Affinage

EIF2S1

Eukaryotic translation initiation factor 2 subunit 1 · UniProt P05198

Length
315 aa
Mass
36.1 kDa
Annotated
2026-06-09
61 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2S1 (eIF-2α) is the regulatory alpha subunit of eukaryotic initiation factor 2, and its phosphorylation at Ser51 by stress-sensing kinases (PKR, HRI, PERK/PEK, GCN2) is the central switch that downregulates global cap-dependent translation initiation during cellular stress (PMID:8903508, PMID:10026192). Phosphorylated eIF-2α acts by sequestering the guanine-nucleotide exchange factor eIF-2B into a non-functional 15S complex, blocking the recycling needed for new rounds of initiation (PMID:9236156); quantitatively, this Ser51/Ser52 phosphorylation is the dominant rate-limiting bottleneck on translational output in human cell-derived systems [PMID:bio_10.1101_2025.11.16.688697]. Beyond globally repressing synthesis, the modification reprograms gene expression: it permits selective IRES-dependent translation of specific mRNAs during G2/M (PMID:15330758), reduces translation of the NF-κB inhibitor IκB-α to amplify IFN-β induction following viral or dsRNA challenge (PMID:22948139), and is required for nuclear translocation of the autophagy master transcription factors TFEB and TFE3 during ER stress, driving autophagosome and autolysosome formation (PMID:36719671). Within this integrated stress response, eIF-2α phosphorylation also governs SQSTM1-dependent selective autophagy downstream of SEC61 inhibition (PMID:34424124) and the ATF4 arm that links it to AKT-MTOR autophagy control during viral infection (PMID:29166823). The pathway is reversed by phosphatase activity: the HSV-1 γ134.5/ICP34.5 protein recruits protein phosphatase 1 through a C-terminal motif to dephosphorylate eIF-2α and restore viral protein synthesis (PMID:9696792, PMID:11264356). EIF2S1 protein abundance is itself set post-translationally by the deubiquitinase USP8, which removes K48-linked polyubiquitin chains to prevent proteasomal degradation (PMID:41147744). Among its upstream kinases, HRI is the most extensively characterized: a heme-sensing hemoprotein homodimer whose activity is downregulated by heme binding at a regulatory site (PMID:9874252), that requires Hsp90 chaperoning for maturation (PMID:9111082) and is restrained by Hsc70 (PMID:9738893), and that controls protein synthesis during erythroid differentiation (PMID:11050009).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1996 High

    Established the foundational principle that eIF-2α phosphorylation at Ser51 by dedicated kinases is the primary mechanism coupling diverse stresses to a shutdown of translation initiation.

    Evidence In vitro phosphorylation and genetic studies in yeast and mammalian cells

    PMID:8903508

    Open questions at the time
    • Did not resolve the structural basis of eIF-2B sequestration
    • Did not address selective translational outcomes downstream of phosphorylation
  2. 1997 High

    Resolved how the HRI kinase upstream of eIF-2α acquires competence, showing Hsp90 binds HRI co-translationally and is obligatory for its activable conformation.

    Evidence Co-IP, in vitro translation in reticulocyte lysate, geldanamycin disruption

    PMID:9111082

    Open questions at the time
    • Did not define the HRI residues contacted by Hsp90
    • Did not test whether other eIF-2α kinases share this dependence
  3. 1997 Medium

    Defined a negative-regulatory layer on HRI activation by showing Hsc70 inhibits HRI hyper-autophosphorylation and that stress-induced protein denaturation relieves this inhibition.

    Evidence In vitro kinase assays with Hsc70 add-back in reticulocyte lysate, glycerol gradient centrifugation

    PMID:9738893

    Open questions at the time
    • Reconstituted in lysate from a single lab
    • Direct Hsc70-HRI binding stoichiometry not established
  4. 1997 Medium

    Clarified that Hsp90/cohort association stabilizes HRI under proteotoxic stress and is separable from heme-mediated inhibition, partitioning chaperone protection from heme sensing.

    Evidence Co-IP, glycerol gradient/gel filtration, reconstitution with purified Hsp90

    PMID:9208939

    Open questions at the time
    • Single-lab characterization
    • In vivo relevance of FKBP52/p23 cohorts not tested
  5. 1997 Medium

    Established in vivo that the eIF-2α regulatory phosphosite tunes organismal growth, with phosphomimetic and non-phosphorylatable substitutions producing opposite developmental rate and body-size phenotypes.

    Evidence Transgenic Drosophila S50D/S50A phosphosite mutants with developmental and protein-synthesis readouts

    PMID:9495316

    Open questions at the time
    • Phenotype mapped in Drosophila ortholog only
    • Did not identify which downstream mRNAs drive the growth difference
  6. 1997 Medium

    Demonstrated redox/context-dependent HRI modulation and confirmed the downstream eIF-2B sequestration mechanism, linking phospho-eIF-2α to a non-functional 15S eIF-2B complex.

