Affinage

EIF2AK1

Eukaryotic translation initiation factor 2-alpha kinase 1 · UniProt Q9BQI3

Length
630 aa
Mass
71.1 kDa
Annotated
2026-06-09
71 papers in source corpus 26 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2AK1/HRI is a stress-sensing eIF2α kinase that integrates diverse cytosolic, mitochondrial, and metabolic stress inputs into the integrated stress response by phosphorylating eIF2α and inducing the ATF4 transcriptional program (PMID:32132707, PMID:11726526). Kinase activation requires autophosphorylation of Thr485 in the activation loop, which converts HRI from a hypophosphorylated inactive state to the active enzyme, while phosphorylated HRI forms a stable complex with its substrate eIF2α (PMID:12767237). Heme acts as the central negative regulator: it binds via a Cys385 axial ligand in the kinase-insertion domain and triggers large allosteric rearrangements that suppress autophosphorylation, distinct from ATP-competitive inhibition (PMID:17597215, PMID:40471279). In erythroid precursors, HRI is the physiological kinase that matches globin synthesis to heme availability, and its loss causes accumulation of heme-free globin aggregates and anemia under iron deficiency (PMID:11726526); it concurrently couples eIF2α phosphorylation to ATF4 induction and mTORC1 suppression to support erythroid differentiation and antioxidant defense (PMID:29101239, PMID:31033440). Through an HRI→ATF4→BCL11A→γ-globin axis, in which ATF4 directly activates the BCL11A enhancer, HRI represses fetal hemoglobin in adult erythroid cells (PMID:30026227, PMID:32299090). Beyond erythropoiesis, HRI is the principal eIF2α kinase activated by proteasome inhibition and cytosolic proteotoxicity sensed via an Hsp70-Bag3 module, and it drives chaperone-assisted autophagic clearance of protein aggregates (PMID:18290760, PMID:33168630, PMID:35573186). Mitochondrial stress activates HRI through the OMA1/HtrA2-DELE1 axis, in which cleaved DELE1 accumulates in the cytosol and directly binds and activates the kinase (PMID:32132707, PMID:38555279); HRI is itself recruited to mitochondria during the mitochondrial unfolded-protein response to restrain mitochondrial translation and import, and selectively induces mitophagy via mitochondrial localization of phospho-eIF2 while negatively regulating PINK1-dependent mitophagy (PMID:38340717, PMID:40344059, PMID:39168261). HRI activity is further tuned by an activating Hsp90 interaction through its K1 subdomain and by ubiquitin-mediated degradation through the UBR4 and KCMF1 E3 ligases, which restrain ISR overactivation (PMID:30170366, PMID:41548766, PMID:41391693).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 High

    Established HRI as the physiological in vivo eIF2α kinase that balances globin translation against heme supply, answering whether HRI's biochemical activity has a defined organismal role.

    Evidence Targeted HRI knockout mice challenged with iron deficiency, with globin aggregation and erythroid histology readouts

    PMID:11726526

    Open questions at the time
    • Did not resolve the molecular sensor coupling heme levels to kinase state
    • Restricted to the erythroid lineage
  2. 2003 High

    Defined the activation switch of HRI by showing Thr485 activation-loop autophosphorylation is essential for kinase activity, explaining how the enzyme transitions to its active form.

    Evidence Site-directed mutagenesis of activation-loop residues with in vitro autokinase and eIF2α kinase assays and phosphopeptide mapping

    PMID:12767237

    Open questions at the time
    • Did not connect autophosphorylation to physiological activating stimuli
    • No structural model of the active site
  3. 2007 High

    Identified the heme-binding chemistry of HRI by assigning Cys385 as the C-terminal heme axial ligand, defining how heme is sensed at the molecular level.

    Evidence Mutagenesis with optical, resonance Raman, and ESR spectroscopy on the isolated kinase-insertion domain

    PMID:17597215

    Open questions at the time
    • Did not show how heme binding propagates to the kinase domain
    • Used isolated domain rather than full-length protein
  4. 2008 High

    Demonstrated HRI is the essential eIF2α kinase for the proteasome-inhibition stress response, extending its role beyond heme/erythroid biology to proteostasis.

    Evidence Genetic epistasis across four single-kinase knockout MEF lines treated with proteasome inhibitors

    PMID:18290760

    Open questions at the time
    • Did not identify the sensor coupling proteasome inhibition to HRI
    • Mechanism of activation unresolved
  5. 2010 Medium

    Showed hepatic HRI mediates heme-dependent translational control of CYP2B and modulates basal ER stress tone, broadening its tissue functions.

