Affinage

PPP1R15A

Protein phosphatase 1 regulatory subunit 15A · UniProt O75807

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP1R15A (GADD34) is a stress-inducible regulatory subunit of protein phosphatase 1 (PP1) that serves as the principal negative-feedback effector of the integrated stress response (ISR) by scaffolding PP1c and eIF2α into a holophosphatase complex at the endoplasmic reticulum, thereby directing dephosphorylation of eIF2α at Ser51 and restoring global protein synthesis after stress (PMID:11381086, PMID:26095357, PMID:12824288). The protein employs a bipartite C-terminal PP1-binding domain (KVRF and RARA motifs) and a separate conserved eIF2α-docking motif for independent substrate recruitment, while an N-terminal amphipathic helix mediates monotopic ER membrane insertion and controls proteasomal turnover via an N-terminal degron (PMID:12556489, PMID:26100893, PMID:21518769, PMID:18794359). Beyond eIF2α, GADD34 redirects PP1 to additional substrates including TAK1 (attenuating NF-κB/MAPK signaling), TSC2 (inhibiting mTOR to promote autophagy), TβRI (via Smad7, dampening TGFβ signaling), and SIRT1, and under chronic oxidative stress it acts as a kinase scaffold recruiting CK1ε to phosphorylate TDP-43 at pathological sites (PMID:24534530, PMID:21439266, PMID:14718519, PMID:28984870, PMID:29109149). GADD34 expression is tightly controlled at multiple levels: transcriptionally by ATF4 and TFEB, translationally by 5′ UTR upstream ORFs that permit preferential translation during eIF2α phosphorylation, and post-transcriptionally by ZFP36-family-mediated ARE-dependent mRNA decay that establishes ISR memory (PMID:19131336, PMID:32978159, PMID:38602876).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    The foundational question of how cells recover from stress-induced translational arrest was answered by showing that GADD34 recruits PP1c to form a holophosphatase that specifically dephosphorylates eIF2α, establishing GADD34 as the negative-feedback node of the ISR.

    Evidence Co-immunoprecipitation, in vitro phosphatase assays with PP1c-binding mutants, and CHOP::GFP reporter in cells

    PMID:11381086 PMID:11564868

    Open questions at the time
    • Structural basis of PP1–GADD34 interaction unresolved
    • Substrate selectivity mechanism unknown
    • In vivo requirement not yet demonstrated
  2. 2003 High

    Domain-mapping and genetic ablation established that GADD34 contains a bipartite C-terminal PP1-binding module and an N-terminal ER-targeting region, and that GADD34 is required in vivo for timely recovery of protein synthesis after ER stress.

    Evidence Structure-function deletion mutagenesis with GFP imaging, GADD34 knockout MEFs with eIF2α phosphorylation and translation recovery assays

    PMID:12556489 PMID:12824288

    Open questions at the time
    • Identity of the eIF2α-binding site on GADD34 unknown
    • Physiological consequences of GADD34 loss in whole organisms not yet explored beyond MEFs
  3. 2004 High

    The discovery that Smad7 recruits the GADD34–PP1c complex to TβRI for dephosphorylation revealed that GADD34 is not exclusively an eIF2α phosphatase scaffold but can be redirected to diverse substrates via adaptor proteins.

    Evidence Reciprocal Co-IP, Smad7 RNAi, TβRI phosphorylation assays, and TGFβ-dependent cell-cycle-arrest readouts

    PMID:14718519

    Open questions at the time
    • Whether GADD34–PP1 acts on TβRI in vivo under physiological stress not tested
    • Structural basis of Smad7-mediated substrate redirection unknown
  4. 2006 High

    Analysis of Gadd34-null mice revealed a physiological requirement for GADD34-mediated eIF2α dephosphorylation in erythropoiesis, where it counterbalances HRI kinase to permit globin translation in reticulocytes.

    Evidence Gadd34-null mouse phenotyping with erythrocyte hemoglobin quantification and reticulocyte translation analysis

    PMID:16478986

    Open questions at the time
    • Whether additional tissues show translational defects in Gadd34-null mice not systematically examined
  5. 2008 High

    Identification of an N-terminal degron driving proteasomal polyubiquitination and rapid turnover of GADD34 explained how GADD34 protein levels are kept low basally, with functional consequences: stabilized GADD34 enhances eIF2α dephosphorylation and promotes misfolded-protein aggregation.

    Evidence Proteasome inhibitor treatment, polyubiquitination assays, N-terminal deletion mutagenesis, CFTRΔF508 aggregation readout

    PMID:18794359

    Open questions at the time
    • E3 ubiquitin ligase responsible for GADD34 ubiquitination not identified
    • Relationship between ER localization and degradation not fully resolved
  6. 2009 High

    Demonstration that 5′ UTR uORFs mediate translational derepression of GADD34 mRNA during eIF2α phosphorylation revealed the feed-forward mechanism by which the ISR auto-induces its own negative regulator.

    Evidence Polysome fractionation with 5′ UTR reporter constructs and uORF mutagenesis

    PMID:19131336

    Open questions at the time
    • Relative contribution of transcriptional (ATF4) vs. translational (uORF) induction under different stresses not quantified
  7. 2011 High

    The N-terminal amphipathic helix was shown to mediate monotopic ER membrane insertion, controlling GADD34 mobility and proteasomal degradation rate, linking subcellular localization to protein turnover and function.

