Affinage

EIF2S1

Eukaryotic translation initiation factor 2 subunit 1 · UniProt P05198

Round 2 corrected
Length
315 aa
Mass
36.1 kDa
Annotated
2026-04-28
130 papers in source corpus 38 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2S1 (eIF2α) is the regulatory subunit of the heterotrimeric translation initiation factor eIF2, serving as the central integrator of the integrated stress response (ISR) through phosphorylation of its Ser51 residue by four stress-activated kinases—HRI, PKR, PERK, and GCN2—which converts eIF2 from a substrate into a competitive inhibitor of the guanine-nucleotide exchange factor eIF2B, thereby globally repressing cap-dependent translation while selectively promoting translation of uORF-containing mRNAs such as ATF4 (PMID:6928683, PMID:3352609, PMID:9472020, PMID:9874252, PMID:9819435). Phospho-eIF2α binds the regulatory subcomplex of eIF2B with increased affinity, sequestering it from its catalytic subcomplex and blocking GDP–GTP exchange needed for ternary complex (eIF2·GTP·Met-tRNAi) regeneration; cryo-EM structures show this inhibition arises from enhanced affinity rather than large-scale conformational change, and the small molecule ISRIB antagonizes this inhibition allosterically at eIF2B (PMID:9472020, PMID:31086188, PMID:33220178). Dephosphorylation is mediated by PP1 complexes directed to the ER by GADD34 or constitutive CReP, completing a feedback loop essential for translational recovery (PMID:12556489, PMID:12941928). Beyond translational control, Ser51 phosphorylation nucleates stress granule assembly through downstream recruitment of TIA-1/TIAR and is required for nuclear translocation of autophagy transcription factors TFEB/TFE3 during ER stress (PMID:10613902, PMID:36719671).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1980 High

    Establishing that a dsRNA-activated kinase phosphorylates the α subunit of eIF2 and that this phosphorylation inhibits translation initiation by sequestering limiting eIF2B resolved the molecular basis of interferon-mediated translational shutoff.

    Evidence In vitro kinase assay with purified reticulocyte lysate fractions; eIF2B rescue experiment

    PMID:6928683

    Open questions at the time
    • Identity and cloning of the kinase not yet achieved
    • Phosphorylation site not mapped
  2. 1983 High

    Demonstrating that eIF2α phosphorylation permits 48S preinitiation complex formation but blocks 60S subunit joining revealed the precise step in initiation that is inhibited, linking phospho-eIF2α to eIF2B-dependent GDP–GTP exchange.

    Evidence Sucrose gradient sedimentation of initiation complexes in reticulocyte lysate treated with dsRNA; 2-aminopurine rescue

    PMID:6557115

    Open questions at the time
    • Identity of the phosphorylated serine residue not yet mapped
    • Whether additional kinases target the same site was unknown
  3. 1988 High

    Mapping the regulatory phosphorylation site to Ser51 (not Ser48) via site-directed mutagenesis established the single residue whose modification controls the entire ISR translational switch.

    Evidence S51A and S48A mutagenesis of human EIF2S1 cDNA; in vitro kinase assays with HRI and PKR; 2D gel electrophoresis

    PMID:3352609

    Open questions at the time
    • Whether Ser48 plays any auxiliary role was unclear
    • Number of kinases converging on Ser51 not yet fully enumerated
  4. 1986 High

    Showing that adenovirus VAI RNA and influenza virus suppress the eIF2α kinase to evade translational shutoff established viral subversion of eIF2α phosphorylation as a general immune-evasion strategy.

    Evidence Cell-free kinase assays with purified VAI RNA; cell-free translation with influenza co-infection extracts; eIF2B add-back rescue

    PMID:3698097 PMID:3785177

    Open questions at the time
    • Whether all virus families use this mechanism was unknown
    • Direct structural basis of VAI RNA inhibition of PKR unresolved
  5. 1998 High

    Biochemical dissection of eIF2B into regulatory and catalytic subcomplexes, combined with discovery of the ER-resident kinase PERK (PEK/EIF2AK3) and characterization of HRI as a heme-sensing homodimer, defined the full kinase–substrate–exchange factor axis of the ISR.

    Evidence Purified yeast eIF2B subcomplexes in nucleotide-exchange and affinity-binding assays; recombinant PEK kinase assay and yeast GCN2 complementation; HRI purification with Soret spectroscopy

    PMID:9472020 PMID:9819435 PMID:9874252

    Open questions at the time
    • Structural basis of phospho-eIF2α recognition by eIF2B regulatory subcomplex unresolved
    • Whether heme regulation of HRI operates identically in non-erythroid cells unknown
  6. 1999 High

    Demonstrating that phospho-eIF2α (S51D) is necessary and sufficient for stress granule assembly, acting upstream of TIA-1/TIAR, extended the function of EIF2S1 phosphorylation beyond translational repression to mRNP remodeling and granule biology.

    Evidence Phosphomimetic S51D and non-phosphorylatable S51A transfection; immunofluorescence for SG markers; dominant-negative TIA-1

    PMID:10613902

    Open questions at the time
    • How phospho-eIF2α triggers TIA-1 aggregation mechanistically was unknown
    • Whether SG assembly is a cause or consequence of translational arrest was unresolved
  7. 1995 High

    The finding that non-phosphorylatable S51A eIF2α causes malignant transformation of NIH 3T3 cells established eIF2α phosphorylation as a tumor-suppressive checkpoint.