    Evidence HRI-/- hepatocytes with heme depletion, phenobarbital induction, and ER-stress marker immunoblotting

    PMID:20071449

    Open questions at the time
    • Mechanism linking HRI loss to elevated PERK/ER stress not defined
    • Single lab
  6. 2015 Medium

    Revealed a neuronal HRI function in which NO-activated HRI stimulates BACE1 translation and synaptic spine growth, indicating context-dependent positive translational outputs of eIF2α phosphorylation.

    Evidence HRI inhibitor and siRNA in hippocampal neurons with luciferase reporters, immunofluorescence, and mouse behavior

    PMID:25706765

    Open questions at the time
    • How eIF2α phosphorylation selectively promotes BACE1 translation not detailed
    • Pharmacologic tools alongside knockdown
  7. 2017 High

    Established that HRI-eIF2αP-ATF4 signaling suppresses mTORC1 in erythroid cells, integrating two translational control arms during iron deficiency.

    Evidence Erythroid-specific eIF2α knock-in and HRI-KO mice with ribosome profiling and pharmacologic mTORC1 inhibition

    PMID:29101239

    Open questions at the time
    • Mechanism by which ATF4 suppresses mTORC1 not resolved
    • Erythroid-specific context
  8. 2018 High

    Identified HRI as a fetal hemoglobin repressor in human erythroid cells acting through BCL11A, and uncovered an activating Hsp90 interaction, defining both an output pathway and an upstream modulator.

    Evidence Kinase-focused CRISPR screen and KO with HbF/BCL11A readouts; Co-IP, two-hybrid, and kinase assays mapping the HRI K1-Hsp90 interaction

    PMID:30026227 PMID:30170366

    Open questions at the time
    • Hsp90 study is single-lab without reciprocal IP
    • How HRI loss lowers BCL11A mechanistically left for follow-up
  9. 2019 High

    Showed HRI globally represses ribosomal protein mRNA translation during iron deficiency and supports mitochondrial function via ATF4 targets, defining the breadth of its translational repression.

    Evidence Ribosome profiling in primary HRI-/- erythroblasts with mitochondrial respiration assays

    PMID:31033440

    Open questions at the time
    • Did not establish selectivity rules for ATF4 target induction
    • Erythroid model only
  10. 2020 High

    Identified the OMA1-DELE1-HRI axis as the relay transmitting mitochondrial stress to the ISR, answering how mitochondrial damage triggers HRI.

    Evidence Genome-wide CRISPRi screen, DELE1-HRI Co-IP, knockouts, and subcellular fractionation with eIF2α/ATF4 readouts

    PMID:32132707

    Open questions at the time
    • Structural basis of DELE1-HRI activation not defined
    • Did not map which mitochondrial insults engage this axis
  11. 2020 High

    Placed ATF4 directly upstream of BCL11A transcription and established HRI's role in autophagic aggregate clearance, completing the erythroid HbF pathway order and expanding proteostasis functions.

    Evidence CRISPR screens with ATF4 ChIP-seq and chromatin contacts (BCL11A); HRI knockdown/KO with α-synuclein aggregation and BAG3/HSPB8 readouts

    PMID:32299090 PMID:33168630

    Open questions at the time
    • Autophagy study is single-lab Medium confidence
    • How HRI controls BAG3/HSPB8 levels not mechanistically defined
  12. 2022 Medium

    Defined a cytosolic Hsp70-Bag3-HRI proteotoxicity-sensing axis, identifying the upstream module that couples cytosolic misfolding to HRI.

    Evidence Co-IP of Hsp70-Bag3-HRI, JG-98 disruption, RNAseq, and HRI knockdown

    PMID:35573186

    Open questions at the time
    • Single Co-IP without reciprocal validation of direct binding
    • How disruption of the chaperone module activates HRI not fully resolved
  13. 2024 High

    Resolved HRI's mitochondrial roles by showing it senses matrix protein-folding/import stress and selectively induces mitophagy via mitochondrial p-eIF2 localization while operating distinctly from PINK1-PARKIN.