    Evidence Reticulocyte lysate translation and eIF-2B exchange assays plus purified HRI kinase assay with PQQ

    PMID:9236156

    Open questions at the time
    • Opposite PQQ effects in lysate vs purified protein left unresolved
    • Physiological redox effector not identified
  7. 1998 High

    Defined HRI as a heme-sensing hemoprotein homodimer with a regulatory heme site whose occupancy directly downregulates kinase activity, explaining how heme availability is coupled to translation.

    Evidence Purification to homogeneity, Soret spectrophotometry, in vitro kinase assay, hemin titration

    PMID:9874252

    Open questions at the time
    • Atomic structure of the heme sites not determined here
    • Did not address heme exchange kinetics in vivo
  8. 1998 High

    Revealed the principal viral countermeasure to the pathway: HSV-1 ICP34.5 binds PP1α to redirect dephosphorylation of eIF-2α and restore synthesis, with a distinct US11 route bypassing phosphorylation.

    Evidence Recombinant HSV mutants, in vitro kinase/phosphatase assays, protein synthesis measurement

    PMID:9696792

    Open questions at the time
    • Did not define the ICP34.5–PP1 binding interface
    • US11 mechanism characterized only as phosphatase-independent
  9. 1999 High

    Extended the kinase repertoire by characterizing PERK/PEK as a tissue-localized eIF-2α kinase requiring a defined catalytic lysine, broadening stress inputs converging on eIF-2α.

    Evidence In vitro kinase assay with recombinant protein, K614A mutagenesis, immunohistochemistry

    PMID:10026192

    Open questions at the time
    • ER-stress activation mechanism not addressed here
    • Substrate specificity vs other kinases not compared
  10. 1999 Medium

    Provided a pharmacological signature distinguishing eIF-2α kinases, showing HRI and PKR resist staurosporine, enabling activity measurement in crude extracts.

    Evidence In vitro kinase assays with purified HRI and PKR plus staurosporine

    PMID:10400313

    Open questions at the time
    • Structural basis of inhibitor resistance not determined
    • Single-lab in vitro characterization
  11. 2000 High

    Connected eIF-2α phosphorylation to a physiological cell-fate output, showing HRI controls protein synthesis and erythroid differentiation through gain- and loss-of-function effects.

    Evidence Retroviral wild-type and dominant-negative HRI in NIH 3T3 and MEL cells, protein synthesis and hemoglobin assays

    PMID:11050009

    Open questions at the time
    • Did not identify the selectively translated effectors of differentiation
    • In vivo erythropoiesis not directly tested here
  12. 2001 High

    Dissected the ICP34.5–PP1 phosphatase mechanism, mapping a C-terminal AlaArg/PP1-binding motif and a separate effector domain both required for eIF-2α dephosphorylation.

    Evidence Site-directed mutagenesis, baculovirus reconstitution in Sf9 cells, phosphatase assay, Co-IP

    PMID:11264356

    Open questions at the time
    • Effector domain's molecular contribution not defined
    • Substrate-targeting determinants on eIF-2α not mapped
  13. 2003 Medium

    Determined that eIF-2α dephosphorylation by ICP34.5 is necessary for interferon resistance but insufficient for replication, separating translation control from other viral functions.

    Evidence HSV-1 γ134.5 truncation mutants, eIF-2α phospho western blot, plaque and interferon assays

    PMID:12941928

    Open questions at the time
    • Additional γ134.5 functions not identified
    • Single-lab genetic study
  14. 2003 Medium

    Defined the spectroscopic/structural character of the HRI regulatory heme, revealing a 6-coordinated Fe(II) heme with anomalous CO kinetics that distinguish it from globins.

    Evidence Stopped-flow CO kinetics and resonance Raman spectroscopy on the mouse HRI N-terminal heme domain

    PMID:12922173

    Open questions at the time
    • Full-length kinase structure not solved
    • Coordinating residues only inferred
  15. 2005 Medium

    Showed both PKR and ER-resident PERK phosphorylate eIF-2α during HSV infection and that γ134.5 suppresses both inputs, integrating ER stress into the viral translation-control conflict.

    Evidence PKR+/+ vs PKR-/- comparison, phospho western blots, pharmacological dissection, global synthesis measurement

    PMID:15650164

    Open questions at the time
    • Relative contribution of each kinase not quantified
    • Mechanism of γ134.5 suppression of PERK not defined
  16. 2005 Medium

    Established that phospho-eIF-2α selectively enhances cellular IRES-mediated translation (PITSLRE, ODC) during G2/M, demonstrating gene-specific translational reprogramming rather than uniform repression.

