrades multiple ER-localized mRNAs beyond XBP1 (RIDD), revealing a second major functional output.

    Evidence In vitro cleavage assay combined with exon microarray; structural analysis of cleavage sites

    PMID:20507909

    Open questions at the time
    • Physiological relevance of each RIDD target not established
    • Whether RIDD operates under all stress conditions or only sustained stress
  7. 2011 High

    Crystal structures of the human IRE1α kinase-RNase cassette, combined with catalytic-residue identification in yeast, defined the structural basis for allosteric coupling between autophosphorylation and RNase activation, and showed that phosphorylation-loop conformation gates enzymatic output.

    Evidence X-ray crystallography of human IRE1α; catalytic-residue mutagenesis in yeast Ire1; kinase inhibitor studies

    PMID:21317875 PMID:21444691 PMID:21729333

    Open questions at the time
    • Full-length transmembrane structure unavailable
    • How luminal domain conformational change propagates through the transmembrane helix to the cytoplasmic domain
  8. 2014 High

    Separation of XBP1 splicing (cooperative, oligomer-dependent) from RIDD (non-cooperative, monomer-competent) via oligomerization-interface mutants answered how a single RNase domain produces two mechanistically distinct outputs, and activation-loop phosphorylation was shown to quantitatively tune both activities.

    Evidence In vitro RNase assays with oligomerization mutants and defined phospho-species; cell-based splicing assays

    PMID:24704861 PMID:25437541

    Open questions at the time
    • How oligomer size is regulated in vivo
    • Whether RIDD substrate selection involves additional factors
    • Whether phosphorylation differentially tunes XBP1 versus RIDD in physiological contexts
  9. 2017 High

    Showing that the human IRE1α luminal domain directly binds unfolded peptides via its MHC-like groove to drive oligomerization resolved the long-standing question of whether IRE1 senses misfolded proteins directly or solely through BiP titration, establishing a dual-input activation model.

    Evidence Peptide binding assays; mutagenesis of the oligomerization interface; cell-based IRE1 activity assays

    PMID:28971800

    Open questions at the time
    • Relative contribution of direct binding versus BiP release under different stresses
    • Whether peptide specificity selects for particular client proteins
  10. 2019 High

    Reconstitution of the human BiP–IRE1 interaction showed BiP enters a 'sensor cycle' distinct from its chaperone cycle upon binding IRE1 luminal domains, with ATP-dependent priming for misfolded protein-triggered dissociation, providing the biochemical mechanism for the BiP-release arm of activation.

    Evidence In vitro reconstitution with purified human BiP, IRE1, and cochaperones; ATPase and binding assays

    PMID:31695187

    Open questions at the time
    • How the two activation arms (BiP release and direct binding) are integrated quantitatively in vivo
    • Structural view of the BiP–IRE1 luminal domain complex still missing
  11. 2020 High

    Discovery of kinase-pocket ligands that inhibit kinase activity yet allosterically activate RNase revealed that activation-loop conformation, not phosphotransfer per se, is the conformational switch controlling RNase output, refining the interdomain regulatory model.

    Evidence Crystal structures of ligand-bound IRE1α; cellular XBP1 splicing assays; kinase selectivity profiling

    PMID:33318494

    Open questions at the time
    • Whether such conformational states exist physiologically or only with synthetic ligands
    • Whether RIDD and XBP1 splicing are differentially affected by these conformational switches
  12. 2022 Medium

    Identification of non-RNA kinase substrates (FMRP, Pumilio, RtcB) and the upstream kinase AKT expanded IRE1 beyond a unidimensional RNase/splicing machine into a signaling hub that phosphorylates effectors controlling cholesterol efflux, mRNA stability, and metabolic gene expression.