    Evidence GFP-GADD34 live imaging, FRAP, fluorescence protease protection, cysteine chemical modification, V25R mutagenesis

    PMID:21518769

    Open questions at the time
    • Whether ER anchoring affects substrate access beyond eIF2α not tested
  8. 2007 Medium

    GADD34's substrate repertoire was expanded to mTOR regulation when it was shown to scaffold PP1-mediated dephosphorylation of TSC2 at Thr1462, inhibiting mTOR signaling during energy depletion and starvation-induced autophagy.

    Evidence Co-IP of GADD34–TSC1/TSC2 complex, TSC2 phosphorylation assays, mTOR readouts, confirmed in Gadd34 KO mice under starvation

    PMID:17273797 PMID:21439266

    Open questions at the time
    • Whether GADD34-mediated TSC2 dephosphorylation involves direct PP1 catalysis or indirect signaling not fully distinguished
    • Structural basis of TSC2 recruitment unknown
  9. 2012 High

    GADD34 was shown to be essential for type I IFN and IL-6 production in response to dsRNA via the PKR–ATF4 axis, establishing GADD34 as a critical node linking innate immune sensing to translational recovery needed for cytokine production.

    Evidence GADD34-deficient MEFs and neonatal mice challenged with dsRNA and Chikungunya virus; cytokine measurement and survival analysis

    PMID:22615568

    Open questions at the time
    • Which specific mRNAs require GADD34-mediated eIF2α dephosphorylation for translation during antiviral response not identified
  10. 2014 High

    GADD34 was found to direct PP1 to dephosphorylate TAK1 at Ser412, attenuating TLR-triggered NF-κB and MAPK activation, thereby functioning as an anti-inflammatory phosphatase scaffold.

    Evidence Reciprocal Co-IP of GADD34–PP1–TAK1, TAK1 S412A mutant, siRNA epistasis, in vivo LPS endotoxin shock model

    PMID:24534530

    Open questions at the time
    • Whether GADD34-mediated TAK1 dephosphorylation is PP1α-specific or involves other PP1 isoforms not tested
  11. 2015 High

    Structural and functional studies resolved how GADD34 simultaneously but independently engages PP1 and eIF2α through separate binding motifs, explaining how a single scaffold achieves substrate specificity; a conserved C-terminal eIF2α-binding motif was defined by mutagenesis.

    Evidence NMR/biochemical structural analysis, in vitro reconstitution, point mutagenesis across GADD34 and viral orthologs, yeast PKR suppression assay

    PMID:26095357 PMID:26100893

    Open questions at the time
    • Full atomic-resolution structure of the ternary GADD34–PP1–eIF2α complex not available
    • Conformational dynamics during catalysis not characterized
  12. 2017 High

    Pharmacological studies with Guanabenz and Sephin1 revealed that these compounds induce conformational changes in GADD34 that alter eIF2α recruitment, though an independent study found no effect of these drugs on reconstituted holophosphatase activity or cellular eIF2α dephosphorylation kinetics, leaving the mechanism of these inhibitors unresolved.

    Evidence In vitro reconstituted holophosphatases with limited proteolysis (PMID:28759048); independent reconstitution plus CRISPR-edited Ppp1r15a-deleted and eIF2α-S51A cells (PMID:28447936)

    PMID:28447936 PMID:28759048

    Open questions at the time
    • Contradictory findings on Sephin1/Guanabenz selectivity for GADD34 not resolved
    • In vivo target engagement of these drugs not definitively demonstrated
  13. 2017 High

    GADD34 was revealed to have dual scaffolding functions under oxidative stress: directing PP1α to dephosphorylate SIRT1 (activating its deacetylase function) and simultaneously acting as a kinase scaffold recruiting CK1ε to phosphorylate TDP-43 at pathological sites.

    Evidence Mass spectrometry interactome, reciprocal Co-IP, GADD34 KO MEFs, SIRT1 activity assays, TDP-43 S409/410 phosphorylation in KO vs WT cells

    PMID:28984870 PMID:29109149

    Open questions at the time
    • Whether GADD34-mediated TDP-43 phosphorylation contributes to ALS/FTLD pathology in vivo not tested
    • Structural basis for dual phosphatase/kinase scaffold switching unknown
  14. 2020 Medium

    TFEB was identified as a direct transcriptional activator of GADD34 during starvation, establishing that GADD34 integrates the mTORC1 and ISR pathways by dephosphorylating eIF2α to permit translation of the TFEB-driven lysosomal biogenesis program.

    Evidence GADD34 KO cells, TFEB ChIP and reporter assays, eIF2α phosphorylation and autophagic flux measurements

    PMID:32978159

    Open questions at the time
    • Whether other transcription factors cooperate with TFEB at the GADD34 promoter not examined
    • Quantitative contribution of TFEB vs ATF4 to GADD34 induction during starvation unclear
  15. 2024 Medium

    Post-transcriptional regulation of GADD34 was shown to involve ZFP36-family-mediated recognition of an ARE in the 3′ UTR, promoting rapid mRNA decay basally and stabilization during stress, functioning as a mechanism of ISR memory that tunes stress responsiveness.