    Evidence Stable S51A transfection; focus-formation assay; Western blot for eIF2α phosphorylation

    PMID:7641700

    Open questions at the time
    • Which downstream targets mediate tumor suppression not identified
    • Whether this applies in vivo (xenograft or transgenic models) not tested
  8. 2003 High

    Identification of GADD34 and HSV-1 γ134.5 as PP1 targeting subunits that dephosphorylate eIF2α at the ER defined the feedback dephosphorylation arm of the ISR and a viral counterstrategy exploiting the same phosphatase.

    Evidence Structure-function analysis of GADD34 deletion mutants; GFP imaging; PP1 co-IP; in vitro phosphatase reconstitution with γ134.5 mutants; viral growth assays

    PMID:12556489 PMID:12941928

    Open questions at the time
    • Whether CReP uses the same structural mechanism as GADD34 was not fully dissected
    • Relative contributions of GADD34 vs. CReP to basal dephosphorylation in different tissues unknown
  9. 2010 High

    Discovering that eIF5 functions as a GDP dissociation inhibitor (GDI) for eIF2, independent of its GAP activity, and participates in the phospho-eIF2α inhibitory complex on eIF2B revealed an additional layer of regulation in the ISR.

    Evidence In vitro nucleotide-binding and GDI assays with purified yeast proteins; eIF5 mutagenesis; eIF2B inhibition assays

    PMID:20485439

    Open questions at the time
    • Structural basis of eIF5 GDI activity not determined
    • Whether mammalian eIF5 has identical GDI activity not confirmed
  10. 2019 High

    Cryo-EM structures of eIF2–eIF2B and phospho-eIF2α–eIF2B complexes showed that translational control arises from increased affinity of phospho-eIF2α for eIF2B rather than from a large conformational switch, providing the structural framework for understanding ISRIB antagonism.

    Evidence Cryo-EM of both complexes; in vitro nucleotide-exchange assays

    PMID:31086188

    Open questions at the time
    • Dynamic intermediate states during exchange not captured
    • How eIF2B decamer symmetry influences inhibition not fully resolved
  11. 2020 High

    Discovery of the OMA1–DELE1–HRI mitochondrial stress relay and viral competitive inhibitors of the phospho-eIF2α–eIF2B interaction expanded the ISR input repertoire and revealed that phospho- and unphospho-eIF2α contacts with eIF2B can be selectively antagonized.

    Evidence Genome-wide CRISPRi screen; DELE1–HRI co-IP; OMA1/DELE1 KO; in vitro competition binding with viral proteins; cell-based translation assays

    PMID:32132706 PMID:32132707 PMID:32690955

    Open questions at the time
    • Whether additional mitochondrial signals feed through DELE1–HRI is unknown
    • Structural basis of viral protein mimicry of eIF2α not determined
  12. 2020 High

    Structural and biochemical work showed that ISRIB allosterically opposes phospho-eIF2α binding to eIF2B by remodeling the ISRIB-binding pocket, explaining the drug's ability to rescue ISR-driven translational repression and diseases of eIF2 complex assembly such as MEHMO syndrome.

    Evidence Cryo-EM of eIF2B with eIF2αP and ISRIB; nucleotide-exchange assay; mutagenesis; ISRIB rescue of MEHMO patient iPSCs

    PMID:31836389 PMID:33220178

    Open questions at the time
    • In vivo pharmacokinetics and tissue-specific efficacy of ISRIB incompletely characterized
    • Whether ISRIB equally rescues all four kinase arms of the ISR not established
  13. 2023 High

    Demonstrating that EIF2S1 Ser51 phosphorylation is required for TFEB/TFE3 nuclear translocation during ER stress linked the ISR to transcriptional activation of autophagy, broadening eIF2α function beyond translational control.

    Evidence EIF2S1-S51A/A knock-in cells; TFEB/TFE3 immunofluorescence; autophagy flux; adenoviral rescue with ATF6/XBP1s/ATF4

    PMID:36719671

    Open questions at the time
    • Whether eIF2α phosphorylation directly or indirectly promotes calcineurin-mediated TFEB dephosphorylation is unresolved
    • Tissue-specific contributions of this pathway to autophagy in vivo not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Unresolved questions include the structural basis by which phospho-eIF2α nucleates stress granule assembly, the in vivo tissue-specific contributions of the four eIF2α kinases to selective mRNA translation, and whether non-canonical translational stimulation by phospho-eIF2α (as observed in axons) represents a widespread alternative signaling mode.
  • No structural model of how phospho-eIF2α reorganizes mRNP granules
  • Quantitative in vivo contribution of each kinase arm to ATF4-class selective translation unknown
  • Non-canonical local translation stimulation by phospho-eIF2α reported only in axonal context