    Evidence IRES reporter assays in G2/M-synchronized cells with eIF-2α phospho correlation

    PMID:15330758

    Open questions at the time
    • Why viral EMCV/HRV IRESs were unaffected not explained
    • Direct mechanism of IRES enhancement not resolved
  17. 2012 High

    Linked eIF-2α phosphorylation to innate immune amplification, showing PKR-mediated phospho-eIF-2α lowers IκB-α translation to boost NF-κB-driven IFN-β induction.

    Evidence PKR knockdown, eIF-2α S51A mutant, IκB-α mRNA/protein quantitation, IFN-β reporter, cycloheximide

    PMID:22948139

    Open questions at the time
    • Did not address other translationally repressed immune regulators
    • In vivo antiviral consequence not tested
  18. 2018 Medium

    Connected the EIF2S1-ATF4 axis to virus-induced autophagy, showing FMDV VP2 engages HSPB1 to activate this pathway and inhibit AKT-MTOR, promoting replication.

    Evidence Co-IP, phospho/ATF4 western blots, siRNA knockdown, autophagy flux assays

    PMID:29166823

    Open questions at the time
    • Kinase responsible for EIF2S1 phosphorylation here not pinpointed
    • Single-lab study
  19. 2021 Medium

    Placed eIF-2α phosphorylation upstream of SQSTM1-dependent selective autophagy in response to SEC61 inhibition, defining an ISR-controlled autophagic program.

    Evidence ISRIB inhibition, EIF2AK3/PERK knockout, autophagy marker imaging, patient biopsy staining

    PMID:34424124

    Open questions at the time
    • Direct effectors translationally regulated to drive SQSTM1 induction not identified
    • Single-lab study
  20. 2023 High

    Established a transcriptional output of phospho-eIF-2α, showing Ser51 phosphorylation is required for ER-stress-driven nuclear translocation of TFEB/TFE3 and downstream autophagosome/autolysosome formation.

    Evidence EIF2S1 S51A knock-in cells, TFEB/TFE3 immunofluorescence, autophagy flux, proximity ligation assay

    PMID:36719671

    Open questions at the time
    • Mechanistic link between phospho-eIF-2α and TFEB nuclear retention not fully defined
    • Did not identify intermediary translation targets
  21. 2023 Medium

    Identified post-transcriptional and protein-stability control of EIF2S1 itself via miR-3074-5p targeting and lncRNA LCETRL4 binding, with functional consequences for trophoblast biology and AKT-driven drug resistance.

    Evidence Luciferase target validation, RNA-protein binding, ubiquitination/proteasome assays, rescue and functional assays

    PMID:35095099 PMID:38151653

    Open questions at the time
    • Mechanism of LCETRL4-mediated ubiquitination protection not defined
    • Single-lab studies in specific cell contexts
  22. 2025 Medium

    Demonstrated EIF2S1 protein stability is set by USP8-mediated removal of K48-linked polyubiquitin, with degradation control influencing CML drug sensitivity.

    Evidence IP-MS, Co-IP, K48-linkage-specific ubiquitination assay, USP8 shRNA knockdown, tumor growth assays

    PMID:41147744

    Open questions at the time
    • E3 ligase opposing USP8 not identified
    • Single-lab study
  23. 2025 High

    Quantitatively established Ser52 phosphorylation as the dominant translational bottleneck, with active-site editing or kinase removal increasing output, providing engineering routes to enhance translation.

    Evidence CRISPR S52A knock-in, PKR knockout, GADD34/K3L decoy expression, cell-free translation assays (preprint)

    PMID:bio_10.1101_2025.11.16.688697

    Open questions at the time
    • Preprint, not peer-reviewed
    • Did not test whether selective translation outputs are altered by S52A

Open questions

Synthesis pass · forward-looking unresolved questions
  • How phospho-eIF-2α mechanistically links to TFEB/TFE3 nuclear retention and to selective IRES choice, and what defines the full set of selectively translated effectors, remains unresolved.
  • No molecular bridge identified between phospho-eIF-2α and TFEB nuclear retention
  • Determinants of cellular-vs-viral IRES selectivity unknown
  • No structure of the eIF-2α–eIF-2B sequestered complex in the timeline

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 3 GO:0140110 transcription regulator activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-168256 Immune System 1
Partners
EIF2AK1EIF2AK2EIF2AK3EIF2B5PPP1CAUSP8
Complex memberships
eIF-2 (eIF-2α·β·γ complex)