    Evidence Phosphoproteomic identification; in vitro kinase assays; FMRP-knockout atherosclerosis model; Drosophila genetics; liver-specific AKT–IRE1 phosphorylation studies

    PMID:35191199 PMID:35193953 PMID:35332141 PMID:35863429

    Open questions at the time
    • Full kinase substrate repertoire unknown
    • Whether FMRP and Pumilio phosphorylation occurs under all ER stress conditions or only specific ones
    • AKT-mediated S724 phosphorylation not confirmed by independent labs
  13. 2022 Medium

    Identification of co-regulators EI24 (inhibitory ER transmembrane partner) and BRCA1 (E3 ligase targeting IRE1 for degradation) showed that IRE1 protein levels and activation threshold are controlled by stress-responsive protein–protein interactions and ubiquitin-dependent turnover.

    Evidence Co-immunoprecipitation; EI24 and BRCA1 knockout studies; ubiquitination assays; IRE1 activity measurements

    PMID:35005829 PMID:36471805

    Open questions at the time
    • EI24–IRE1 interaction not structurally characterized
    • BRCA1 ubiquitination of IRE1 not independently confirmed
    • How EI24 dissociation is triggered by ER stress is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the luminal, transmembrane, and cytoplasmic domains coordinately transmit unfolded-protein signals into graded kinase and RNase outputs in full-length IRE1 within native ER membranes remains unresolved, as does the complete inventory of IRE1 kinase substrates and the molecular basis for cell-type-specific IRE1 signaling outcomes.
  • No full-length IRE1 structure in a membrane environment
  • Kinase substrate scope beyond FMRP, Pumilio, RtcB, and XBP1 mRNA unknown
  • Mechanisms determining cell-type-specific balance between adaptive and pro-death outputs unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0140098 catalytic activity, acting on RNA 6 GO:0098772 molecular function regulator activity 4 GO:0140657 ATP-dependent activity 3 GO:0140299 molecular sensor activity 2
Localization
GO:0005783 endoplasmic reticulum 5
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 GO:0005634 nucleus 1
Partners
AKT1BRCA1EI24FMRPHSPA5RTCBSDF2L1XBP1
Complex memberships
IRE1-BiP/GRP78 inhibitory complexIRE1-RtcB splicing complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Yeast Ire1p is a bifunctional enzyme with both kinase and site-specific endoribonuclease activities; it cleaves HAC1 mRNA at both splice junctions, and the splicing reaction was reconstituted in vitro from purified Ire1p and tRNA ligase. In vitro reconstitution with purified components; biochemical cleavage assay Cell High 9323131
1996 Yeast Ire1p oligomerizes in response to ER stress and undergoes trans-autophosphorylation as a consequence of oligomerization; a C-terminal tail domain beyond the kinase domain is also required for UPR induction. Molecular genetic and biochemical studies; autophosphorylation assays; dominant-negative and deletion mutant analysis The EMBO journal High 8670804
2001 Mammalian IRE1 splices XBP1 mRNA (analogous to yeast Ire1p splicing HAC1 mRNA) to produce an active transcription factor; only the spliced XBP1 form efficiently activates the UPR, and XBP1 is a transcriptional target of ATF6. mRNA splicing assay; reporter assays; IRE1 knockout MEF experiments Cell High 11779464
2000 In yeast, the ER chaperone Kar2p/BiP binds the luminal domain of Ire1p and keeps it in an inactive, unphosphorylated state; ER stress causes Kar2p dissociation from Ire1p, leading to Ire1p activation. Co-immunoprecipitation; phosphorylation state analysis; genetic studies Biochemical and biophysical research communications High 11118306
2011 Crystal structure of the cytoplasmic portion of dephosphorylated human IRE1α bound to ADP revealed a face-to-face dimeric complex competent for autophosphorylation (phosphoryl-transfer); XBP1 RNase activity depends on autophosphorylation, and ATP-competitive inhibitors that block autophosphorylation in vitro also block XBP1 splicing in vivo. Activated IRE1α can phosphorylate a heterologous peptide substrate. Crystal structure determination; in vitro kinase and RNase assays; mutational analysis; cell-based XBP1 splicing assay The EMBO journal High 21317875
2011 Yeast Ire1 RNase uses histidine H1061 and tyrosine Y1043 as the general acid-general base pair for RNA cleavage, with asparagine N1057 and arginine R1056 coordinating the scissile phosphate; two crystal structures defined the active site, and Ire1 can also cleave anticodon stem-loop of unmodified tRNAPhe. Crystal structures; site-directed mutagenesis; quantitative in vitro RNase assay BMC biology High 21729333