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 6 GO:0098772 molecular function regulator activity 4
Localization
GO:0005829 cytosol 4 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-392499 Metabolism of proteins 8 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-8953854 Metabolism of RNA 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
EIF2AK1EIF2AK2EIF2AK3EIF2AK4EIF2B1EIF2S2EIF2S3PPP1CA
Complex memberships
43S preinitiation complexeIF2 heterotrimer (eIF2α·eIF2β·eIF2γ)eIF2·GTP·Met-tRNAi ternary complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1980 Double-stranded RNA activates a latent cytoplasmic kinase (dsI/PKR) that phosphorylates the alpha subunit of eIF-2 (EIF2S1) and inhibits protein chain initiation; the phosphorylation can be reversed by eIF-2B, demonstrating that functional eIF-2B is limiting when eIF-2α is phosphorylated. In vitro kinase assay with purified reticulocyte lysate fractions; partial purification of dsI kinase; inhibition reversal by exogenous eIF-2B Proceedings of the National Academy of Sciences of the United States of America High 6928683
1983 Phosphorylation of eIF-2α by dsRNA-activated kinase allows formation of a 48S initiation complex (40S + Met-tRNAf + mRNA + eIF-2·GDP·αP) but blocks joining of the 60S subunit; eIF-2B-mediated dissociation of eIF-2·GDP is required for 80S formation and is impaired when eIF-2α is phosphorylated. Sucrose gradient sedimentation of initiation complexes in reticulocyte lysate pre-treated with dsRNA; rescue by 2-aminopurine The Journal of biological chemistry High 6557115
1986 Adenovirus VAI RNA prevents activation of the interferon-induced eIF-2α kinase (PKR/dsI), thereby blocking phosphorylation of EIF2S1 and antagonizing the antiviral translational shutdown. Cell-free kinase assay: purified VAI RNA added to extracts of interferon-treated cells; inhibition of dsRNA-dependent kinase activity measured Cell High 3698097
1986 Influenza virus suppresses the eIF-2α kinase that phosphorylates EIF2S1, allowing selective translation of influenza mRNAs; a limiting pool of functional eIF-2B explains why reduced eIF-2α kinase activity favors translation of stronger (influenza) mRNAs over weaker ones. Cell-free translation assays with extracts from doubly infected cells; addition of exogenous eIF-2B or dsRNA to modulate kinase/eIF-2B activity Molecular and cellular biology High 3785177
1987 Phosphorylation of eIF-2α prevents eIF-2B-mediated dissociation of eIF-2·GDP from the 60S ribosomal subunit of complete initiation complexes, causing accumulation of half-mer polysomes; exogenous eIF-2B rescues this block. Polysome sedimentation in reticulocyte lysate; Western analysis of ribosomal fractions; rescue with exogenous eIF-2B The Journal of biological chemistry High 3646234
1988 Serine-51 (not Ser-48) of the EIF2S1 alpha subunit is the site phosphorylated by eIF-2 kinases (HRI and PKR) that leads to inhibition of protein synthesis; Ser51→Ala substitution abolishes phosphorylation, whereas Ser48→Ala has no effect. Site-directed mutagenesis of human EIF2S1 cDNA; in vitro transcription/translation; 2D gel electrophoresis; kinase assay with HRI and PKR Molecular and cellular biology High 3352609
1995 Expression of a non-phosphorylatable EIF2S1 mutant (S51A) causes malignant transformation of NIH 3T3 cells, demonstrating that eIF-2α phosphorylation is required for suppression of cell proliferation and that dominant-negative PKR transforms cells by abolishing EIF2S1 phosphorylation. Stable transfection of NIH 3T3 cells with S51A eIF-2α mutant; focus-formation assay; Western blot for eIF-2α phosphorylation The EMBO journal High 7641700
1998 eIF2B has two functionally distinct subcomplexes: a regulatory subcomplex (GCN3/GCD7/GCD2) that binds phosphorylated EIF2S1 (eIF2αP) with higher affinity but lacks nucleotide-exchange activity, and a catalytic subcomplex (GCD1/GCD6) with nucleotide-exchange activity not inhibited by eIF2αP. Binding of eIF2αP to the regulatory subcomplex prevents productive interaction with the catalytic subcomplex, thereby inhibiting GDP–GTP exchange. In vitro nucleotide-exchange assay with purified yeast eIF2B; affinity-binding assay with eIF2 and eIF2αP; regulatory mutations in GCN3 and GCD7 characterized Genes & development High 9472020
1998 The heme-regulated eIF-2α kinase (HRI) purifies as a hemoprotein with two distinct heme-binding sites: one stable site and one labile regulatory site whose occupation by heme rapidly inhibits HRI kinase activity (Ki ~0.5 µM); HRI functions as a homodimer and is both an autokinase and an eIF-2α kinase. Purification of HRI to homogeneity; Soret absorption spectroscopy; in vitro autokinase and eIF-2α kinase assays; hemin titration; sedimentation analysis European journal of biochemistry High 9874252
1999 EIF2S1 (eIF2α) phosphorylation at Ser51 initiates stress granule (SG) assembly: a phosphomimetic S51D mutant induces SG formation whereas the non-phosphorylatable S51A mutant prevents it; the RNA-binding proteins TIA-1 and TIAR act downstream of EIF2S1 phosphorylation to sequester untranslated mRNAs at SGs. Transfection of phosphomimetic (S51D) and non-phosphorylatable (S51A) EIF2S1 mutants; immunofluorescence microscopy for SG markers; dominant-negative TIA-1 lacking RNA-binding domains The Journal of cell biology High 10613902
1999 Serine-48 of EIF2S1 is required for high-affinity interaction between phospho-eIF2α (Ser51-P) and eIF2B; S48A mutation reduces the ability of phospho-eIF2α to sequester eIF2B and inhibit nucleotide exchange, without affecting the extent of Ser51 phosphorylation itself. Baculovirus expression of wild-type and S48A EIF2S1; in vitro eIF2B activity assay; eIF2α(P)–eIF2B complex formation measured in reticulocyte lysate Biochemistry Medium 10563826