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Phosphorylation of eIF-2alpha (EIF2S1) at serine-51 by eIF-2alpha kinases (PKR, HRI, GCN2) inhibits global protein synthesis by blocking translation initiation; this is the primary mechanism for stress-induced translational downregulation in eukaryotes. Biochemical assays, in vitro phosphorylation, genetic studies in yeast and mammalian cells FASEB Journal High 8903508
1997 Hsp90 interacts with the heme-regulated eIF-2alpha kinase (HRI) co-translationally and is obligatory for HRI to acquire and maintain an activable conformation; geldanamycin disruption of Hsp90-HRI interaction inhibits HRI maturation and autophosphorylation. Coimmunoprecipitation with anti-hsp90 antibody, in vitro translation in rabbit reticulocyte lysate, geldanamycin treatment Journal of Biological Chemistry High 9111082
1998 Purified HRI (heme-regulated eIF-2alpha kinase) is itself a hemoprotein with two distinct heme-binding sites: one stable site and one regulatory site whose heme binding rapidly downregulates HRI kinase activity (Ki ~0.5 µM hemin). HRI functions as a homodimer and directly senses heme availability to regulate eIF-2alpha phosphorylation. Protein purification to homogeneity, spectrophotometry (Soret band), in vitro kinase assay, hemin inhibition titration European Journal of Biochemistry High 9874252
1998 In HSV-1 gamma134.5-null mutant infected cells, eIF-2alpha is phosphorylated by PKR leading to protein synthesis shutoff; wild-type virus expressing ICP34.5 binds protein phosphatase 1alpha and redirects it to dephosphorylate eIF-2alpha, restoring protein synthesis. A compensatory second-site mutation in the US11 gene prevents eIF-2alpha phosphorylation by a distinct, phosphatase-independent mechanism. Recombinant virus construction, in vitro eIF-2alpha kinase and phosphatase assays on cell lysates, protein synthesis measurement Journal of Virology High 9696792
1997 Hsc70 negatively modulates HRI activation in reticulocyte lysate by inhibiting HRI hyper-autophosphorylation; during heat shock, accumulation of denatured proteins sequesters Hsc70, relieving its inhibition of HRI and allowing HRI to phosphorylate eIF-2alpha. In vitro kinase assay in rabbit reticulocyte lysate, Hsc70 add-back experiments, glycerol gradient centrifugation European Journal of Biochemistry Medium 9738893
1997 Hsp90 and its cohorts (FKBP52, p23) remain associated with HRI during heat, N-ethylmaleimide, and heavy metal stress without affecting HRI apparent molecular mass; Hsp90 stabilizes HRI from denaturation under stress, and heme-induced inhibition of HRI activity does not require Hsp90 reassociation. Coimmunoprecipitation, glycerol gradient centrifugation, gel filtration, in vitro reconstitution with purified Hsp90 European Journal of Biochemistry Medium 9208939
1999 PEK (PERK/EIF2AK3), a pancreatic eIF-2alpha kinase, phosphorylates eIF-2alpha in vitro; unlike PKR or HRI, its kinase activity requires the conserved Lys-614 residue but autophosphorylation proceeds independently. PEK co-localizes with somatostatin in pancreatic islet delta cells. In vitro kinase assay with recombinant protein in Sf-9 cells, K614A point mutation, immunohistochemistry, Northern blot Journal of Biological Chemistry High 10026192
2001 The gamma(1)34.5 protein of HSV-1 recruits cellular protein phosphatase 1 (PP1) via its carboxyl terminus, forming a high-molecular-weight complex that specifically dephosphorylates eIF-2alpha. An AlaArg motif in the carboxyl terminus is required for complex formation; PP1-binding domain and an effector domain are both necessary for eIF-2alpha dephosphorylation activity. Mutagenesis of gamma(1)34.5 (Val193Glu, Phe195Leu substitutions; deletion mutants), baculovirus expression in Sf9 cells, eIF-2alpha phosphatase assay, co-immunoprecipitation Journal of Virology High 11264356
2000 Expression of wild-type HRI in NIH 3T3 cells inhibits protein synthesis and causes loss of proliferation; dominant-negative HRI mutants in erythroleukemic MEL cells increase hemoglobin production and proliferative capacity during differentiation, demonstrating HRI's direct role in controlling protein synthesis and erythroid differentiation through eIF-2alpha phosphorylation. Retrovirus-mediated gene transfer of wild-type and dominant-negative HRI mutants into NIH 3T3 and MEL cells, protein synthesis measurement, hemoglobin assay Blood High 11050009