2014 IRE1 has two mechanistically distinct RNase modes: XBP1/HAC1 intron cleavage requires cooperative action of IRE1 subunits within oligomers, whereas RIDD is performed by single IRE1 subunits without cooperativity. These activities can be separated by mutations at oligomerization interfaces and by complementation with catalytically inactive IRE1. In vitro RNase assays; IRE1 oligomerization mutants; complementation experiments; selective RNase inhibitor STF-083010 Cell reports High 25437541
2014 Phosphorylation of Ire1 within the kinase activation loop significantly increases RNase splicing activity in vitro; Ire1 mutants that cannot be phosphorylated on the activation loop show decreased XBP1 and RIDD splicing activity in cells, coupling the kinase phosphorylation reaction to RNase activation state. Isolation of distinct phosphorylated Ire1 species; in vitro RNase assays; cell-based splicing assays with phosphomutants Nature communications High 24704861
2019 Human BiP switches from its chaperone cycle to an ER stress sensor cycle upon binding to the luminal domains of IRE1 and PERK; this interaction prevents co-chaperone binding and loss of ATPase stimulation. Misfolded protein-dependent dissociation of BiP from IRE1 is primed by ATP but not ADP. Reconstitution of human UPR, ER stress, and BiP chaperone systems in vitro; biochemical binding and ATPase assays Nature structural & molecular biology High 31695187
2017 Human IRE1α luminal domain (hIRE1α LD) binds unfolded peptides via its MHC-like groove, inducing allosteric changes that drive oligomerization; a hydrophobic patch at the oligomerization interface is required for oligomerization and for IRE1 activity in living cells, establishing direct unfolded protein binding as the activation trigger. Peptide binding assays; mutagenesis of oligomerization interface; cell-based IRE1 activity assays; structural analysis eLife High 28971800
2010 IRE1α recognizes and cleaves target RNAs at a consensus sequence (CUGCAG) accompanied by a stem-loop structure; genome-wide screening identified 13 novel IRE1α cleavage targets using a combined in vitro cleavage assay and exon microarray approach. In vitro cleavage assay combined with exon microarray; sequence-structure analysis of cleavage sites Nucleic acids research High 20507909
2015 Crystal structure of human IRE1 in a back-to-back conformation revealed autoinhibition through a Tyr-down mechanism; a compound that potently inhibits IRE1 kinase activity was shown to stimulate XBP1 splicing, and its crystal structure showed increased ordering of the kinase activation loop, consistent with allosteric coupling between the kinase and RNase domains via back-to-back dimer formation. X-ray crystallography; structure-function analysis; kinase inhibition assays; XBP1 splicing assay Oncotarget High 25968568
2011 Dephosphorylation of Ire1 (yeast) is an important step in RNase deactivation: cells expressing phosphomimetic kinase activation loop mutants sustain HAC1 mRNA splicing after ER stress recovery; mutations in the conserved DFG motif or activation loop also sustain splicing, and the inability to attenuate RNase activity causes lethality under ER stress. In vivo HAC1 splicing assay; phosphomimetic and DFG mutant analysis; growth assays under ER stress The Journal of cell biology High 21444691
2006 The phosphatase Dcr2 physically interacts with phosphorylated yeast Ire1, dephosphorylates Ire1 in vitro, and overexpression of catalytically active (but not inactive) Dcr2 delays HAC1 mRNA splicing, identifying Dcr2 as a negative regulator that downregulates the UPR by dephosphorylating Ire1. Genetic interaction analysis; in vitro dephosphorylation assay; in vivo HAC1 splicing assay; co-immunoprecipitation EMBO reports High 16990850
2007 The ATP-bound (substrate-free) conformation of Kar2p/BiP binds Ire1p through lobe IB of the ATPase domain; glutamine 88 on lobe IB is critical for the Ire1p interaction, and unfolded polypeptide binding to Kar2p likely releases Ire1p to activate UPR signaling. Oligosaccharide shielding/protection experiments; site-directed mutagenesis; binding assays; kinetic analysis Journal of molecular biology Medium 17276461