2001 During apoptosis, caspase-3, -7, and -8 cleave PKR at Asp251, releasing the kinase domain which then phosphorylates EIF2S1 at Ser51 and inhibits translation; this caspase-dependent PKR activation and EIF2S1 phosphorylation is an early event coinciding with caspase activation. Site-directed mutagenesis of PKR caspase cleavage site; recombinant caspase cleavage assay in vitro; overexpression of truncated PKR kinase domain; reporter mRNA translation assay The Journal of biological chemistry High 11555640
2001 The glycoprotein p67 protects EIF2S1 from phosphorylation (POEP activity) through its lysine-rich domain I (residues 36–44); substitution of this domain abolishes POEP activity, while mutation of the acidic domain does not affect it. C-terminal deletion and internal substitution mutants of rat p67 expressed in KRC-7 cells; Western blot for eIF-2α phosphorylation; reporter gene translation assays Biochimie Medium 11728629
2003 HSV-1 γ134.5 protein recruits protein phosphatase 1 (PP1) via its PP1-binding motif (KVRF) and an effector AlaArg motif to form a high-molecular-weight complex that dephosphorylates EIF2S1 at Ser51, thereby counteracting PKR-mediated translational shutoff; this dephosphorylation is required for viral resistance to interferon but is not sufficient for efficient viral replication. γ134.5 deletion and point mutants expressed in Sf9 cells via baculovirus; in vitro eIF-2α phosphatase assay; PP1 co-immunoprecipitation; viral growth assays in interferon-treated cells Journal of virology High 11264356 12941928
2003 GADD34 targets protein phosphatase 1α to the endoplasmic reticulum and promotes dephosphorylation of EIF2S1 in cells; a bipartite C-terminal domain (PP1-binding motif KVRF + RARA sequence) is required for PP1 binding, and the N-terminal 180 residues direct ER localization. Structure-function analysis of GADD34 deletion mutants; GFP-GADD34 imaging; Western blot for eIF-2α phosphorylation after thapsigargin/tunicamycin treatment; PP1 co-immunoprecipitation Molecular and cellular biology High 12556489
2007 HCV and CSFV IRES domain II facilitates eIF5-induced GTP hydrolysis and eIF2·GDP release from 48S initiation complexes during 80S ribosome assembly; this function requires the bent conformation of domain II and two conserved RNA motifs (apical hairpin loop and loop E). In vitro ribosome assembly assays with purified components; functional deletion and loop mutants of IRES domain II; sucrose gradient sedimentation The EMBO journal High 17255934
2010 eIF5 acts as a GDP dissociation inhibitor (GDI) for EIF2S1·GDP, stabilizing the GDP-bound state independently of its GTPase-accelerating (GAP) function; eIF5 is also a critical component of the eIF2αP regulatory complex that inhibits eIF2B, and conserved eIF5 residues required for GDI activity are identified. In vitro nucleotide-binding and GDI assays with purified yeast proteins; mutagenesis of conserved eIF5 residues; eIF2B inhibition assays; genetic analyses Nature High 20485439
2011 eIF2γ domain III contacts 18S rRNA helix h44 on the 40S ribosomal subunit via directed hydroxyl radical probing; this domain is important for ribosome binding rather than Met-tRNAi binding, which is mediated primarily through eIF2γ contacts with the acceptor stem of Met-tRNAi — a fundamental difference from the analogous domain III in the elongation factor EF-Tu. Directed hydroxyl radical probing of yeast eIF2 on the ribosome; biochemical binding assays for ribosome vs. Met-tRNAi interaction; domain III mutant analysis Nature structural & molecular biology High 22002225
2011 SIRT1 physically interacts with EIF2S1 (eIF2α); loss of SIRT1 increases EIF2S1 phosphorylation and delays downstream ISR signaling (CHOP and GADD34 induction) and post-stress translation recovery; SIRT1 co-immunoprecipitates with eIF2α phosphatase complex components GADD34 and CReP. Co-immunoprecipitation; Western blot for pEIF2S1; siRNA knockdown of SIRT1; polysome profiling Scientific reports Medium 22355666
2014 EIF2S1 phosphorylation at Ser51 is indispensable for efficient 43S preinitiation complex formation; human eIF2-GTP-Met-tRNAi ternary complex and eIF3 cooperate to stabilize the 43S PIC, with TC recruitment increasing eIF1 affinity and indirectly enhancing eIF1A binding. Fluorescence anisotropy binding assays; reconstituted human 43S PIC with purified components; systematic measurement of affinities of eIF1, eIF1A, eIF3j The Journal of biological chemistry High 25246524
2015 OLA1 (an Obg-family GTPase) inhibits protein synthesis and promotes the integrated stress response by binding EIF2S1/eIF2 and hydrolyzing GTP to interfere with ternary complex (eIF2-GTP-Met-tRNAi) formation, representing a novel mechanism distinct from eIF2α phosphorylation. Co-immunoprecipitation; in vitro GTPase assay; ternary complex formation assay; OLA1 depletion and overexpression with polysome profiling; ATF4 and CHOP induction Scientific reports Medium 26283179
2015 Post-translational modifications of EIF2S1 (eIF2α) cluster at subunit interfaces and regulate interactions between eIF2 and eIF2B; eIF2β is the most labile subunit of the eIF2 trimer; the ternary complex (eIF2:GTP:Met-tRNAi) constrains conformational dynamics of all three subunits relative to apo-eIF2, where eIF2α is highly mobile. Native mass spectrometry of intact yeast eIF2 complex; comparative chemical cross-linking of ternary complex vs. apo-eIF2; novel PTM identification by LC-MS/MS Cell discovery High 27462419
2015 Cdc123, an ATP-grasp protein, promotes eIF2 complex assembly by binding domain III of eIF2γ; conserved residues contacting ATP-Mg2+ are essential for Cdc123 to support eIF2 assembly and cell viability. Crystal structure of S. pombe Cdc123 alone and bound to S. cerevisiae eIF2γ domain III; ATP-binding mutagenesis; in vivo complementation assay; biochemical eIF2 assembly assay Structure High 26211610
2018 FMDV capsid protein VP2 activates the EIF2S1-ATF4 pathway by interacting with HSPB1, leading to autophagy induction and enhanced viral replication. Co-immunoprecipitation of VP2 with HSPB1; Western blot for pEIF2S1 and ATF4; ATF4/HSPB1 knockdown; autophagy markers (LC3, p62); FMDV replication assay Autophagy Medium 29166823