    Evidence 3′ UTR reporter assays, ZFP36 protein binding assays, mRNA stability measurements, repeated stress-exposure ISR memory experiments

    PMID:38602876

    Open questions at the time
    • Identity of kinase(s) that inactivate ZFP36 to allow GADD34 mRNA stabilization not determined
    • Whether ARE-mediated regulation differs across cell types not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full atomic-resolution structure of the ternary GADD34–PP1–eIF2α complex is lacking, the E3 ligase(s) responsible for GADD34 ubiquitination remain unidentified, and whether GADD34's kinase-scaffold function (CK1ε–TDP-43) contributes to neurodegenerative disease in vivo has not been tested.
  • No ternary complex structure available
  • E3 ubiquitin ligase for GADD34 degradation unknown
  • In vivo disease relevance of GADD34-mediated TDP-43 phosphorylation untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 5
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-8953854 Metabolism of RNA 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2
Partners
CSNK1EEIF2S1MAP3K7PPP1CASIRT1SMAD7TARDBPTSC2
Complex memberships
GADD34–PP1c holophosphataseGADD34–PP1–TAK1 complexSmad7–GADD34–PP1c complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 GADD34 (PPP1R15A) forms a complex with the catalytic subunit of protein phosphatase 1 (PP1c) that specifically promotes dephosphorylation of eIF2α in vitro, acting as a negative feedback regulator of the unfolded protein response and stress-induced translational repression. Co-immunoprecipitation, in vitro phosphatase assay, retroviral overexpression with CHOP::GFP reporter, PP1c-binding mutants The Journal of cell biology High 11381086
2001 GADD34 assembles a novel signaling complex containing PP1 and inhibitor 1 (I-1); the GADD34/PP1 complex retains eIF2α phosphatase activity while the GADD34-bound PP1 is inhibited for dephosphorylation of phosphorylase a, demonstrating substrate selectivity. Yeast two-hybrid screen, recombinant protein pulldown, affinity isolation of cellular complexes, in vitro phosphatase assay with eIF2α and phosphorylase a substrates Molecular and cellular biology High 11564868
2003 GADD34 contains a bipartite C-terminal PP1-binding domain (canonical KVRF motif plus novel RARA sequence) required for PP1 binding; its N-terminal 180 residues direct ER localization and target PP1α to the ER, and N-terminal sequences are required beyond PP1 binding for eIF2α dephosphorylation in cells. Structure-function deletion analysis, GFP-GADD34 live-cell imaging, eIF2α phosphorylation reversal assay in thapsigargin/tunicamycin-treated cells Molecular and cellular biology High 12556489
2003 GADD34-deficient mouse embryonic fibroblasts show delayed recovery from eIF2α phosphorylation and protein synthesis shutoff induced by thapsigargin or DTT, establishing GADD34 as required in vivo for recovery from ER stress-induced translational arrest. GADD34 knockout mice/MEFs, eIF2α phosphorylation Western blot, protein synthesis recovery assay after ER stress FASEB journal High 12824288
2004 Smad7 acts as an adaptor recruiting the GADD34–PP1c complex to the TGFβ type I receptor (TβRI), leading to dephosphorylation of TβRI and negative feedback inhibition of TGFβ signaling; SARA enhances PP1c recruitment to the Smad7–GADD34 complex. Co-immunoprecipitation, RNAi knockdown of Smad7, TβRI phosphorylation assay, cell cycle arrest functional assay The Journal of cell biology High 14718519
2015 Crystal/structural and functional analysis of the GADD34:PP1 holoenzyme revealed that GADD34 functions as a scaffold with independent binding sites for PP1 and eIF2α, demonstrating that eIF2α recruitment to the complex is distinct from PP1 binding. Structural analysis (NMR/biochemical), in vitro reconstitution, mutagenesis, cellular functional assays Cell reports High 26095357
2015 A novel eIF2α-binding motif in the C-terminus of GADD34 (consensus Rx[Gnl]x(1-2)Wxxx[Arlv]x[Dn][Rg]xRFxx[Rlvk][Ivc]), distinct from the PP1-binding site, is required for eIF2α interaction, eIF2α dephosphorylation promotion, and suppression of PKR toxicity; this motif is conserved in viral GADD34 orthologs (HSV ICP34.5, ASFV, Canarypox). Point mutagenesis, Co-IP/pulldown, eIF2α dephosphorylation assays, yeast PKR toxicity suppression assay Proceedings of the National Academy of Sciences of the United States of America High 26100893
2017 Reconstituted human recombinant R15A(GADD34)–PP1 and R15B(CReP)–PP1 holophosphatases showed that Guanabenz and Sephin1 selectively induce a conformational change in R15A detected by limited proteolysis, altering eIF2α recruitment and preventing its dephosphorylation without disrupting the R15A–PP1 interaction. In vitro reconstitution of recombinant holophosphatases, limited proteolysis, eIF2α dephosphorylation assay, inhibitor binding studies Nature structural & molecular biology High 28759048
2017 In vitro, Guanabenz and Sephin1 do not affect stability of the PP1–PPP1R15A complex nor substrate-specific eIF2α dephosphorylation; in cells, eIF2α-P dephosphorylation after kinase shutoff proceeds normally in Sephin1-treated cells; Sephin1's effect on IRE1 branch is independent of PPP1R15A and eIF2α phosphorylation status. In vitro phosphatase assay with reconstituted complex, kinase shut-off experiment, CRISPR-edited Ppp1r15a-deleted cells and eIF2α-S51A knock-in cells eLife High 28447936
2008 GADD34 is degraded by the 26S proteasome via polyubiquitination; an N-terminal degron drives this rapid turnover; PEST repeat deletions modulate PP1 binding and activity; stabilization of GADD34 by proteasome inhibition enhances eIF2α dephosphorylation and promotes accumulation/aggregation of misfolded CFTRΔF508. Proteasomal inhibitor treatment, polyubiquitination assay, N-terminal deletion/epitope-tag stabilization, eIF2α phosphorylation assay, CFTR aggregation assay Molecular and cellular biology High 18794359