    Evidence Genome-wide and reporter-based CRISPR screens, ribosome profiling, mitochondrial import and recruitment assays, and p-eIF2 localization imaging; HtrA2/OMA1 DELE1 cleavage assays

    PMID:38340717 PMID:38555279 PMID:39168261

    Open questions at the time
    • How mitochondrial localization of p-eIF2 mechanistically triggers mitophagy unresolved
    • Cell-line-dependent protease usage for DELE1 cleavage not reconciled
  14. 2025 Medium

    Provided structural and regulatory mechanisms for HRI: heme inhibits via large allosteric rearrangements, UBR4 and KCMF1 ubiquitinate HRI to limit ISR, and HRI negatively regulates PINK1-dependent mitophagy.

    Evidence HDX-MS and AlphaFold modeling of hemin-bound HRI; conditional Ubr4 KO and KCMF1 KD/OE with ubiquitination and ISR readouts; siRNA kinome screen with PINK1/ubiquitin phosphorylation reporters across four cell lines

    PMID:40344059 PMID:40471279 PMID:41391693 PMID:41548766

    Open questions at the time
    • Single-lab studies for each regulatory arm
    • Recognition determinants for UBR4/KCMF1 targeting of HRI not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HRI integrates competing positive (DELE1, Hsp70-Bag3, Hsp90/GABARAPL1) and negative (heme, UBR4, KCMF1, ROCK1) inputs into a graded ISR output, and the structural basis of substrate-engaged active HRI, remain unresolved.
  • No integrated structural model of activated, eIF2α-bound HRI from peer-reviewed work
  • Quantitative hierarchy of activating vs inhibitory regulators undefined
  • Translation-independent infection-associated functions mechanistically unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0045182 translation regulator activity 3 GO:0016740 transferase activity 2 GO:0140299 molecular sensor activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005739 mitochondrion 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
BAG3DELE1EIF2S1GABARAPL1HSP90HSPA8KCMF1UBR4