2018 In axons, Sema3A induces a non-canonical burst of local translation by stimulating PERK-dependent EIF2S1 phosphorylation that, contrary to canonical signaling, does not globally repress translation but instead selectively promotes it via differential eIF2B activity mediated by protein phosphatase 1; proteomics identified 75 axonally translated proteins controlled by this pathway. Axon isolation; quantitative phospho-proteomics; PERK inhibition; PP1 activity assay; in vivo visual pathway tracing after PERK knockdown Molecular cell High 30595434
2019 Cryo-EM structures of eIF2 (phosphorylated and unphosphorylated) bound to eIF2B reveal that eIF2 undergoes large conformational rearrangements to bind the regulatory core of eIF2B (α, β, δ subunits); only minor structural differences exist between eIF2 and eIF2αP binding to eIF2B, indicating that increased affinity of eIF2αP for eIF2B (rather than a conformational change) drives translational control. Electron cryo-microscopy of eIF2–eIF2B and eIF2αP–eIF2B complexes; in vitro nucleotide-exchange assays Nature communications High 31086188
2019 The MEHMO syndrome mutation eIF2γ-I259M impairs Met-tRNAiMet binding to the eIF2 complex both in vivo and in vitro; overexpression of tRNAiMet restores Met-tRNAi binding and rescues yeast growth, indicating I259M causes MEHMO syndrome by reducing ternary complex availability. Yeast model of eIF2γ-I318M; GCN4/ATF4 derepression assay; in vivo and in vitro Met-tRNAi binding assays; tRNAiMet overexpression rescue; near-cognate start codon initiation assay Nucleic acids research High 30517694
2019 A MEHMO syndrome mutation at the C terminus of eIF2γ (EIF2S3) impairs CDC123-mediated eIF2 complex assembly and reduces eIF2-GTP-Met-tRNAiMet ternary complex levels; the drug ISRIB, which activates eIF2B, rescues cell growth, translation, and neuronal differentiation defects in patient-derived iPSCs. Patient iPSCs; polysome profiling; ternary complex measurements; neuronal differentiation assays; ISRIB treatment rescue Molecular cell High 31836389
2020 ISRIB antagonizes ISR activation by allosteric antagonism on eIF2B: phosphorylated EIF2S1 (eIF2αP) binding to the eIF2B regulatory sites remodels the ISRIB-binding pocket and eIF2α-engagement pockets, reciprocally opposing ISRIB and eIF2αP binding to eIF2B; ISRIB accelerates nucleotide exchange preferentially in the presence of eIF2αP. Cryo-EM of eIF2B with eIF2αP and ISRIB; in vitro nucleotide-exchange assay; mutagenesis of eIF2B regulatory sites; cell-based ISR reporter assays Molecular cell High 33220178
2020 Mitochondrial stress activates the OMA1–DELE1–HRI pathway: OMA1 cleaves DELE1, generating a short cytosolic form that directly binds and activates the eIF2α kinase HRI, leading to EIF2S1 phosphorylation, ATF4 translation, and the integrated stress response. Genome-wide CRISPR interference screen; co-immunoprecipitation of DELE1 with HRI; subcellular fractionation; OMA1/DELE1 knockout cells; in vitro HRI kinase assay Nature High 32132706 32132707
2020 Two viral proteins (from a coronavirus and a picornavirus) independently act as competitive inhibitors of the phospho-EIF2S1–eIF2B interaction, blocking translational shutdown despite high p-eIF2 levels; this reveals that eIF2αP and unphosphorylated eIF2 differ in their interaction with eIF2B in a way that can be selectively inhibited. In vitro competition binding assay; ternary complex formation assay; cell-based translation assays; viral mutant rescue Nature microbiology High 32690955
2023 EIF2S1 phosphorylation at Ser51 is required for nuclear translocation of autophagy transcription factors TFEB and TFE3 during ER stress; EIF2AK3/PERK, PPP3/calcineurin-mediated dephosphorylation, and YWHA/14-3-3 dissociation are necessary but insufficient for nuclear retention without EIF2S1 phosphorylation; overexpression of ATF6, XBP1s, or ATF4 can rescue autophagic defects in EIF2S1-S51A (A/A) cells. EIF2S1 phosphorylation-deficient (A/A) knock-in cells; immunofluorescence for TFEB/TFE3 nuclear localization; autophagy flux assays; adenoviral overexpression of ATF6/XBP1s/ATF4; pharmacological inhibition of PERK and calcineurin Autophagy High 36719671
2022 lncRNA LCETRL4 interacts with EIF2S1 protein and stabilizes it by reducing ubiquitin-proteasome-mediated degradation, leading to elevated EIF2S1 levels, increased phosphorylated PDK1, activated AKT signaling, and EGFR-TKI resistance in NSCLC. RNA immunoprecipitation; Co-IP of LCETRL4 with EIF2S1; ubiquitination assay; Western blot; NSCLC cell viability assays with EGFR-TKI treatment Signal transduction and targeted therapy Medium 35095099
2006 An age-induced CUGBP1–eIF2 complex (containing eIF2α, β, and γ subunits along with ER chaperones) binds to C/EBPβ mRNA and stimulates translation of all three C/EBPβ isoforms; formation of this complex requires both elevated CUGBP1 levels and cyclin D3-cdk4-mediated hyperphosphorylation of CUGBP1. Co-immunoprecipitation; cell-free translation system with purified complex; mRNA binding assay; transgenic mouse and cyclin D3 overexpression models The Journal of biological chemistry Medium 16931514
2002 Hypoxia activates the ER kinase PERK to phosphorylate EIF2S1 at Ser51, inhibiting global protein synthesis; expression of a non-phosphorylatable EIF2S1 (S51A) or dominant-negative PERK attenuates hypoxia-induced translational repression and reduces cell survival under prolonged hypoxia. Stable expression of S51A EIF2S1 transdominant mutant; PERK overexpression; PERK-null MEFs; [35S]-methionine incorporation for protein synthesis rates; Western blot for pEIF2S1 Molecular and cellular biology High 12370288
1998 PEK (PERK/EIF2AK3) is a new eIF-2α kinase that phosphorylates EIF2S1 specifically on Ser51; recombinant PEK inhibits translation in reticulocyte lysates in a dose-dependent manner and functionally substitutes for GCN2 in yeast, requiring the Ser51 site on eIF2α. Recombinant PEK expression in E. coli and Sf-9 cells; in vitro kinase assay; reticulocyte lysate translation inhibition; yeast GCN2 complementation with eIF2α-S51A control Molecular and cellular biology High 9819435