2011 GADD34's N-terminal amphipathic helix (with hydrophobic residues V25 and L29) mediates monotopic insertion into the ER outer membrane, while the same helix's polar surface mediates mitochondrial association; ER-associated GADD34 has reduced mobility (FRAP) and enhanced proteasomal degradation compared to cytosolic mutant V25R; both WT and V25R scaffold PP1α for eIF2α dephosphorylation, but only WT modifies ER morphology. Deletion mutagenesis, GFP-GADD34 live imaging, fluorescence protease protection, FRAP, cysteine chemical modification, eIF2α dephosphorylation assay The Journal of biological chemistry High 21518769
2006 Gadd34-null mice display reduced hemoglobin content in erythrocytes due to reduced initiation of globin translation machinery in reticulocytes, revealing a physiological role for Gadd34/PP1c in eIF2α dephosphorylation to counterbalance heme-regulated inhibitor kinase during hemoglobin synthesis. Gadd34-null mouse analysis, erythrocyte/reticulocyte biochemical analysis of hemoglobin and globin translation initiation Molecular and cellular biology High 16478986
2009 GADD34 mRNA translation is preferentially induced during eIF2α phosphorylation via upstream ORFs (uORFs) in its 5' UTR; the downstream uORF mediates repression of basal translation and redirects translation during stress, allowing maximal GADD34 expression when needed for negative feedback. Polysome fractionation, 5'UTR reporter constructs, uORF mutagenesis The Journal of biological chemistry High 19131336
2013 GADD34 upregulation following traumatic brain injury (TBI) is induced by ATF4 binding to the GADD34 promoter; GADD34 then binds TRAF6, preventing TRAF6-mediated ubiquitination-coupled Akt phosphorylation at T308, retaining Akt in the cytosol and reducing cell survival; in vivo lentiviral knockdown of GADD34 rescues Akt activation and attenuates TBI-induced cell death. Controlled cortical impact TBI mouse model, Co-IP (GADD34-TRAF6 interaction), lentiviral shRNA knockdown, Akt phosphorylation assay, cell death quantification Cell death & disease Medium 23907468
2012 GADD34/Ppp1r15a is absolutely required for type I IFN and IL-6 production by mouse embryonic fibroblasts in response to dsRNA; GADD34 expression depends on PKR activation linking cytosolic microbial sensing to the ATF4 branch of the UPR; GADD34-deficient mice are extremely susceptible to Chikungunya virus infection. GADD34-deficient MEFs and neonatal mice, dsRNA stimulation, cytokine measurement, viral infection survival assay PLoS pathogens High 22615568
2014 GADD34 acts as a regulatory subunit directing PP1 to dephosphorylate TAK1 at serine 412, attenuating TLR-triggered NF-κB and MAPK signaling; GADD34 depletion abolishes the PP1–TAK1 interaction and enhances pro-inflammatory cytokine production. Co-IP (GADD34-PP1-TAK1), GADD34 siRNA knockdown, TAK1 S412A mutant, NF-κB/MAPK activation assays, LPS endotoxin shock in vivo Journal of immunology High 24534530
2007 GADD34 forms a stable complex with TSC1/TSC2 and promotes dephosphorylation of TSC2 at Thr1462, thereby inhibiting mTOR signaling; this mechanism protects cells from apoptosis during energy depletion. Co-IP (GADD34-TSC1/TSC2 complex), TSC2 phosphorylation assay, mTOR downstream readouts (S6K, 4EBP1), cell viability assay International journal of molecular medicine Medium 17273797
2011 Starvation-induced GADD34 suppresses mTOR by binding and dephosphorylating TSC2 at Thr1462, promoting autophagy; autophagy induction is absent in Gadd34 KO mice under starvation. Gadd34 KO mice, starvation model, Co-IP (Gadd34-TSC2), TSC2 Thr1462 phosphorylation assay, autophagy marker analysis Biochemical and biophysical research communications Medium 21439266
2017 Oxidative stress promotes recruitment of SIRT1 to the GADD34/PP1α complex in the cytoplasm; GADD34-scaffolded PP1α dephosphorylates both eIF2α (pSer51) and SIRT1 (pSer47); SIRT1 dephosphorylation increases its deacetylase activity; GADD34-/- MEFs show persistent phosphorylation of both eIF2α and SIRT1 after arsenite exposure. Mass spectrometry of GADD34 interactome, Co-IP, GADD34 KO MEFs, SIRT1 deacetylase activity assay in vitro and in cells, WT vs PP1-binding mutant rescue Cell death and differentiation High 28984870
2017 In response to chronic oxidative stress (arsenite), GADD34 functions as a kinase scaffold by recruiting TDP-43 and casein kinase-1ε (CK1ε); GADD34-bound CK1ε phosphorylates TDP-43 at serines 409/410 (pathological phosphorylation); these phosphorylations are diminished in GADD34-/- cells. Co-IP (GADD34-TDP-43-CK1ε), GADD34 KO MEFs, TDP-43 phosphorylation assay at S409/410, arsenite vs. ER stress comparison The Journal of biological chemistry High 29109149
2013 HTLV-1 HBZ protein is exported from the nucleus via CRM1-dependent NES, interacts with the C-terminal region of GADD34 in the cytoplasm, and inhibits GADD34 function to activate mTOR signaling (increased S6K phosphorylation) and suppress starvation-induced autophagy. Co-IP (HBZ-GADD34), NES mutagenesis, CRM1 inhibitor (leptomycin B), S6K phosphorylation assay, autophagy assay Oncogene Medium 23708656
2017 GADD34/PP1 phosphatase activity reverses hyperosmotic-stress-induced Golgi fragmentation, promotes cis-to-trans Golgi trafficking of the neutral amino acid transporter SNAT2, and enables SNAT2 plasma membrane localization and function, independent of GADD34's ISR role. GADD34 KO cells, Golgi morphology imaging, SNAT2 trafficking assay, amino acid uptake functional assay, PP1 phosphatase inhibitor treatment Cell reports Medium 29212034
2002 hSNF5/INI1 binds GADD34 (partly through the PP1-docking domain homologous to HSV ICP34.5), forms a stable heterotrimeric complex with GADD34 and PP1, and weakly stimulates PP1 phosphatase activity; EBNA2 disrupts hSNF5/INI1-GADD34 interaction and partially reverses GADD34-mediated growth suppression. Co-IP, affinity pulldown, in vitro PP1 phosphatase activity assay, colony formation assay The Journal of biological chemistry Medium 12016208