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 HRI (EIF2AK1) is the eIF2α kinase necessary and sufficient to relay mitochondrial stress signals to ATF4 induction. A genome-wide CRISPR interference screen identified OMA1 (mitochondrial stress-activated protease) and DELE1 as upstream factors; mitochondrial stress triggers OMA1-dependent cleavage of DELE1, causing accumulation of DELE1 in the cytosol where it directly interacts with HRI and activates its eIF2α kinase activity. Genome-wide CRISPRi screen, co-immunoprecipitation (DELE1-HRI interaction), genetic knockout/knockdown with eIF2α phosphorylation and ATF4 induction readouts, subcellular fractionation Nature High 32132707
2001 HRI is the physiological eIF2α kinase in erythroid precursors that inhibits globin translation when heme is limiting. HRI knockout mice on an iron-deficient diet accumulate heme-free globin aggregates in red blood cells, causing hyperchromic normocytic anemia, erythroid hyperplasia, and accelerated apoptosis, establishing HRI as the in vivo regulator of heme-globin balance via eIF2α phosphorylation. Targeted gene disruption (HRI-/- mice), iron-deficiency challenge, histology, globin aggregation assays, erythroid cell analysis The EMBO journal High 11726526
2003 Autophosphorylation of Thr485 (but not Thr483) in the activation loop of HRI is essential for attaining eIF2α kinase activity. Thr490, though not itself an autophosphorylation site, is critical for catalytic activity and for the efficient phosphorylation of Thr485. Disruption of Thr485 autophosphorylation locks HRI in a hypophosphorylated, kinase-inactive state. Site-directed mutagenesis of activation-loop residues, in vitro autokinase and eIF2α kinase assays, 32P-labeling phosphopeptide mapping Biochemistry High 12767237
2007 Cys385 in the kinase insertion (KI) domain of HRI is the heme axial ligand in the C-terminal region. Spectroscopic analysis of isolated KI domain showed a 5-coordinate high-spin heme complex with thiol (Cys385) as axial ligand; the Cys385Ser mutant displayed markedly different Soret band position and ESR parameters, confirming this assignment. Site-directed mutagenesis, optical absorption spectroscopy, resonance Raman spectroscopy, electron spin resonance (ESR), heme spectral titration Journal of inorganic biochemistry High 17597215
2008 HRI is the primary eIF2α kinase activated by 26S proteasome inhibition. In MEF knockout cell lines lacking PKR, PERK, or GCN2 individually, proteasome inhibitor (MG-132 or bortezomib) still increased eIF2α phosphorylation, whereas HRI-/- cells failed to show this increase, establishing HRI as the essential kinase in this proteostatic stress response. Knockout MEF cells (HRI-/-, PKR-/-, PERK-/-, GCN2-/-) treated with proteasome inhibitors; eIF2α phosphorylation and protein synthesis rate measurements The Biochemical journal High 18290760
2018 HRI (EIF2AK1) functions as an HbF repressor in adult human erythroid cells. CRISPR-Cas9 knockout of HRI markedly increased HbF production; mechanistically, HRI depletion reduced BCL11A levels, which accounts for a large part of the γ-globin de-repression. Protein kinase domain-focused CRISPR-Cas9 screen in primary human erythroid cells; HbF quantification; BCL11A protein/mRNA analysis upon HRI knockdown Science High 30026227
2020 The HRI-regulated transcription factor ATF4 directly activates BCL11A transcription by binding to its enhancer and fostering enhancer-promoter contacts, defining a linear HRI→ATF4→BCL11A→γ-globin signaling pathway in human erythroblasts. CRISPR-Cas9 loss-of-function screen in human erythroblasts; ChIP-seq for ATF4 at BCL11A enhancer; chromatin conformation assays; murine model comparisons Blood High 32299090
2017 HRI coordinates two translation-regulation pathways during iron deficiency: eIF2α phosphorylation (eIF2αP) and mTORC1 suppression. HRI-eIF2αP-ATF4 signaling suppresses mTORC1 specifically in erythroid cells; erythroid-specific ablation of eIF2αP abolished ATF4 induction in vivo and impaired erythroid differentiation and antioxidant responses. Erythroid-specific eIF2α knock-in mouse model (eAA); HRI knockout mice; pharmacologic mTORC1 inhibition; ribosome profiling; in vivo iron deficiency challenge Blood High 29101239
2019 HRI globally represses translation of cytosolic and mitochondrial ribosomal protein mRNAs during iron deficiency, causing decreased cytosolic and mitochondrial protein synthesis. Absence of HRI during iron deficiency elicits a cytoplasmic unfolded protein response and impairs mitochondrial respiration; ATF4 target genes are activated downstream of HRI to maintain mitochondrial function. Ribosome profiling in murine primary erythroblasts from HRI-/- and wild-type mice under iron deficiency; mitochondrial respiration assays eLife High 31033440