2003 Dephosphorylation of eIF-2alpha mediated by the HSV-1 gamma(1)34.5 protein is required for HSV resistance to interferon but is not sufficient for efficient viral replication, indicating additional functions of gamma(1)34.5 contribute to productive infection. Recombinant virus with gamma(1)34.5 truncation mutations, eIF-2alpha phosphorylation western blot, plaque assay, interferon resistance assay Journal of Virology Medium 12941928
2005 During HSV infection, both PKR and the ER-resident kinase PERK phosphorylate eIF-2alpha; the viral gamma(1)34.5 protein suppresses ER stress-induced eIF-2alpha phosphorylation (from PERK as well as PKR) to maintain protein synthesis during productive infection. PKR+/+ vs PKR-/- cell comparison, western blot for PERK and eIF-2alpha phosphorylation, cycloheximide/phosphonoacetic acid treatment, global protein synthesis measurement Journal of Virology Medium 15650164
2005 Phosphorylation of eIF-2alpha has a permissive effect on PITSLRE IRES-mediated and ornithine decarboxylase IRES-mediated translation during G2/M phase, selectively enhancing internal ribosome entry site activity; this effect was not observed with viral EMCV or HRV IRESs. IRES reporter assays, G2/M cell synchronization, eIF-2alpha phosphorylation measurement by western blot Biochemical Journal Medium 15330758
2012 PKR-mediated phosphorylation of eIF-2alpha is required for maximal IFN-β induction after virus infection or dsRNA transfection; phosphorylation of eIF-2alpha reduces translation of the NF-κB inhibitor IκB-α (increasing its mRNA/protein ratio), thereby enhancing NF-κB activity and IFN-β gene expression. Mutation of eIF-2alpha to prevent phosphorylation (S51A) impaired IFN-β induction. PKR knockdown, eIF-2alpha S51A phosphorylation-deficient mutation, IκB-α mRNA and protein level measurement, IFN-β reporter assay, cycloheximide treatment Journal of Biological Chemistry High 22948139
1997 Mutations at Ser50 (the regulatory phosphorylation site) of Drosophila eIF-2alpha affect developmental rate and body weight: the phosphomimetic Asp substitution causes slow growth and small body size with reduced protein synthesis, while the non-phosphorylatable Ala substitution causes fast growth and larger body size. Transgenic Drosophila with site-directed mutations (S50D, S50A) under hsp70 promoter, developmental phenotype analysis, protein synthesis measurement Gene Expression Medium 9495316
2003 CO binding kinetics and resonance Raman spectroscopy of the N-terminal heme-binding domain of mouse HRI reveal a 6-coordinated Fe(II) heme with very slow CO on/off rates compared to myoglobin, and an almost linear Fe-C-O structure with weak interactions with nearby residues, defining the structural character of the regulatory heme-binding environment in HRI. Stopped-flow CO binding kinetics, resonance Raman spectroscopy Biochimica et Biophysica Acta Medium 12922173
1997 Pyrroloquinoline quinone (PQQ) at high concentrations activates HRI in reticulocyte lysate, increasing eIF-2alpha phosphorylation and inhibiting eIF-2B guanine nucleotide exchange activity; phosphorylated eIF-2alpha sequesters eIF-2B in a 15S complex making it non-functional. Conversely, PQQ directly inhibits purified HRI in vitro, indicating context-dependent (redox-based) modulation. In vitro translation assay in rabbit reticulocyte lysate, eIF-2alpha phosphorylation assay, eIF-2B guanine nucleotide exchange activity assay, purified HRI kinase assay Blood Cells, Molecules & Diseases Medium 9236156
2009 Transcription factor Elk-1 (activated through the ERK pathway) upregulates human HRI expression during stress (lead exposure, heat shock), while MZF-1 with HDAC-1 downregulates HRI expression during hemin treatment; chromatin immunoprecipitation confirmed Elk-1 and co-activator p300 bind the HRI promoter during stress. Chromatin immunoprecipitation (ChIP), promoter-reporter assays, ERK pathway pharmacological inhibition, western blot Biochemical and Biophysical Research Communications Medium 19133234