2003 Human BAG-1 cochaperone proteins interact with GADD34 in cells undergoing apoptosis; BAG-1 negatively modulates GADD34-bound PP1 activity; Hsp70/Hsc70 and PP1 associate reversibly with the GADD34-BAG-1 complex in an ATP-dependent manner; BAG-1 expression masks GADD34-mediated growth suppression and apoptosis. Yeast two-hybrid screen, Co-IP in SW480 cells, in vitro PP1 phosphatase activity assay, colony formation suppression assay Molecular and cellular biology Medium 12724406
2009 Disruption of the PP1/GADD34 complex (by a competing GADD34-derived peptide fused to a membrane-translocation domain) is sufficient to stimulate eIF2α phosphorylation and trigger calreticulin surface exposure on tumor cells, dissociating CRT exposure from cell death. Molecular modeling-guided peptide design, cellular eIF2α phosphorylation assay, CRT surface exposure assay, Co-IP to verify PP1/GADD34 complex disruption Cell cycle Medium 19901557
2013 GADD34 promotes MCL-1 protein stability in hepatocellular carcinoma cells by inhibiting proteasomal degradation of MCL-1 through a TRAF6–TAB1–ERK signaling axis; GADD34 overexpression promotes ERK phosphorylation via TRAF6, which stabilizes MCL-1 and protects against TRAIL-induced apoptosis. Immunoblotting, GADD34 overexpression/knockdown, ERK phosphorylation assay, proteasome inhibitor (MG132) rescue, TRAF6 and GADD34 siRNA co-knockdown The Journal of biological chemistry Medium 30782845
2013 TC-PTP (PTPN2) is a phosphatase that dephosphorylates GADD34 at tyrosine 262 (identified by substrate-trapping); phosphorylation at Y262 enhances GADD34 protein turnover; TC-PTP-null MEFs show reduced GADD34 protein after ER stress and increased susceptibility to ER stress-induced apoptosis rescued by ectopic GADD34. Mass spectrometry (GADD34 phosphosite identification), substrate-trapping Co-IP (TC-PTP-GADD34), TC-PTP-null MEFs, GADD34 turnover assay, apoptosis assay The Journal of biological chemistry Medium 24092754
2020 TFEB directly activates GADD34 expression during starvation; GADD34 in turn dephosphorylates eIF2α to permit translation of the TFEB-driven lysosomal biogenesis program, enabling sustained autophagic flux; GADD34 thus integrates the mTORC1 and ISR pathways during starvation. GADD34 KO cells, TFEB ChIP/reporter assays, eIF2α phosphorylation assay, autophagic flux measurement (lysosomal biogenesis markers) Science advances Medium 32978159
2024 The 3' UTR of PPP1R15A mRNA contains an AU-rich element (ARE) recognized by ZFP36 family RNA-binding proteins, promoting rapid mRNA decay under normal conditions and mRNA stabilization during stress; this post-transcriptional control of PPP1R15A mRNA stability functions as a component of ISR memory, setting the threshold for stress responsiveness and adaptation. 3'UTR reporter assays, ZFP36 family protein binding assays, mRNA stability assays, ISR memory experiments with repeated stress exposure Cell reports Medium 38602876
1999 GADD34 interacts with HRX (MLL) proteins; leukemic HRX fusion proteins (HRX-ENL, HRX-AF9, HRX-ELL) bind GADD34 and abrogate GADD34-induced apoptosis after ionizing radiation; wild-type HRX does not inhibit this apoptosis; GADD34 also binds hSNF5/INI1. Yeast two-hybrid, Co-IP in human cells, apoptosis assay (nuclear fragmentation) after ionizing radiation Molecular and cellular biology Medium 10490642
2000 GADD34 interacts with GAHSP40 (a DnaJ/Hsp40 family member); interaction requires the ICP34.5-homology domain of GADD34 and the C-terminus of GAHSP40; interaction confirmed by Co-IP in cultured cells. Yeast two-hybrid, Co-IP, in vitro binding assay The Biochemical journal Low 11104688
2000 GADD34 interacts with KIF3A (kinesin superfamily motor protein) via KIF3A's C-terminal tail domain, identified by yeast two-hybrid and confirmed by in vivo two-hybrid in NIH3T3 cells. Yeast two-hybrid, in vivo two-hybrid in NIH3T3 cells Biochemical and biophysical research communications Low 10631107
1999 GADD34 interacts with Translin (a DNA translocation-associated RNA-binding protein); interaction was confirmed by in vitro binding assay and in vivo two-hybrid in NIH3T3 cells. Yeast two-hybrid, in vitro binding assay, in vivo two-hybrid Biochimica et biophysica acta Low 10434033
2016 GADD34-containing eIF2α phosphatase drives substantial translational changes in unstressed cells targeting the secretome; upon UPR activation, rapid GADD34 translation is essential for UPR progression — in GADD34-absence eIF2α phosphorylation is persistently elevated and UPR translational program is significantly attenuated; compensatory AKT-mediated PERK suppression and CReP induction partially restore protein synthesis. GADD34 KO cells, polysome profiling, translational analysis, AKT/PERK signaling assays, CReP expression measurement Molecular and cellular biology Medium 27161320
2022 In sepsis-induced acute kidney injury, Ppp1r15a/GADD34 expression is blunted by its own 5' upstream ORF (uORF); antisense oligonucleotides targeting the uORF enable Ppp1r15a overexpression, rescuing eIF2α dephosphorylation, restoring translation, and improving kidney function in a murine endotoxemia model. Ribosome profiling (Ribo-seq), proteomics, polyribosome profiling, antisense oligonucleotides, Ppp1r15a knock-in mouse model, mutant cell lines Journal of the American Society of Nephrology Medium 36283811
2016 HES1 (hairy and enhancer of split 1) binds to the GADD34 promoter and represses its transcription during ER stress; HES1 depletion leads to GADD34 upregulation and increased cell death during ER stress in a GADD34-dependent manner. HES1 depletion (siRNA), GADD34 promoter ChIP, cell death assay, epistasis with GADD34 KD The Journal of biological chemistry Medium 29491143