2020 HRI controls autophagy to clear cytosolic protein aggregates when the ubiquitin-proteasome system is inhibited. HRI silencing decreased BAG3 and HSPB8 levels (chaperone-assisted selective autophagy components), caused cytotoxic accumulation of α-synuclein, and aged HRI-/- mice accumulated misfolded α-synuclein and protein aggregates in spinal cord white matter. HRI siRNA knockdown; overexpression of α-synuclein; immunofluorescence for protein aggregates; aged HRI-/- mouse histopathology; BAG3/HSPB8 immunoblotting The Journal of biological chemistry Medium 33168630
2024 The HRI branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eIF2 (p-eIF2), which is sufficient to induce mitophagy. This HRI-driven mitophagy pathway operates in parallel with and is mechanistically distinct from the PINK1-PARKIN pathway. Whole-genome CRISPR screen; mitophagy reporters; ISR branch-specific genetic activation; immunofluorescence for p-eIF2 subcellular localization Molecular cell High 38340717
2018 Hsp90 interacts with HRI and modulates its kinase activity under stress. Co-immunoprecipitation showed that the HRI K1 subdomain is required for HRI-Hsp90 complex formation. In vitro kinase assay with co-immunoprecipitated HRI-Hsp90 complex showed increased eIF2α phosphorylation upon heavy metal stress and heat shock. Co-immunoprecipitation with truncated HRI domains; mammalian two-hybrid assay; in silico protein-protein interaction modeling; in vitro kinase assay International journal of biological macromolecules Medium 30170366
2020 HRI is activated by nanosecond pulsed electric fields (nsPEFs) via reactive oxygen species (ROS). In quadruple eIF2α kinase KO MEF cells, nsPEF-induced eIF2α phosphorylation was abolished and rescued only by HRI overexpression; the ROS scavenger NAC blocked nsPEF-induced eIF2α phosphorylation, establishing a ROS→HRI→eIF2α axis. eIF2α kinase quadruple KO and single kinase-rescued MEF cells; nsPEF treatment; ROS detection (CM-H2DCFDA); NAC scavenger rescue; eIF2α phosphorylation immunoblotting PloS one Medium 32155190
2022 Cytosolic proteotoxicity activates HRI through the Hsp70-Bag3 module. Hsp70-Bag3 directly interacted with HRI (Co-IP), and disruption of this interaction (JG-98 inhibitor) activated eIF2α phosphorylation via HRI but not PERK, establishing a cytosolic Hsp70-Bag3-HRI-eIF2α proteotoxicity-sensing axis. Co-immunoprecipitation of Hsp70-Bag3-HRI complex; JG-98 Hsp70-Bag3 interaction inhibitor; RNAseq pathway analysis; genetic knockdown of HRI iScience Medium 35573186
2024 Mitochondrial protein import stress (MPIS) is the overarching trigger for the DELE1-HRI pathway. Endogenous DELE1 can be cleaved into two forms (DELE1-S and DELE1-VS); OMA1 is crucial for DELE1 cleavage in HeLa cells but dispensable in HEK293T cells. HtrA2, a mitochondrial protease, mediates DELE1 cleavage into DELE1-VS, and a Parkinson's disease-associated HtrA2 mutant showed reduced DELE1 processing. Epitope-tagged and endogenous DELE1 cleavage assays; OMA1/HtrA2 genetic knockdown; cell fractionation; comparison across HeLa and HEK293T cell lines Communications biology Medium 38555279
2025 EIF2AK1/HRI is a negative regulator of PINK1-dependent mitophagy. siRNA knockdown of HRI in HeLa, SK-OV-3, U2OS, and ARPE-19 cells enhanced mitochondrial depolarization-induced PINK1 stabilization and phosphorylation of ubiquitin and Rab8A. Knockdown of DELE1 (HRI activator) produced similar effects, and ISR inhibitor ISRIB also enhanced PINK1 activation. siRNA kinome screen; PINK1 stabilization/ubiquitin phosphorylation assays; mito-QC mitophagy reporters; genetic confirmation in four cell lines Science advances Medium 40344059
2025 The UBR4 ubiquitin ligase complex promotes ubiquitination and degradation of activated HRI, thereby restraining ISR overactivation. Tubule-specific Ubr4 deficiency exacerbated cisplatin-induced AKI with elevated HRI-ISR activity, and genetic enhancement of UBR4 or pharmacologic ISR inhibition mitigated nephrotoxicity. Conditional Ubr4 knockout mice; cisplatin AKI model; ubiquitination assays; ISRIB pharmacologic inhibition; eIF2α phosphorylation immunoblotting Free radical biology & medicine Medium 41548766
2025 KCMF1 regulates HRI ubiquitination to inhibit the ISR. KCMF1 knockdown reduced HRI ubiquitination and promoted eIF2α phosphorylation and ATF4/ATF3/SESN2 expression; KCMF1 overexpression reversed these effects; ISR inhibitor rescued the effects of KCMF1 knockdown on cancer cell behavior. Ni-NTA pull-down ubiquitination assay; KCMF1 knockdown/overexpression; eIF2α phosphorylation immunoblotting; xenograft mouse model Biochemical pharmacology Medium 41391693