2001 Mammalian IRE1 associates with RNA in vivo (UV crosslinking); the IRE1-RNA complex changes dynamically during ER stress (shorter fragments, more end-labelable RNA in stressed cells); complex formation requires both the kinase and endonuclease domains of IRE1. In vivo UV crosslinking; immunoprecipitation; domain mutagenesis Journal of cell science Medium 11590247
2006 Yeast Ire1p contains a nuclear localization sequence (NLS) in its linker region recognized by importin alpha (Kap60p) and multiple importin beta homologues; NLS mutations that impair nuclear localization also inhibit ER stress-induced HAC1 mRNA splicing, linking nuclear import to UPR signaling. GFP nuclear targeting assay; importin binding studies; mutagenesis; HAC1 splicing assay; genetic analysis of Ran GTPase cycle mutants Molecular biology of the cell Medium 17035634
2001 RNase L and yeast Ire1p show mutually exclusive RNA substrate specificity despite belonging to the same endoribonuclease superfamily; conserved active-site residues in the nuclease domains of both enzymes partially overlap but are not identical, defining distinct catalytic requirements. Comparative mutational analysis; in vitro RNA cleavage assays with wild-type and mutant enzymes RNA (New York, N.Y.) Medium 11333017
2017 IRE1 (mammalian) mediates RIDD in addition to XBP1 splicing; sustained IRE1 activity (achieved artificially) enhances cell survival under persistent ER stress, while IRE1 and ATF6 activities are naturally attenuated during chronic stress whereas PERK signaling is maintained, causally linking IRE1 duration of activity to cell fate. Chemical-genetic strategy (analog-sensitive IRE1); cell viability assays; photoreceptor animal model validation Science (New York, N.Y.) High 17991856
2009 Sustained IRE1 signaling (uncoupled from ER stress by chemical-genetic activation) enhances cell proliferation without promoting apoptosis, whereas equivalent sustained PERK signaling impairs proliferation and promotes apoptosis, demonstrating opposite cell fate effects of these two UPR kinases. Chemical-genetic strategy with analog-sensitive kinases; cell proliferation and apoptosis assays PloS one High 19137072
2020 A class of ATP-competitive small molecules binds the IRE1 kinase front pocket, induces a distinct conformation of the activation loop, and allosterically activates RNase activity with high selectivity and strong cellular activity, revealing exquisitely precise interdomain regulation within IRE1. Crystal structure of inhibitor-bound IRE1; kinase inhibition assay; cellular XBP1 splicing assay; selectivity profiling Nature communications High 33318494
2021 IRE1 kinase activity (but not RNase activity) is required for inflammation-induced adipocyte lipolysis; IRE1 kinase inhibition blocks NF-κB activation, IL-6 secretion, and lipolysis from multiple inflammatory ligands but not from adrenergic/cAMP stimuli; adipocyte-specific IRE1 knockout reduced blood triglycerides after endotoxin challenge in vivo. IRE1 kinase inhibitor treatment; adipocyte-specific Cre knockout; adipose tissue explant assays; in vivo endotoxin model The Journal of biological chemistry High 33610548
2022 Insulin-activated AKT directly phosphorylates IRE1 at S724, which in turn mediates XBP1 mRNA splicing in liver, driving lipogenesis; this defines AKT as an upstream kinase that activates IRE1 RNase activity under physiological nutrient conditions. Phosphorylation assay; AKT kinase assay; liver-specific overexpression/knockdown; gene expression analysis The Journal of biological chemistry Medium 35863429
2022 ER stress induces IRE1 kinase-dependent phosphorylation of FMRP (Fragile X Mental Retardation protein), which suppresses macrophage cholesterol efflux and efferocytosis; IRE1 kinase inhibition or FMRP deficiency enhances efflux and reduces atherosclerosis in mice. Phosphoproteomic identification; IRE1 kinase inhibitor; FMRP knockout; cholesterol efflux assay; mouse atherosclerosis model EMBO molecular medicine Medium 35191199
2022 The ER transmembrane protein EI24 binds the kinase domain of IRE1 under non-stressed conditions to inhibit its activation; upon ER stress, EI24 dissociates from IRE1, permitting UPR activation; EI24 simultaneously targets IP3R1 to prevent ER calcium depletion, coordinately promoting cell survival. Co-immunoprecipitation; EI24 knockout; IRE1 activity assays; calcium homeostasis measurements EMBO reports Medium 35005829