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1999 RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules. The Journal of cell biology 1066 10613902
2006 Coping with stress: eIF2 kinases and translational control. Biochemical Society transactions 1050 16246168
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1991 Translational control in mammalian cells. Annual review of biochemistry 977 1883206
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2005 Nucleolar proteome dynamics. Nature 934 15635413
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2016 The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress. Current molecular medicine 721 27211800
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
1998 Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Molecular and cellular biology 670 9819435
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2002 Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Molecular and cellular biology 575 12370288
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2020 Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. Nature 513 32132707
2007 Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 485 18082745
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2011 Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 405 22020285
2020 A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. Nature 393 32132706
2015 Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry. Nature methods 370 26414014
2011 Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer cell 356 21575865
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2011 Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. The Journal of biological chemistry 339 21285359
1986 Adenovirus VAI RNA antagonizes the antiviral action of interferon by preventing activation of the interferon-induced eIF-2 alpha kinase. Cell 339 3698097
2011 The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Molecular biology of the cell 330 21917591
2004 eIF2 and the control of cell physiology. Seminars in cell & developmental biology 319 15659334
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2003 Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Molecular and cellular biology 318 12556489
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
1999 Eukaryotic initiation factor eIF2. The international journal of biochemistry & cell biology 270 10216940
1995 Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells. The EMBO journal 269 7641700
1996 The eIF-2alpha kinases and the control of protein synthesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 253 8903508
1995 Regulation of protein synthesis by heme-regulated eIF-2 alpha kinase. Trends in biochemical sciences 251 7709427
2014 Keeping the eIF2 alpha kinase Gcn2 in check. Biochimica et biophysica acta 235 24732012
1998 eIF2 independently binds two distinct eIF2B subcomplexes that catalyze and regulate guanine-nucleotide exchange. Genes & development 218 9472020
2002 Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation. Cell stress & chaperones 217 12380690
2004 Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. The Journal of biological chemistry 188 15213227
2001 Initiation factor eIF2 alpha phosphorylation in stress responses and apoptosis. Progress in molecular and subcellular biology 169 11575161
2001 Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation. The Journal of biological chemistry 157 11555640
2020 ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Molecular cell 150 33220178
2019 The structural basis of translational control by eIF2 phosphorylation. Nature communications 134 31086188
1994 The eIF-2 alpha kinases: regulators of protein synthesis in starvation and stress. Seminars in cell biology 127 7711290
1994 eIF-2 kinases: regulators of general and gene-specific translation initiation. Trends in biochemical sciences 127 7855893
2007 HCV and CSFV IRES domain II mediate eIF2 release during 80S ribosome assembly. The EMBO journal 124 17255934
2009 Genome-wide analysis of tRNA charging and activation of the eIF2 kinase Gcn2p. The Journal of biological chemistry 122 19546227
2012 Eukaryotic initiation factor 2 (eIF2) signaling regulates proinflammatory cytokine expression and bacterial invasion. The Journal of biological chemistry 120 22761422
2021 Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer's disease. Science signaling 110 33531382
1996 Histidyl-tRNA synthetase-related sequences in GCN2 protein kinase regulate in vitro phosphorylation of eIF-2. The Journal of biological chemistry 103 8798780
2014 Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα. Molecular biology of the cell 98 24648495
1988 Generation of a mutant form of protein synthesis initiation factor eIF-2 lacking the site of phosphorylation by eIF-2 kinases. Molecular and cellular biology 98 3352609
1980 Characterization of double-stranded-RNA-activated kinase that phosphorylates alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha) in reticulocyte lysates. Proceedings of the National Academy of Sciences of the United States of America 92 6928683