2015 In hippocampal neurons, nitric oxide (NO) activates HRI, which phosphorylates eIF2α to stimulate translation of BACE1 mRNA. This HRI-eIF2α-BACE1 axis is activated by glutamate signaling and promotes synaptic spine growth and memory consolidation; HRI inhibition or siRNA knockdown blocked BACE1 expression and spine growth. Western blot, luciferase reporter assay for BACE1 translation; HRI inhibitor and HRI siRNA in hippocampal neurons; immunofluorescence; mouse behavioral assays with HRI/nNOS inhibitors Antioxidants & redox signaling Medium 25706765
2013 HRI kinase activation in the CA1 hippocampus is required for object recognition memory consolidation; learning induced a transient increase in eIF2α phosphorylation in dorsal CA1 that was blocked by the HRI inhibitor AMI, and this phosphorylation correlated with increased BACE1 and ATF4 protein expression. Intra-hippocampal injection of HRI kinase inhibitor (AMI); object recognition behavioral task in rats; eIF2α phosphorylation and BACE1/ATF4 immunoblotting in CA1 Hippocampus Medium 23418065
2010 Hepatic HRI is the eIF2α kinase mediating heme-dependent translational regulation of CYP2B enzymes. In HRI-KO hepatocytes, phenobarbital-induced CYP2B protein induction proceeded undeterred even after acute heme depletion. Genetic HRI ablation also elevated basal ER stress (PERK activation, Grp78/Grp94 induction, protein ubiquitination), indicating HRI normally modulates hepatic ER stress tone. HRI-/- mouse hepatocyte model; heme depletion + phenobarbital treatment; CYP2B protein assays; PERK/Grp78/Grp94/ubiquitination immunoblotting Molecular pharmacology Medium 20071449
2024 Hemin binding to HRI induces large-scale allosteric structural rearrangements detected by HDX-MS that are not seen with ATP-mimetic competitive inhibitors; these rearrangements primarily suppress HRI autophosphorylation (including tyrosine phosphorylation not previously observed in eIF2α kinases), providing a structural basis for heme-mediated allosteric inhibition distinct from ATP-competitive inhibition. Hydrogen-deuterium exchange mass spectrometry (HDX-MS); biochemical kinase assays; AlphaFold 3 structural modeling; comparison of hemin vs. dabrafenib/encorafenib/GCN2iB inhibitors The Biochemical journal Medium 40471279
2025 HRI forms a dimer in solution through its N-terminal domain, but N-terminal domain-mediated dimerization is not essential for autophosphorylation activity. Phosphorylated HRI forms a stable complex with eIF2α whereas dephosphorylated HRI fails to bind eIF2α. Phosphate groups at Thr488 and Thr493 interact with adjacent basic residues to enhance eIF2α recognition. Heme-induced deactivation selectively targets the dephosphorylated kinase domain to suppress autophosphorylation. Biochemical reconstitution; N-terminal domain deletion mutants; autophosphorylation assays; eIF2α binding assays; structural modeling based on AlphaFold predictions bioRxivpreprint Medium
2013 HRI is required for bacterial pathogens to execute virulence-associated cellular activities in host cells. HRI-null cells were resistant to Yersinia Yop-mediated cytoskeleton damage (reduced type 3 secretion), showed dramatically reduced Chlamydia intracellular proliferation, and blocked Listeria trafficking to the cytosol. These infection-associated functions of HRI appeared independent of its eIF2α kinase/protein synthesis regulation activity. HRI-null cells infected with Yersinia, Chlamydia, and Listeria; cytoskeletal damage assays; T3S functional assays; intracellular proliferation counts; eIF2α phosphorylation analysis PloS one Medium 23874749
2025 ROCK1 phosphorylates BACH2 to protect it from heme-driven degradation in differentiating B cells, and also restrains HRI activity by controlling HRI's interaction with HSP90 and limiting recruitment of HRI and HSP90 to p62/SQSTM1 complexes that also contain mTOR complex 1 and TBK1. Co-immunoprecipitation of HRI-HSP90-p62 complex; ROCK1 KO B cells; phosphorylation assays; proteomics of p62 complexes JCI insight Low 39903532
2024 Unfolded proteins accumulating in the mitochondrial matrix activate HRI kinase, which then phosphorylates eIF2α to inhibit mitochondrial protein translation and mitochondrial protein import. HRI was recruited to mitochondria upon induction of mitochondrial unfolded protein response (UPRmt) and interacted with other proteins there, as confirmed by CRISPR-Cas9 HRI deletion abolishing the UPRmt eIF2α phosphorylation response. CRISPR-Cas9 HRI deletion; ribosome profiling; mitochondrial protein import assays; mitochondrial recruitment/co-IP of HRI; ROS and morphology assays Cellular signalling Medium 39168261
2026 GABARAPL1 facilitates the interaction between HSP90 and HRI, which is required for full activation of HRI during sodium arsenite-induced stress. In GABARAPL1-deficient A549 cells, eIF2α phosphorylation was decreased and stress granule formation was impaired upon arsenite treatment. GABARAPL1 knockout/knockdown; eIF2α phosphorylation immunoblotting; stress granule immunofluorescence; co-immunoprecipitation of HSP90-HRI Scientific reports Medium 41904211