2022 IRE1 kinase can phosphorylate the RNA ligase RtcB; phosphorylation of RtcB at Y306 (by c-Abl, reversed by PTP1B) perturbs RtcB interaction with IRE1α, attenuating XBP1 mRNA splicing and thereby modulating adaptive versus pro-death UPR outputs. Phosphoproteomic identification; in vitro kinase assay; co-immunoprecipitation; XBP1 splicing assay; cell fate analysis Life science alliance Medium 35193953
2022 IRE1 kinase phosphorylates Pumilio (RNA-binding protein) during ER stress in Drosophila; phosphorylated Pumilio binds spliced Xbp1 mRNA and protects it from RIDD degradation, thus selectively shielding the pro-survival Xbp1s mRNA from the degradative arm of IRE1. Drosophila genetics; in vitro IRE1 kinase assay with Pumilio; RNA binding assay; mRNA stability analysis Nature communications Medium 35332141
2022 BRCA1 functions as an E3 ubiquitin ligase in the ER that ubiquitinates IRE1 (and PERK) for proteasome-mediated degradation; BRCA1 deficiency leads to increased IRE1 protein levels and constitutively activated UPR. Ubiquitination assay; proteasome inhibition; BRCA1 knockdown/knockout; protein level analysis iScience Medium 36471805
2013 Murine cytomegalovirus M50 protein directly interacts with IRE1 (identified by affinity purification) and causes downregulation of IRE1 protein levels; the N-terminal conserved region of M50 is required for interaction. Human CMV UL50 (M50 homolog) similarly downregulates IRE1, repressing IRE1-mediated XBP1 splicing. Affinity purification/mass spectrometry; co-immunoprecipitation; IRE1 protein level analysis; XBP1 splicing assay PLoS pathogens Medium 23950715
2015 IRE1 kinase activity prevents ER membrane permeabilization by suppressing accumulation of the BH3-only protein Bnip3; Bnip3 accumulation upon IRE1 loss triggers Bax/Bak oligomerization in the ER membrane, ER membrane permeabilization, calcium transfer to mitochondria, and cell death. IRE1 kinase inhibition; Bnip3 knockdown epistasis; Bax/Bak oligomerization assay; ER membrane permeabilization assay; calcium measurement Science signaling Medium 26106220
2014 Cab45S inhibits ER stress-induced IRE1 activation by binding to GRP78/BiP at its nucleotide-binding domain and stabilizing the GRP78/BiP–IRE1 interaction, thereby keeping IRE1 inactive and reducing JNK phosphorylation and apoptosis. Co-immunoprecipitation; Cab45S depletion/overexpression; IRE1 activity (XBP1 splicing) assay; apoptosis assay Cell death & disease Medium 24810055
2019 IRE1α knockdown in colon cancer cells inhibits migration/invasion by reducing XBP1s formation and decreasing fibronectin-1 (FN1) expression, which in turn reduces Src/FAK phosphorylation and inactivates RhoA, Rac1, and CDC42 GTPases; XBP1s directly binds the FN1 promoter as a transcription factor. IRE1α knockdown; ChIP assay; migration/invasion assays; rescue with exogenous FN1; phosphorylation analysis; in vivo metastasis model The international journal of biochemistry & cell biology Medium 31326465
2018 MYC directly controls IRE1 transcription by binding to its promoter and enhancer; MYC also forms a transcriptional complex with XBP1s and enhances its transcriptional activity, establishing a MYC–IRE1–XBP1 regulatory axis. ChIP; co-immunoprecipitation; transcriptional reporter assays; IRE1 promoter analysis; patient-derived xenograft models The Journal of clinical investigation Medium 29480818
2018 ERN1/IRE1 non-kinase function (not kinase activity) in KRAS-mutant colon cancer cells confers resistance to MEK inhibitors; the ERN1-JNK-JUN signaling axis mediates this resistance, as identified by a genome-wide CRISPR/Cas9 screen in ERN1-knockout cells. CRISPR/Cas9 genetic knockout; genome-wide CRISPR screen; yeast synthetic lethality screen; MEK inhibitor sensitivity assays Genome medicine Medium 30482246
2022 IRE1α signaling (via XBP1s) in alveolar type 2 cells drives cell reprogramming toward a pathological cell state associated with lung fibrosis; pharmacological inhibition of IRE1α reduced this reprogrammed state, granulocyte recruitment, and alveolitis in vivo. Single-cell RNA sequencing; organoid modeling; IRE1α inhibitor treatment; in vivo mouse model with SP-C mutations Proceedings of the National Academy of Sciences of the United States of America Medium 36252035
2024 IRE1 via XBP1s signaling sustains PERK expression during prolonged ER stress, demonstrating cross-talk between the IRE1 and PERK UPR branches wherein IRE1 modulates the adaptive capacity of the PERK pathway. XBP1s induction; IRE1 inhibition; PERK protein level analysis under chronic ER stress Cell death & disease Low 38637497