2010 eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation. Nature 85 20485439
1986 Translational control by influenza virus: suppression of the kinase that phosphorylates the alpha subunit of initiation factor eIF-2 and selective translation of influenza viral mRNAs. Molecular and cellular biology 85 3785177
2014 ER stress-induced eIF2-alpha phosphorylation underlies sensitivity of striatal neurons to pathogenic huntingtin. PloS one 80 24594939
2018 Foot-and-mouth disease virus capsid protein VP2 activates the cellular EIF2S1-ATF4 pathway and induces autophagy via HSPB1. Autophagy 79 29166823
2018 Noncanonical Modulation of the eIF2 Pathway Controls an Increase in Local Translation during Neural Wiring. Molecular cell 75 30595434
2006 Age-specific CUGBP1-eIF2 complex increases translation of CCAAT/enhancer-binding protein beta in old liver. The Journal of biological chemistry 75 16931514
1994 Translation initiation factor eIF-2. Cloning and expression of the human cDNA encoding the gamma-subunit. The Journal of biological chemistry 75 8106381
2004 Parasite-specific eIF2 (eukaryotic initiation factor-2) kinase required for stress-induced translation control. The Biochemical journal 73 14989696
2016 Activation of the EIF2AK4-EIF2A/eIF2α-ATF4 pathway triggers autophagy response to Crohn disease-associated adherent-invasive Escherichia coli infection. Autophagy 63 26986695
1983 Phosphorylation of initiation factor eIF-2 alpha, binding of mRNA to 48 S complexes, and its reutilization in initiation of protein synthesis. The Journal of biological chemistry 61 6557115
1994 Erythroid expression of the heme-regulated eIF-2 alpha kinase. Molecular and cellular biology 60 7910943
2002 Characterization of mammalian eIF2A and identification of the yeast homolog. The Journal of biological chemistry 59 12133843
1998 Heme-regulated eIF-2alpha kinase purifies as a hemoprotein. European journal of biochemistry 59 9874252
1994 Regulation of the interferon-inducible eIF-2 alpha protein kinase by small RNAs. Biochimie 59 7534482
2011 SIRT1 associates with eIF2-alpha and regulates the cellular stress response. Scientific reports 56 22355666
2014 Human eukaryotic initiation factor 2 (eIF2)-GTP-Met-tRNAi ternary complex and eIF3 stabilize the 43 S preinitiation complex. The Journal of biological chemistry 54 25246524
2020 A Retrospective on eIF2A-and Not the Alpha Subunit of eIF2. International journal of molecular sciences 51 32192132
2020 Neuroinflammation and EIF2 Signaling Persist despite Antiretroviral Treatment in an hiPSC Tri-culture Model of HIV Infection. Stem cell reports 51 32220329
2011 Initiation factor eIF2γ promotes eIF2-GTP-Met-tRNAi(Met) ternary complex binding to the 40S ribosome. Nature structural & molecular biology 50 22002225
2009 Control of HIF-1alpha expression by eIF2 alpha phosphorylation-mediated translational repression. Cancer research 50 19244104
2022 GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis. eLife 49 36107759
2010 The eIF2 kinase GCN2 is essential for the murine immune system to adapt to amino acid deprivation by asparaginase. The Journal of nutrition 49 20861212
1991 Tissue distribution and immunoreactivity of heme-regulated eIF-2 alpha kinase determined by monoclonal antibodies. Biochemistry 49 1672093
1989 Association of mRNA and eIF-2 alpha with the cytoskeleton in cells lacking vimentin. Experimental cell research 49 2466674
2019 EIF2A promotes cell survival during paclitaxel treatment in vitro and in vivo. Journal of cellular and molecular medicine 48 31211507
2013 Involvement of the immune system, endocytosis and EIF2 signaling in both genetically determined and sporadic forms of Parkinson's disease. Neurobiology of disease 48 24269915
2011 Methods for analyzing eIF2 kinases and translational control in the unfolded protein response. Methods in enzymology 48 21266259
1994 Multicopy tRNA genes functionally suppress mutations in yeast eIF-2 alpha kinase GCN2: evidence for separate pathways coupling GCN4 expression to unchanged tRNA. Molecular and cellular biology 47 7969132
1990 Increased eIF-2 alpha expression in mitogen-activated primary T lymphocytes. The EMBO journal 47 1701139
2018 ER-stress regulates macrophage polarization through pancreatic EIF-2alpha kinase. Cellular immunology 46 30594305
2007 Double stranded RNA activated EIF2 alpha kinase (EIF2AK2; PKR) is associated with Alzheimer's disease. Neurobiology of aging 42 17420072
2019 PUM1 knockdown prevents tumor progression by activating the PERK/eIF2/ATF4 signaling pathway in pancreatic adenocarcinoma cells. Cell death & disease 41 31395860
2017 Kinases of eIF2a Switch Translation of mRNA Subset during Neuronal Plasticity. International journal of molecular sciences 41 29065505
2017 The eIF2-alpha kinase HRI: a potential target beyond the red blood cell. Expert opinion on therapeutic targets 40 29063813
2020 Inhibition of the integrated stress response by viral proteins that block p-eIF2-eIF2B association. Nature microbiology 38 32690955
2019 Suppression of MEHMO Syndrome Mutation in eIF2 by Small Molecule ISRIB. Molecular cell 38 31836389