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. Nature 531 32132707
2001 Heme-regulated eIF2alpha kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency. The EMBO journal 307 11726526
2018 Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells. Science (New York, N.Y.) 128 30026227
2008 Phosphorylation of eIF2alpha in response to 26S proteasome inhibition is mediated by the haem-regulated inhibitor (HRI) kinase. The Biochemical journal 71 18290760
2020 The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression. Blood 66 32299090
2017 HRI coordinates translation by eIF2αP and mTORC1 to mitigate ineffective erythropoiesis in mice during iron deficiency. Blood 61 29101239
2020 De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation. American journal of human genetics 59 32197074
2019 HRI coordinates translation necessary for protein homeostasis and mitochondrial function in erythropoiesis. eLife 56 31033440
2020 The eIF2α kinase HRI in innate immunity, proteostasis, and mitochondrial stress. The FEBS journal 54 32892501
2024 The HRI branch of the integrated stress response selectively triggers mitophagy. Molecular cell 49 38340717
2017 The eIF2-alpha kinase HRI: a potential target beyond the red blood cell. Expert opinion on therapeutic targets 41 29063813
2003 Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2alpha kinase activity of HRI. Biochemistry 41 12767237
2021 Environmental cadmium impairs blood-testis barrier via activating HRI-responsive mitochondrial stress in mice. The Science of the total environment 39 34896485
2009 Discovery of the first known small-molecule inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase. Bioorganic & medicinal chemistry letters 35 19854648
2020 The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates. The Journal of biological chemistry 34 33168630
2015 Physiological Control of Nitric Oxide in Neuronal BACE1 Translation by Heme-Regulated eIF2α Kinase HRI Induces Synaptogenesis. Antioxidants & redox signaling 30 25706765
2013 Consolidation of object recognition memory requires HRI kinase-dependent phosphorylation of eIF2α in the hippocampus. Hippocampus 29 23418065
2017 The eIF2-alpha kinase HRI is a novel therapeutic target in multiple myeloma. Leukemia research 28 28119225
2010 Hepatic heme-regulated inhibitor (HRI) eukaryotic initiation factor 2alpha kinase: a protagonist of heme-mediated translational control of CYP2B enzymes and a modulator of basal endoplasmic reticulum stress tone. Molecular pharmacology 26 20071449
2018 HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells. Oncogene 21 29720726
2019 New activators of eIF2α Kinase Heme-Regulated Inhibitor (HRI) with improved biophysical properties. European journal of medicinal chemistry 20 31881453
2024 Cytosolic retention of HtrA2 during mitochondrial protein import stress triggers the DELE1-HRI pathway. Communications biology 19 38555279
2019 Oral administration of a new HRI activator as a new strategy to improve high-fat-diet-induced glucose intolerance, hepatic steatosis, and hypertriglyceridaemia through FGF21. British journal of pharmacology 16 30927369
2022 Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts. Blood cancer discovery 15 35926182
2021 Wnt5a promotes hippocampal postsynaptic development and GluN2B-induced expression via the eIF2α HRI kinase. Scientific reports 15 33795747
2020 HRI depletion cooperates with pharmacologic inducers to elevate fetal hemoglobin and reduce sickle cell formation. Blood advances 15 32956454
1986 Reevaluation of hemorrhagic toxin, HR-I, from Agkistrodon halys blomhoffii venom: proof of proteolytic enzyme. The International journal of biochemistry 14 3081384
2025 HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: Relevance to hematological and mitochondrial diseases. The Journal of biological chemistry 12 40209956
2020 Nanosecond pulsed electric fields induce the integrated stress response via reactive oxygen species-mediated heme-regulated inhibitor (HRI) activation. PloS one 11 32155190
2007 Identification of Cys385 in the isolated kinase insertion domain of heme-regulated eIF2 alpha kinase (HRI) as the heme axial ligand by site-directed mutagenesis and spectral characterization. Journal of inorganic biochemistry 11 17597215
2025 Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling. Science advances 10 40344059
2018 Activation of HRI is mediated by Hsp90 during stress through modulation of the HRI-Hsp90 complex. International journal of biological macromolecules 10 30170366
2013 The host-encoded Heme Regulated Inhibitor (HRI) facilitates virulence-associated activities of bacterial pathogens. PloS one 10 23874749
2000 Cloning of hHRI, human heme-regulated eukaryotic initiation factor 2alpha kinase: down-regulated in epithelial ovarian cancers. Molecules and cells 10 11101152
2022 An mTORC1 to HRI signaling axis promotes cytotoxicity of proteasome inhibitors in multiple myeloma. Cell death & disease 8 36400754
2018 iCub-HRI: A Software Framework for Complex Human-Robot Interaction Scenarios on the iCub Humanoid Robot. Frontiers in robotics and AI 8 33500909