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 3312 11779464
2007 IRE1 signaling affects cell fate during the unfolded protein response. Science (New York, N.Y.) 1175 17991856
1997 The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 705 9323131
2014 Getting RIDD of RNA: IRE1 in cell fate regulation. Trends in biochemical sciences 483 24657016
2013 IRE1: ER stress sensor and cell fate executor. Trends in cell biology 458 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 408 30931312
2019 UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor. Nature structural & molecular biology 322 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 233 30111846
2011 Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response. The EMBO journal 215 21317875
2004 Hepatitis C virus suppresses the IRE1-XBP1 pathway of the unfolded protein response. The Journal of biological chemistry 193 14960590
2018 Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. The Journal of clinical investigation 190 29480818
2017 An unfolded protein-induced conformational switch activates mammalian IRE1. eLife 177 28971800
2014 Ire1 has distinct catalytic mechanisms for XBP1/HAC1 splicing and RIDD. Cell reports 149 25437541
2010 Identification of a consensus element recognized and cleaved by IRE1 alpha. Nucleic acids research 133 20507909
2014 Phosphoregulation of Ire1 RNase splicing activity. Nature communications 110 24704861
2020 Pharmacological Targeting of IRE1 in Cancer. Trends in cancer 105 32861679
2014 Physiological roles of regulated Ire1 dependent decay. Frontiers in genetics 96 24795742
2017 LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 signalling pathway. Scientific reports 95 28332555
2001 Basis for regulated RNA cleavage by functional analysis of RNase L and Ire1p. RNA (New York, N.Y.) 89 11333017
2017 Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival. Nature cell biology 88 28459443
2011 Attenuation of yeast UPR is essential for survival and is mediated by IRE1 kinase. The Journal of cell biology 84 21444691
2023 Melatonin Ameliorates Hepatic Ferroptosis in NAFLD by Inhibiting ER Stress via the MT2/cAMP/PKA/IRE1 Signaling Pathway. International journal of biological sciences 77 37564204
2014 Cab45S inhibits the ER stress-induced IRE1-JNK pathway and apoptosis via GRP78/BiP. Cell death & disease 77 24810055
2018 ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells. Journal of neuroinflammation 75 30241539
2017 The ERN1 transcription factor gene is a target of the CCaMK/CYCLOPS complex and controls rhizobial infection in Lotus japonicus. The New phytologist 74 28503742
2004 Discordance of UPR signaling by ATF6 and Ire1p-XBP1 with levels of target transcripts. Biochemical and biophysical research communications 72 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 65 30773986
2021 IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis. Journal of cellular physiology 62 34297411
2022 Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging. The EMBO journal 61 36314651
2002 Characterization of two homologs of Ire1p, a kinase/endoribonuclease in yeast, in Arabidopsis thaliana. Biochimica et biophysica acta 61 12020828
2024 IRE1 signaling increases PERK expression during chronic ER stress. Cell death & disease 60 38637497
2019 The ER stress sensor IRE1 and MAP kinase ERK modulate autophagy induction in cells infected with coronavirus infectious bronchitis virus. Virology 59 31082732
2011 Structural and functional basis for RNA cleavage by Ire1. BMC biology 59 21729333
2013 Cytomegalovirus downregulates IRE1 to repress the unfolded protein response. PLoS pathogens 56 23950715