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. The Journal of cell biology 1166 11381086
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
2001 Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1. Molecular and cellular biology 227 11564868
2004 GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. The Journal of cell biology 208 14718519
2009 An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation. The Journal of biological chemistry 200 19131336
2003 The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: elucidation by GADD34-deficient mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 200 12824288
1997 Mammalian GADD34, an apoptosis- and DNA damage-inducible gene. The Journal of biological chemistry 155 9153226
1996 A herpesvirus genetic element which affects translation in the absence of the viral GADD34 function. The EMBO journal 136 8887567
1999 Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. Molecular and cellular biology 132 10490642
2015 Structural and Functional Analysis of the GADD34:PP1 eIF2α Phosphatase. Cell reports 122 26095357
2001 Peroxynitrite induces GADD34, 45, and 153 VIA p38 MAPK in human neuroblastoma SH-SY5Y cells. Free radical biology & medicine 114 11163539
2015 Is there a causal relationship between genetic changes and radiomics-based image features? An in vivo preclinical experiment with doxycycline inducible GADD34 tumor cells. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 109 26163091
2012 Induction of GADD34 is necessary for dsRNA-dependent interferon-β production and participates in the control of Chikungunya virus infection. PLoS pathogens 99 22615568
2009 Inhibition of protein kinase R activation and upregulation of GADD34 expression play a synergistic role in facilitating coronavirus replication by maintaining de novo protein synthesis in virus-infected cells. Journal of virology 89 19776135
1997 The herpes simplex virus virulence factor ICP34.5 and the cellular protein MyD116 complex with proliferating cell nuclear antigen through the 63-amino-acid domain conserved in ICP34.5, MyD116, and GADD34. Journal of virology 86 9371605
2017 PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz. eLife 81 28447936
1998 Myc suppresses induction of the growth arrest genes gadd34, gadd45, and gadd153 by DNA-damaging agents. Oncogene 80 9811446
2017 Decoding the selectivity of eIF2α holophosphatases and PPP1R15A inhibitors. Nature structural & molecular biology 74 28759048
2015 An eIF2α-binding motif in protein phosphatase 1 subunit GADD34 and its viral orthologs is required to promote dephosphorylation of eIF2α. Proceedings of the National Academy of Sciences of the United States of America 73 26100893
2013 GADD34 induces cell death through inactivation of Akt following traumatic brain injury. Cell death & disease 68 23907468
1999 A herpesvirus ribosome-associated, RNA-binding protein confers a growth advantage upon mutants deficient in a GADD34-related function. Journal of virology 67 10074192
2012 Protein phosphatase 1 subunit Ppp1r15a/GADD34 regulates cytokine production in polyinosinic:polycytidylic acid-stimulated dendritic cells. Proceedings of the National Academy of Sciences of the United States of America 66 22315398
2017 Protein synthesis inhibition and GADD34 control IFN-β heterogeneous expression in response to dsRNA. The EMBO journal 60 28100675
2008 Control of cellular GADD34 levels by the 26S proteasome. Molecular and cellular biology 60 18794359
2004 Up-regulation of GADD34 mediates the synergistic anticancer activity of mitomycin C and a gamma134.5 deleted oncolytic herpes virus (G207). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 59 15059970
2001 Activation of Gadd34 by diverse apoptotic signals and suppression of its growth inhibitory effects by apoptotic inhibitors. International journal of cancer 56 11241327
2004 Ischaemic preconditioning in the rat brain: effect on the activity of several initiation factors, Akt and extracellular signal-regulated protein kinase phosphorylation, and GRP78 and GADD34 expression. Journal of neurochemistry 55 14675157
2020 GADD34 is a modulator of autophagy during starvation. Science advances 54 32978159
2006 Cisplatin-induced GADD34 upregulation potentiates oncolytic viral therapy in the treatment of malignant pleural mesothelioma. Cancer biology & therapy 54 16294031
2018 Toxicity and Efficacy of a Novel GADD34-expressing Oncolytic HSV-1 for the Treatment of Experimental Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 49 29511029
2003 GADD34 induces p53 phosphorylation and p21/WAF1 transcription. Journal of cellular biochemistry 49 14635196
1999 Activation of MYD116 (gadd34) expression following transient forebrain ischemia of rat: implications for a role of disturbances of endoplasmic reticulum calcium homeostasis. Brain research. Molecular brain research 46 9878749
2008 Overexpression of GADD34 enhances production of recombinant human antithrombin III in Chinese hamster ovary cells. Journal of bioscience and bioengineering 44 19134553
2015 Quercetin reduces eIF2α phosphorylation by GADD34 induction. Neurobiology of aging 43 26070242