2022 Cytoplasmic proteotoxicity regulates HRI-dependent phosphorylation of eIF2α via the Hsp70-Bag3 module. iScience 7 35573186
2023 The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI. International journal of molecular sciences 6 37175767
2025 Structural insights into allosteric inhibition of HRI kinase by heme binding via HDX-MS. The Biochemical journal 5 40471279
2025 Drug repurposing screen identifies an HRI activating compound that promotes adaptive mitochondrial remodeling in MFN2-deficient cells. Proceedings of the National Academy of Sciences of the United States of America 5 41289394
2024 Integrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics. Oncotarget 5 39288289
2023 The Hormetic Effect Observed for Benzalkonium Chloride and Didecyldimethylammonium Chloride in Serratia sp. HRI. Microorganisms 5 36985138
2021 Dihydrocapsaicin induces translational repression and stress granule through HRI-eIF2α phosphorylation axis. Biochemical and biophysical research communications 5 34953209
2021 Addressing joint action challenges in HRI: Insights from psychology and philosophy. Acta psychologica 5 34974283
2019 HRI of Epinephelus coioides is a critical factor in the grouper immune response to RGNNV infection. Fish & shellfish immunology 5 30753915
2025 A Novel Squaramide Derivative, HR-19011, Induces the Integrated Stress Response via the HRI-eIF2α-ATF4 Pathway, Effectively Inhibiting Hematologic Malignancies. Molecular cancer therapeutics 3 40293252
2023 Genomic Islands Identified in Highly Resistant Serratia sp. HRI: A Pathway to Discover New Disinfectant Resistance Elements. Microorganisms 3 36838480
2022 Non-enzymatic glycation of human angiogenin: Effects on enzymatic activity and binding to hRI and DNA. Biochimie 3 36592684
2020 HRI stress signaling and HbF production. Blood 3 32526022
2018 Computational insights into the interaction of small molecule inhibitors with HRI kinase domain. Journal of biomolecular structure & dynamics 3 29663856
2016 HRI, a stress response eIF2α kinase, exhibits structural and functional stability at high temperature and alkaline conditions. International journal of biological macromolecules 3 27888007
2025 Targeting prohibitins activates the ISR through DELE1-HRI by impairing protein import into the mitochondrial matrix. Cell death and differentiation 2 41291210
2025 Trifloxystrobin induces oxidative stress-dependent activation of the OMA1-DELE1-HRI integrated stress response leading to apoptosis in human neuroblastoma cells. Environmental pollution (Barking, Essex : 1987) 2 41422903
2024 Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation. Cellular signalling 2 39168261
2014 [Role of HRI in apoptosis resistance]. Medecine sciences : M/S 2 25311023
2025 ROCK1 promotes B cell differentiation and proteostasis under stress through the heme-regulated proteins, BACH2 and HRI. JCI insight 1 39903532
2025 Modulation of CREB3L2-ATF4 heterodimerization via proteasome inhibition and HRI activation in Alzheimer's disease pathology. Cell death & disease 1 40164587
2025 Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells. bioRxiv : the preprint server for biology 1 40666974
2025 Best practice guidelines on reference interval harmonization in Canada: Evidence-based recommendations from the CSCC working group on reference interval harmonization (CSCC WG-hRI). Clinical biochemistry 1 40763882
2024 Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease. Journal of biomolecular structure & dynamics 1 38555858
2024 Differential Expression Analysis Reveals Possible New Quaternary Ammonium Compound Resistance Gene in Highly Resistant Serratia sp. HRI. Microorganisms 1 39338566
2023 Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease. Research square 1 38168168
2026 UBR4 attenuates cisplatin-induced acute kidney injury by regulating the HRI-ISR axis. Free radical biology & medicine 0 41548766
2026 Embarrassment in HRI: remediation and the role of robot responses in emotion control. Frontiers in robotics and AI 0 41552616
2026 GABARAPL1 is important for the activation of HRI during eIF2α phosphorylation-dependent stress response to sodium arsenite. Scientific reports 0 41904211
2026 Structural insights into HRI kinase activity and inhibition. Biochemical Society transactions 0 42138128
2026 Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease. CNS & neurological disorders drug targets 0 42261169
2025 Reduced White Matter Damage and Lower Neuroinflammatory Potential of Microglia and Macrophages in Hri/Eif2ak1 -/- Mice After Contusive Spinal Cord Injury. Glia 0 39760211
2025 KCMF1 regulates HRI ubiquitination to inhibit the integrated stress response in ovarian cancer. Biochemical pharmacology 0 41391693
2009 [Secretory expression vector V-pLNCX-s-hri inhibits the growth of mouse B16 melanoma]. Ai zheng = Aizheng = Chinese journal of cancer 0 19619436
2005 [Transfection and expression of hRI gene on human umbilical blood stem cells and gene therapy for mouse melanoma]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 0 15859326

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