2018 FMDV capsid protein VP2 interacts with HSPB1 (heat shock protein family B member 1) and activates the EIF2S1-ATF4 signaling pathway, leading to AKT-MTOR inhibition and autophagy induction that facilitates viral replication. Co-immunoprecipitation (VP2-HSPB1 interaction), western blot for EIF2S1 phosphorylation and ATF4, siRNA knockdown, autophagy flux assays Autophagy Medium 29166823
2023 Phosphorylation of EIF2S1 at serine-51 is required for nuclear translocation of the autophagy transcription factors TFEB and TFE3 during ER stress; EIF2S1 phosphorylation-deficient (S51A) cells show defects in autophagosome and autolysosome formation. EIF2AK3/PERK-mediated EIF2S1 phosphorylation and PPP3/calcineurin-mediated dephosphorylation of TFEB/TFE3 are required but insufficient for nuclear retention without EIF2S1 phosphorylation. EIF2S1 S51A knock-in (phosphorylation-deficient A/A cells), immunofluorescence for TFEB/TFE3 localization, autophagy flux assays, adenoviral overexpression of ATF6/XBP1s/ATF4, proximity ligation assay Autophagy High 36719671
2021 EIF2S1 phosphorylation in the integrated stress response (ISR) controls the autophagic response to mycolactone-induced SEC61 inhibition; ISRIB (ISR inhibitor) reversed SQSTM1 upregulation and reduced autophagy initiation markers (RB1CC1, WIPI2, LC3B puncta). EIF2AK3 (PERK) knockout reduced mycolactone-induced SQSTM1 induction, placing EIF2S1 phosphorylation upstream of SQSTM1-dependent selective autophagy. ISRIB pharmacological inhibition, EIF2AK3 knockout cells, SQSTM1 and autophagy marker immunofluorescence, Buruli ulcer patient biopsy immunostaining, cell viability assays Autophagy Medium 34424124
2025 EIF2S1 phosphorylation at Ser52 is the dominant bottleneck for translation in human cell-derived cell-free translation extracts; genome editing of EIF2S1 to S52A (non-phosphorylatable) or knockout of EIF2AK2 (PKR) both improve translational output. Expression of GADD34 (PPP1R15A) or viral K3L decoy rescues translation in cell types not amenable to genome editing. CRISPR genome editing (S52A knock-in, PKR knockout in Expi293F cells), piggyBac-mediated stable expression of GADD34/K3L in iPSCs and primary fibroblasts, cell-free translation assays bioRxivpreprint High bio_10.1101_2025.11.16.688697
2025 The deubiquitinase USP8 stabilizes EIF2S1 protein by removing K48-linked polyubiquitin chains, preventing proteasomal degradation; USP8 knockdown suppresses EIF2S1 expression and sensitizes CML cells to tyrosine kinase inhibitors. Immunoprecipitation-mass spectrometry, molecular docking, Co-IP, ubiquitination assay (K48-linkage specificity), USP8 knockdown with shRNA, in vitro and in vivo tumor growth assays FEBS Journal Medium 41147744
2023 LncRNA LCETRL4 binds EIF2S1 protein and stabilizes it by reducing ubiquitin-proteasome degradation; elevated LCETRL4 increases EIF2S1 levels, activates AKT signaling, and promotes EGFR-TKI resistance in NSCLC cells. RNA-protein interaction assay, ubiquitination and proteasome inhibition assays, western blot, cell viability assays Signal Transduction and Targeted Therapy Medium 35095099
1999 HRI and PKR are resistant to staurosporine at concentrations (0.25 µM) that completely inhibit most serine/threonine kinases, establishing a pharmacological distinction useful for measuring eIF-2alpha kinase activity in crude cellular extracts. In vitro kinase assay with purified HRI and PKR, phosphorylation of eIF-2 and synthetic peptide substrate in presence of staurosporine Cellular Signalling Medium 10400313
2023 miR-3074-5p directly targets EIF2S1 mRNA and reduces EIF2S1 protein expression in trophoblast cells; EIF2S1 acts as an upstream regulator of GDF15 maturation/secretion, and reduced EIF2S1 leads to decreased GDF15, impairing trophoblast proliferation, migration, and invasion. Luciferase reporter for miRNA target validation, EIF2S1 overexpression rescue experiments, GDF15 measurement, HTR8/SVneo cell functional assays (migration, invasion, proliferation) Reproductive Sciences Medium 38151653