2020 Targeting the IRE1-XBP1 axis to overcome endocrine resistance in breast cancer: Opportunities and challenges. Cancer letters 51 32446861
2021 Inflammation promotes adipocyte lipolysis via IRE1 kinase. The Journal of biological chemistry 49 33610548
2020 Local intracerebral inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo. Cancer letters 48 32882336
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
2015 Molecular mechanisms of human IRE1 activation through dimerization and ligand binding. Oncotarget 48 25968568
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 44 26093676
2014 ERβ decreases breast cancer cell survival by regulating the IRE1/XBP-1 pathway. Oncogene 43 25347741
2021 IRE1-mTOR-PERK Axis Coordinates Autophagy and ER Stress-Apoptosis Induced by P2X7-Mediated Ca2+ Influx in Osteoarthritis. Frontiers in cell and developmental biology 42 34222263
2017 The UPR reduces glucose metabolism via IRE1 signaling. Biochimica et biophysica acta. Molecular cell research 42 28093214
2015 IRE1 prevents endoplasmic reticulum membrane permeabilization and cell death under pathological conditions. Science signaling 41 26106220
2003 IRE1- and HAC1-independent transcriptional regulation in the unfolded protein response of yeast. Molecular microbiology 40 12864846
2020 Cholesterol induced autophagy via IRE1/JNK pathway promotes autophagic cell death in heart tissue. Metabolism: clinical and experimental 36 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 36 30482246
2017 The requirement of IRE1 and XBP1 in resolving physiological stress during Drosophila development. Journal of cell science 36 28775151
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
2014 Metabolic respiration induces AMPK- and Ire1p-dependent activation of the p38-Type HOG MAPK pathway. PLoS genetics 35 25356552
2020 Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands. Nature communications 34 33318494
2014 Deficiency of IRE1 and PERK signal pathways in systemic lupus erythematosus. The American journal of the medical sciences 34 25226532
2021 Exome-wide age-of-onset analysis reveals exonic variants in ERN1 and SPPL2C associated with Alzheimer's disease. Translational psychiatry 33 33637690
2021 Genome-wide mRNA profiling identifies X-box-binding protein 1 (XBP1) as an IRE1 and PUMA repressor. Cellular and molecular life sciences : CMLS 33 34636989
2019 Unfolded protein-independent IRE1 activation contributes to multifaceted developmental processes in Arabidopsis. Life science alliance 33 31601623
2022 Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression. EMBO molecular medicine 30 35191199
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 30 36252035
2021 The protein kinase Ire1 impacts pathogenicity of Candida albicans by regulating homeostatic adaptation to endoplasmic reticulum stress. Cellular microbiology 29 33403715
2016 β-Asarone Inhibits IRE1/XBP1 Endoplasmic Reticulum Stress Pathway in 6-OHDA-Induced Parkinsonian Rats. Neurochemical research 29 27097550
2023 A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment. iScience 28 37216120
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
2017 Psoralen Inhibited Apoptosis of Osteoporotic Osteoblasts by Modulating IRE1-ASK1-JNK Pathway. BioMed research international 28 28349059
2024 Exploring the IRE1 interactome: From canonical signaling functions to unexpected roles. The Journal of biological chemistry 27 38494075
2006 Dcr2 targets Ire1 and downregulates the unfolded protein response in Saccharomyces cerevisiae. EMBO reports 27 16990850
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 24 35562870
2022 Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay. Nature communications 23 35332141