2014 Phosphatase holoenzyme PP1/GADD34 negatively regulates TLR response by inhibiting TAK1 serine 412 phosphorylation. Journal of immunology (Baltimore, Md. : 1950) 42 24534530
2016 GADD34 suppresses lipopolysaccharide-induced sepsis and tissue injury through the regulation of macrophage activation. Cell death & disease 40 27171261
2007 GADD34 inhibits mammalian target of rapamycin signaling via tuberous sclerosis complex and controls cell survival under bioenergetic stress. International journal of molecular medicine 40 17273797
2002 The human SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein (GADD34) and modulates GADD34-bound protein phosphatase-1 activity. The Journal of biological chemistry 39 12016208
2013 HTLV-1 HBZ positively regulates the mTOR signaling pathway via inhibition of GADD34 activity in the cytoplasm. Oncogene 38 23708656
2009 Disruption of the PP1/GADD34 complex induces calreticulin exposure. Cell cycle (Georgetown, Tex.) 38 19901557
2016 Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response. Molecular and cellular biology 37 27161320
2011 Gadd34 induces autophagy through the suppression of the mTOR pathway during starvation. Biochemical and biophysical research communications 37 21439266
2011 GADD34 mediates cytoprotective autophagy in mutant huntingtin expressing cells via the mTOR pathway. Experimental cell research 36 21925170
2003 Gadd34 functional domains involved in growth suppression and apoptosis. Oncogene 36 12813455
1999 Cloning of a GADD34-like gene that interacts with the zinc-finger transcription factor which binds to the p21(WAF) promoter. Biochemical and biophysical research communications 36 10066455
2017 Oxidative stress promotes SIRT1 recruitment to the GADD34/PP1α complex to activate its deacetylase function. Cell death and differentiation 35 28984870
2002 Specific expression of the cell cycle regulation proteins, GADD34 and PCNA, in the peri-infarct zone after focal cerebral ischaemia in the rat. The European journal of neuroscience 35 12099899
2017 Chronic oxidative stress promotes GADD34-mediated phosphorylation of the TAR DNA-binding protein TDP-43, a modification linked to neurodegeneration. The Journal of biological chemistry 33 29109149
2003 Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions. Molecular and cellular biology 32 12724406
2006 Gadd34 requirement for normal hemoglobin synthesis. Molecular and cellular biology 31 16478986
2015 Enhancement of the acrolein-induced production of reactive oxygen species and lung injury by GADD34. Oxidative medicine and cellular longevity 30 25821552
2010 Selenium decreases thyroid cancer cell growth by increasing expression of GADD153 and GADD34. Nutrition and cancer 30 20043261
2007 Suppression of viral replication by stress-inducible GADD34 protein via the mammalian serine/threonine protein kinase mTOR pathway. Journal of virology 29 17670836
2017 GADD34 Function in Protein Trafficking Promotes Adaptation to Hyperosmotic Stress in Human Corneal Cells. Cell reports 28 29212034
2011 Association with endoplasmic reticulum promotes proteasomal degradation of GADD34 protein. The Journal of biological chemistry 28 21518769
2000 Interaction between DNA-damage protein GADD34 and a new member of the Hsp40 family of heat shock proteins that is induced by a DNA-damaging reagent. The Biochemical journal 28 11104688
2014 Inhibition of GADD34, the stress-inducible regulatory subunit of the endoplasmic reticulum stress response, does not enhance functional recovery after spinal cord injury. PloS one 25 25386686
2023 The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP). International journal of molecular sciences 24 38139150
2019 The regulatory protein GADD34 inhibits TRAIL-induced apoptosis via TRAF6/ERK-dependent stabilization of myeloid cell leukemia 1 in liver cancer cells. The Journal of biological chemistry 23 30782845
2015 GADD34 inhibits activation-induced apoptosis of macrophages through enhancement of autophagy. Scientific reports 23 25659802
2015 Growth arrest and DNA damage-inducible protein (GADD34) enhanced liver inflammation and tumorigenesis in a diethylnitrosamine (DEN)-treated murine model. Cancer immunology, immunotherapy : CII 23 25832002
2022 A systems biological analysis of the ATF4-GADD34-CHOP regulatory triangle upon endoplasmic reticulum stress. FEBS open bio 22 36097827
2022 Translation Rescue by Targeting Ppp1r15a through Its Upstream Open Reading Frame in Sepsis-Induced Acute Kidney Injury in a Murine Model. Journal of the American Society of Nephrology : JASN 22 36283811
2016 Regulation of de novo translation of host cells by manipulation of PERK/PKR and GADD34-PP1 activity during Newcastle disease virus infection. The Journal of general virology 22 26869028
2016 GADD34 Keeps the mTOR Pathway Inactivated in Endoplasmic Reticulum Stress Related Autophagy. PloS one 22 27992581
2015 GADD34-deficient mice develop obesity, nonalcoholic fatty liver disease, hepatic carcinoma and insulin resistance. Scientific reports 22 26316333