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 The eIF-2alpha kinases and the control of protein synthesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 254 8903508
2005 Herpes simplex virus 1 infection activates the endoplasmic reticulum resident kinase PERK and mediates eIF-2alpha dephosphorylation by the gamma(1)34.5 protein. Journal of virology 132 15650164
1998 The second-site mutation in the herpes simplex virus recombinants lacking the gamma134.5 genes precludes shutoff of protein synthesis by blocking the phosphorylation of eIF-2alpha. Journal of virology 117 9696792
1997 Hsp90 is obligatory for the heme-regulated eIF-2alpha kinase to acquire and maintain an activable conformation. The Journal of biological chemistry 90 9111082
2001 Changes in the phosphorylation of initiation factor eIF-2alpha, elongation factor eEF-2 and p70 S6 kinase after transient focal cerebral ischaemia in mice. Journal of neurochemistry 87 11520898
2018 Foot-and-mouth disease virus capsid protein VP2 activates the cellular EIF2S1-ATF4 pathway and induces autophagy via HSPB1. Autophagy 79 29166823
2012 Protein kinase PKR amplification of interferon β induction occurs through initiation factor eIF-2α-mediated translational control. The Journal of biological chemistry 78 22948139
2005 Regulation of the cell-cycle-dependent internal ribosome entry site of the PITSLRE protein kinase: roles of Unr (upstream of N-ras) protein and phosphorylated translation initiation factor eIF-2alpha. The Biochemical journal 76 15330758
1997 Cloning and characterization of a cDNA encoding a protein synthesis initiation factor-2alpha (eIF-2alpha) kinase from Drosophila melanogaster. Homology To yeast GCN2 protein kinase. The Journal of biological chemistry 69 9139706
1996 Upregulated expression of the genes encoding translation initiation factors eIF-4E and eIF-2alpha in transformed cells. Cancer letters 64 8603359
1998 Heme-regulated eIF-2alpha kinase purifies as a hemoprotein. European journal of biochemistry 60 9874252
1999 Characterization of a mutant pancreatic eIF-2alpha kinase, PEK, and co-localization with somatostatin in islet delta cells. The Journal of biological chemistry 55 10026192
2018 Sirtuin-1 (SIRT1) stimulates growth-plate chondrogenesis by attenuating the PERK-eIF-2α-CHOP pathway in the unfolded protein response. The Journal of biological chemistry 52 29653943
1997 Molecular cloning, characterization and localization of PfPK4, an eIF-2alpha kinase-related enzyme from the malarial parasite Plasmodium falciparum. The Biochemical journal 47 9371731
2019 PERK/eIF-2α/CHOP Pathway Dependent ROS Generation Mediates Butein-induced Non-small-cell Lung Cancer Apoptosis and G2/M Phase Arrest. International journal of biological sciences 46 31360107
2018 ER-stress regulates macrophage polarization through pancreatic EIF-2alpha kinase. Cellular immunology 46 30594305
2003 Expression of translation initiation factor eIF-2alpha is increased in benign and malignant melanocytic and colonic epithelial neoplasms. Cancer 44 12942578
1998 Isolation of the gene encoding the Drosophila melanogaster homolog of the Saccharomyces cerevisiae GCN2 eIF-2alpha kinase. Genetics 43 9649537
2003 Dephosphorylation of eIF-2alpha mediated by the gamma(1)34.5 protein of herpes simplex virus type 1 is required for viral response to interferon but is not sufficient for efficient viral replication. Journal of virology 38 12941928
1997 The role of the 90-kDa heat-shock protein and its associated cohorts in stabilizing the heme-regulated eIF-2alpha kinase in reticulocyte lysates during heat stress. European journal of biochemistry 37 9208939
2001 Upregulation of iNOS expression and phosphorylation of eIF-2alpha are paralleled by suppression of protein synthesis in rat hypothalamus in a closed head trauma model. Journal of neurotrauma 35 11526986
2000 Regulation of hemoglobin synthesis and proliferation of differentiating erythroid cells by heme-regulated eIF-2alpha kinase. Blood 35 11050009
2022 LncRNAs LCETRL3 and LCETRL4 at chromosome 4q12 diminish EGFR-TKIs efficiency in NSCLC through stabilizing TDP43 and EIF2S1. Signal transduction and targeted therapy 34 35095099
2021 Nox4 Promotes RANKL-Induced Autophagy and Osteoclastogenesis via Activating ROS/PERK/eIF-2α/ATF4 Pathway. Frontiers in pharmacology 34 34650437
2001 AlaArg motif in the carboxyl terminus of the gamma(1)34.5 protein of herpes simplex virus type 1 is required for the formation of a high-molecular-weight complex that dephosphorylates eIF-2alpha. Journal of virology 33 11264356
2023 Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress. Autophagy 31 36719671
1998 Evidence that Hsc70 negatively modulates the activation of the heme-regulated eIF-2alpha kinase in rabbit reticulocyte lysate. European journal of biochemistry 29 9738893
2009 Eukaryotic initiation factors (eIF) 2alpha and 4E expression, localization, and phosphorylation in brain tumors. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 28 19188486
2001 Comparison of the eIF-2alpha homologous proteins of seven ranaviruses (Iridoviridae). Virus genes 28 11778703
2016 Stress Granule Induction after Brain Ischemia Is Independent of Eukaryotic Translation Initiation Factor (eIF) 2α Phosphorylation and Is Correlated with a Decrease in eIF4B and eIF4E Proteins. The Journal of biological chemistry 22 27836976
2024 Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis. Journal of advanced research 17 39103048