2022 EI24 promotes cell adaption to ER stress by coordinating IRE1 signaling and calcium homeostasis. EMBO reports 22 35005829
2022 Activation of the canonical ER stress IRE1-XBP1 pathway by insulin regulates glucose and lipid metabolism. The Journal of biological chemistry 22 35863429
2020 The IRE1 and PERK arms of the unfolded protein response promote survival of rhabdomyosarcoma cells. Cancer letters 22 32679165
2020 BCAT1 binds the RNA-binding protein ZNF423 to activate autophagy via the IRE1-XBP-1-RIDD axis in hypoxic PASMCs. Cell death & disease 22 32938905
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
2014 Ethanol stress impairs protein folding in the endoplasmic reticulum and activates Ire1 in Saccharomyces cerevisiae. Bioscience, biotechnology, and biochemistry 22 25130742
2023 PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy. The Journal of cell biology 21 37022709
2020 Peptidomimetic-based identification of FDA-approved compounds inhibiting IRE1 activity. The FEBS journal 21 32446294
2018 Reshaping the Immune Tumor Microenvironment Through IRE1 Signaling. Trends in molecular medicine 21 29804923
2018 Improved IRE1 and PERK Pathway Sensors for Multiplex Endoplasmic Reticulum Stress Assay Reveal Stress Response to Nuclear Dyes Used for Image Segmentation. Assay and drug development technologies 21 30088945
2006 The unfolded protein response transducer Ire1p contains a nuclear localization sequence recognized by multiple beta importins. Molecular biology of the cell 21 17035634
1999 Enlargement of the endoplasmic reticulum membrane in Saccharomyces cerevisiae is not necessarily linked to the unfolded protein response via Ire1p. FEBS letters 21 10403405
2022 Endoplasmic Reticulum Stress in Colonic Mucosa of Ulcerative Colitis Patients Is Mediated by PERK and IRE1 Pathway Activation. Mediators of inflammation 20 35185383
2022 Cholesterol accumulation in hepatocytes mediates IRE1/p38 branch of endoplasmic reticulum stress to promote nonalcoholic steatohepatitis. Free radical biology & medicine 20 35995397
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 19 36215479
2020 Review: The two faces of IRE1 and their role in protecting plants from stress. Plant science : an international journal of experimental plant biology 18 33487343
2001 Alterations in an IRE1-RNA complex in the mammalian unfolded protein response. Journal of cell science 18 11590247
2022 RNA sequencing identifies novel regulated IRE1-dependent decay targets that affect multiple myeloma survival and proliferation. Experimental hematology & oncology 17 35361260
2016 Structural Insights into IRE1 Functions in the Unfolded Protein Response. Current medicinal chemistry 16 27686654
2023 An IRE1-proteasome system signalling cohort controls cell fate determination in unresolved proteotoxic stress of the plant endoplasmic reticulum. Nature plants 15 37563456
2023 Dual RNase activity of IRE1 as a target for anticancer therapies. Journal of cell communication and signaling 15 37721642
2022 Stress-induced tyrosine phosphorylation of RtcB modulates IRE1 activity and signaling outputs. Life science alliance 15 35193953
2022 The Brucella Effector BspI Suppresses Inflammation via Inhibition of IRE1 Kinase Activity during Brucella Infection. Journal of immunology (Baltimore, Md. : 1950) 15 35840160
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
2023 Kai-Xin-San Improves Cognitive Impairment via Wnt/β-Catenin and IRE1/XBP1s Signalings in APP/PS1 Mice. Rejuvenation research 14 37073462
2014 The effects of IRE1, ATF6, and PERK signaling on adRP-linked rhodopsins. Advances in experimental medicine and biology 14 24664756