2010 N-terminally truncated GADD34 proteins are convenient translation enhancers in a human cell-derived in vitro protein synthesis system. Biotechnology letters 22 20349333
1999 Evidence for the interaction between Translin and GADD34 in mammalian cells. Biochimica et biophysica acta 22 10434033
2019 Knockdown of GADD34 in neonatal mutant SOD1 mice ameliorates ALS. Neurobiology of disease 20 31837419
2015 Increased GADD34 in oligodendrocytes in Alzheimer's disease. Neuroscience letters 20 26142647
2016 Unfolded protein response gene GADD34 is overexpressed in rheumatoid arthritis and related to the presence of circulating anti-citrullinated protein antibodies. Autoimmunity 19 26829377
2015 Effects of growth arrest and DNA damage-inducible protein 34 (GADD34) on inflammation-induced colon cancer in mice. British journal of cancer 19 26196182
2000 Interaction between GADD34 and kinesin superfamily, KIF3A. Biochemical and biophysical research communications 19 10631107
2024 Turnover of PPP1R15A mRNA encoding GADD34 controls responsiveness and adaptation to cellular stress. Cell reports 18 38602876
2022 Salidroside attenuates sepsis-associated acute lung injury through PPP1R15A mediated endoplasmic reticulum stress inhibition. Bioorganic & medicinal chemistry 18 35985062
2018 Guanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2α dephosphorylation by the GADD34/PP1c complex. Science signaling 18 29363586
2016 Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression. The Journal of biological chemistry 18 27129771
2004 GADD34 protein levels increase after transient ischemia in the cortex but not in the CA1 subfield: implications for post-ischemic recovery of protein synthesis in ischemia-resistant cells. Journal of neurochemistry 18 15255948
2021 Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF. Scientific reports 17 34732748
2022 Mxi1 participates in the progression of lung cancer via the microRNA-300/KLF9/GADD34 Axis. Cell death & disease 16 35501353
2024 PPP1R15A-expressing monocytic MDSCs promote immunosuppressive liver microenvironment in fibrosis-associated hepatocellular carcinoma. JHEP reports : innovation in hepatology 15 38882672
2017 Functional validation of ATF4 and GADD34 in Neuro2a cells by CRISPR/Cas9-mediated genome editing. Molecular and cellular biochemistry 15 28825160
2015 Coordinated Regulation of the Neutral Amino Acid Transporter SNAT2 and the Protein Phosphatase Subunit GADD34 Promotes Adaptation to Increased Extracellular Osmolarity. The Journal of biological chemistry 15 26041779
2014 Induction of GADD34 Regulates the Neurotoxicity of Amyloid β. American journal of Alzheimer's disease and other dementias 15 25204313
2018 Hairy and enhancer of split 1 (HES1) protects cells from endoplasmic reticulum stress-induced apoptosis through repression of . The Journal of biological chemistry 14 29491143
2009 EBNA3C interacts with Gadd34 and counteracts the unfolded protein response. Virology journal 14 20040105
2021 Growth arrest and DNA damage-inducible protein 34 (GADD34) contributes to cerebral ischemic injury and can be detected in plasma exosomes. Neuroscience letters 13 34098025
2021 GADD34-mediated dephosphorylation of eIF2α facilitates pseudorabies virus replication by maintaining de novo protein synthesis. Veterinary research 13 34930429
2015 GADD34 Facilitates Cell Death Resulting from Proteasome Inhibition. Anticancer research 13 26408692
2023 Single-cell RNA sequencing reveals the suppressive effect of PPP1R15A inhibitor Sephin1 in antitumor immunity. iScience 12 36718369
2004 Up-regulation of a growth arrest and DNA damage protein (GADD34) in the ischaemic human brain: implications for protein synthesis regulation and DNA repair. Neuropathology and applied neurobiology 12 15541008
2013 Phosphorylation at tyrosine 262 promotes GADD34 protein turnover. The Journal of biological chemistry 11 24092754
2025 Protein phosphatase 1 regulatory subunit 15 A (PPP1R15A) promoted the progression of gastric cancer by activating cell autophagy under energy stress. Journal of experimental & clinical cancer research : CR 10 39948597
2019 Capsaicin Induces ATF4 Translation with Upregulation of CHOP, GADD34 and PUMA. Biological & pharmaceutical bulletin 10 31366879
2016 Feasibility of novel PPP1R15A and proposed ANXA11 single nucleotide polymorphisms as predictive markers for bevacizumab regimen in metastatic colorectal cancer. Journal of cancer research and clinical oncology 10 27177629
2007 GADD34 induces p21 expression and cellular senescence. Oncology reports 10 17487408
2005 Evolution of GADD34 expression after focal cerebral ischaemia. Brain research 10 15713259
2021 Guanabenz Sensitizes Glioblastoma Cells to Sunitinib by Inhibiting GADD34-Mediated Autophagic Signaling. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 9 33410111
2019 The antibiotic robenidine exhibits guanabenz-like cytoprotective properties by a mechanism independent of protein phosphatase PP1:PPP1R15A. The Journal of biological chemistry 9 31337709
2019 GADD34 attenuates HIV-1 replication by viral 5'-UTR TAR RNA-mediated translational inhibition. Virology 9 31778897