2015 Hepsin inhibits CDK11p58 IRES activity by suppressing unr expression and eIF-2α phosphorylation in prostate cancer. Cellular signalling 17 25576733
2021 Inhibition of the SEC61 translocon by mycolactone induces a protective autophagic response controlled by EIF2S1-dependent translation that does not require ULK1 activity. Autophagy 14 34424124
2021 Dysregulation of Translation Factors EIF2S1, EIF5A and EIF6 in Intestinal-Type Adenocarcinoma (ITAC). Cancers 14 34830804
2005 Mechanical force activates eIF-2alpha phospho-kinases in fibroblast. Biochemical and biophysical research communications 13 15781241
2003 CO binding study of mouse heme-regulated eIF-2alpha kinase: kinetics and resonance Raman spectra. Biochimica et biophysica acta 12 12922173
1997 Mutations at the Ser50 residue of translation factor eIF-2alpha dominantly affect developmental rate, body weight, and viability of Drosophila melanogaster. Gene expression 12 9495316
2024 Human umbilical cord mesenchymal stem cells improve the ovarian function through oxidative stress-mediated PERK/eIF-2α/ATF4/CHOP signaling in premature ovarian insufficiency mice. Molecular biology reports 9 39724303
2023 Acetylshikonin induces apoptosis through the endoplasmic reticulum stress-activated PERK/eIF2α /CHOP axis in oesophageal squamous cell carcinoma. Journal of cellular and molecular medicine 9 37929884
2002 Lead exposure and heat shock inhibit cell proliferation in human HeLa and K562 cells by inducing expression and activity of the heme-regulated eIF-2alpha kinase. Journal of biochemistry, molecular biology, and biophysics : JBMBB : the official journal of the Federation of Asian and Oceanian Biochemists and Molecular Biologists (FAOBMB) 9 14972793
2022 Anti-Growth, Anti-Angiogenic, and Pro-Apoptotic Effects by CX-4945, an Inhibitor of Casein Kinase 2, on HuCCT-1 Human Cholangiocarcinoma Cells via Control of Caspase-9/3, DR-4, STAT-3/STAT-5, Mcl-1, eIF-2α, and HIF-1α. International journal of molecular sciences 8 35683032
2019 Salubrinal, a novel inhibitor of eIF-2α dephosphorylation, promotes erythropoiesis at early stage targeted by ufmylation pathway. Journal of cellular physiology 8 30908643
2021 Aerobic Exercise Training and In Vivo Akt Activation Counteract Cancer Cachexia by Inducing a Hypertrophic Profile through eIF-2α Modulation. Cancers 7 35008195
2009 Stress-induced overexpression of the heme-regulated eIF-2alpha kinase is regulated by Elk-1 activated through ERK pathway. Biochemical and biophysical research communications 7 19133234
1997 The effects of pyrroloquinoline quinone on heme-regulated eIF-2alpha kinase and eIF-2B activities in eukaryotic protein synthesis. Blood cells, molecules & diseases 7 9236156
2010 Apolipoprotein E-Deficient Lipoproteins Induce Foam Cell Formation by Activation of PERK-EIF-2α Signaling Cascade. Journal of bioanalysis & biomedicine 6 21552349
1999 Resistance of initiation factor 2 (eIF-2alpha) kinases to staurosporine: an approach for assaying the kinases in crude extracts. Cellular signalling 6 10400313
1999 Differential phosphorylation of PKR associates with deregulation of eIF-2alpha phosphorylation and altered growth characteristics in 3T3-F442A fibroblasts. Molecular and cellular biochemistry 6 10497873
2023 MiR-3074-5p Regulates Trophoblasts Function via EIF2S1/GDF15 Pathway in Recurrent Miscarriage. Reproductive sciences (Thousand Oaks, Calif.) 5 38151653
2024 EIF2S1 Silencing Impedes Neuroblastoma Development Through GPX4 Inactivation and Ferroptosis Induction. International journal of genomics 4 39465005
2024 Vitamin E Mitigates Apoptosis in Ovarian Granulosa Cells by Inhibiting Zearalenone-Induced Activation of the PERK/eIF-2α/ATF4/Chop Signaling Pathway. Journal of agricultural and food chemistry 4 39610174
2022 Knockdown of ENTPD5 inhibits tumor metastasis and growth via regulating the GRP78/p-eIF-2α/CHOP pathway in serous ovarian cancer. Journal of ovarian research 4 35668504
2023 Epigallocatechin-3-Gallate Reduces Cd-Induced Developmental Toxicity of Bodysize in Caenorhabditis elegans via the PEK-1/eIF-2α/ATF-4 Pathway. Molecules (Basel, Switzerland) 3 37687170
2025 The GCN-2/eIF-2α/ATF-4 signaling pathway is involved in C. elegans defense against Salmonella enterica infection. Virulence 1 41144701
2025 The deubiquitinating enzyme USP8 promotes tyrosine kinase inhibitors resistance in chronic myeloid leukemia by stabilizing EIF2S1 protein. The FEBS journal 1 41147744
2023 Important roles of heme-regulated eIF-2α kinase in cadmium-induced glycolysis under acute exposure. Environmental science and pollution research international 1 37438509
2012 [Cellular stress and eIF-2alpha kinase]. Journal of UOEH 1 23270257
2026 miR-20b-5p inhibits inflammation-induced endoplasmic reticulum stress through EIF2S1 and promotes osteogenic differentiation of bone marrow mesenchymal stem cells. Biochemistry and cell biology = Biochimie et biologie cellulaire 0 41791093
2026 Inhibition of EIF2S1 expression regulates the PI3K/AKT pathway to mediate apoptosis in glioma cells: an in vitro study. Neurogenetics 0 42213196
2025 EIF2S1 in Urinary Extracellular Vesicles as a Novel Diagnostic Marker for Bladder Cancer. Cancer medicine 0 40365898
2025 USP8-EIF2S1 signaling enhances CML cell survival under TKI-induced stress. The FEBS journal 0 41454439

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