2015 OLA1 regulates protein synthesis and integrated stress response by inhibiting eIF2 ternary complex formation. Scientific reports 38 26283179
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
2024 Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions. Nucleic acids research 37 38281137
2021 Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress. Nucleic acids research 37 34023907
1987 Evidence that phosphorylation of eIF-2(alpha) prevents the eIF-2B-mediated dissociation of eIF-2 X GDP from the 60 S subunit of complete initiation complexes. The Journal of biological chemistry 35 3646234
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
2016 Perturbations in actin dynamics reconfigure protein complexes that modulate GCN2 activity and promote an eIF2 response. Journal of cell science 34 27852836
1994 Inhibition of protein synthesis in insect cells by baculovirus-expressed heme-regulated eIF-2 alpha kinase. The Journal of biological chemistry 34 7929284
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
2001 Protection of translation initiation factor eIF2 phosphorylation correlates with eIF2-associated glycoprotein p67 levels and requires the lysine-rich domain I of p67. Biochimie 33 11728629
2021 eIF2-dependent translation initiation: Memory consolidation and disruption in Alzheimer's disease. Seminars in cell & developmental biology 32 34304995
2011 Gcn1 and actin binding to Yih1: implications for activation of the eIF2 kinase GCN2. The Journal of biological chemistry 32 21239490
2008 The PERK/eIF2 alpha signaling pathway of Unfolded Protein Response is essential for N-(4-hydroxyphenyl)retinamide (4HPR)-induced cytotoxicity in cancer cells. Experimental cell research 32 18342855
2023 Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress. Autophagy 29 36719671
2016 An mRNA-specific tRNAi carrier eIF2A plays a pivotal role in cell proliferation under stress conditions: stress-resistant translation of c-Src mRNA is mediated by eIF2A. Nucleic acids research 29 27899592
2020 Saturated Fatty Acids Promote GDF15 Expression in Human Macrophages through the PERK/eIF2/CHOP Signaling Pathway. Nutrients 28 33302552
2018 Dietary Intake of Curcumin Improves eIF2 Signaling and Reduces Lipid Levels in the White Adipose Tissue of Obese Mice. Scientific reports 28 29899429
2017 Translation of Sindbis Subgenomic mRNA is Independent of eIF2, eIF2A and eIF2D. Scientific reports 28 28240315
2015 eIF2 interactions with initiator tRNA and eIF2B are regulated by post-translational modifications and conformational dynamics. Cell discovery 28 27462419
2001 Comparison of the eIF-2alpha homologous proteins of seven ranaviruses (Iridoviridae). Virus genes 28 11778703
1998 Evidence that Hsc70 negatively modulates the activation of the heme-regulated eIF-2alpha kinase in rabbit reticulocyte lysate. European journal of biochemistry 28 9738893
2019 De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction. Diabetes 27 31882561
2017 The eIF2-alpha kinase HRI is a novel therapeutic target in multiple myeloma. Leukemia research 27 28119225
2010 Selective control of amino acid metabolism by the GCN2 eIF2 kinase pathway in Saccharomyces cerevisiae. BMC biochemistry 27 20684782
2019 Regulation of arginine transport by GCN2 eIF2 kinase is important for replication of the intracellular parasite Toxoplasma gondii. PLoS pathogens 26 31194856
2018 The Initiation Factors eIF2, eIF2A, eIF2D, eIF4A, and eIF4G Are Not Involved in Translation Driven by Hepatitis C Virus IRES in Human Cells. Frontiers in microbiology 26 29487587
2015 Polypeptide from Chlamys farreri suppresses ultraviolet-B irradiation-induced apoptosis through restoring ER redox homeostasis, scavenging ROS generation, and suppressing the PERK-eIF2a-CHOP pathway in HaCaT cells. Journal of photochemistry and photobiology. B, Biology 26 26142622
2011 Insights into the role of yeast eIF2A in IRES-mediated translation. PloS one 26 21915340
2019 MEHMO syndrome mutation EIF2S3-I259M impairs initiator Met-tRNAiMet binding to eukaryotic translation initiation factor eIF2. Nucleic acids research 25 30517694
2019 miR‑195 promotes LPS‑mediated intestinal epithelial cell apoptosis via targeting SIRT1/eIF2a. International journal of molecular medicine 25 31894250
2023 The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP). International journal of molecular sciences 24 38139150
2020 Sialylation and fucosylation modulate inflammasome-activating eIF2 Signaling and microbial translocation during HIV infection. Mucosal immunology 24 32152415
2015 Cdc123, a Cell Cycle Regulator Needed for eIF2 Assembly, Is an ATP-Grasp Protein with Unique Features. Structure (London, England : 1993) 24 26211610
2022 The role of eIF2 phosphorylation in cell and organismal physiology: new roles for well-known actors. The Biochemical journal 23 35604373
2021 Long non-coding RNA NORAD inhibition upregulates microRNA-323a-3p to suppress tumorigenesis and development of breast cancer through the PUM1/eIF2 axis. Cell cycle (Georgetown, Tex.) 23 34125645
1999 Serine 48 in initiation factor 2 alpha (eIF2 alpha) is required for high-affinity interaction between eIF2 alpha(P) and eIF2B. Biochemistry 23 10563826