PPP1R15A encodes GADD34, a stress-inducible regulatory subunit of protein phosphatase 1 (PP1). Its mRNA carries inhibitory uORFs and is translated, and transcribed via ATF4/CHOP, when eIF2alpha is phosphorylated during the integrated stress response. GADD34 binds the PP1 catalytic subunit through a C-terminal bipartite KVRF/RARA motif and recruits phosphorylated eIF2alpha (EIF2S1) through a conserved central substrate-binding region, forming a holophosphatase that dephosphorylates eIF2alpha Ser51 (Ser52 in precursor numbering). This restores eIF2B-mediated recycling and global protein synthesis, providing negative feedback that ends the PERK/ISR translational block and allows recovery from stress; prolonged activity also permits synthesis of pro-apoptotic CHOP targets. An N-terminal amphipathic helix anchors GADD34 peripherally on the cytoplasmic face of the ER membrane (and to a lesser extent mitochondria), targeting PP1alpha there; the protein is short-lived and degraded by the proteasome. GADD34 also interacts with LYN, SMAD7 and other partners, and contributes to restriction of some viruses.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000164 protein phosphatase type 1 complex | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN001046909 (PPP1R15 family) for PP1 complex membership. Reason: PPP1R15A is the stress-inducible regulatory subunit of a PP1 holophosphatase; membership is shown directly by co-purification with PP1c. Supporting Evidence: PMID:11381086 GADD34 formed a complex with the catalytic subunit of protein phosphatase 1 (PP1c) that specifically promoted the dephosphorylation of eIF2alpha in vitro. |
| GO:0000164 protein phosphatase type 1 complex | IDA PMID:11564868 Growth arrest and DNA damage-inducible protein GADD34 assemb... | ACCEPT | Summary: Affinity isolation of cellular GADD34/PP1 complexes that act as eIF-2alpha phosphatase. Reason: Direct evidence for a GADD34-PP1 holoenzyme. Supporting Evidence: PMID:11564868 While GADD34 inhibited PP1-catalyzed dephosphorylation of phosphorylase a, the GADD34-bound PP1 was an active eIF-2alpha phosphatase. |
| GO:0000164 protein phosphatase type 1 complex | IDA PMID:12556489 Growth arrest and DNA damage-inducible protein GADD34 target... | ACCEPT | Summary: GADD34 binds PP1alpha via KVRF and RARA motifs and assembles an ER-associated eIF2alpha phosphatase. Reason: Direct evidence for the PP1 holoenzyme. Supporting Evidence: PMID:12556489 These data provide new insights into the mode of action of GADD34 in assembling an ER-associated eIF-2 alpha phosphatase that regulates protein translation in mammalian cells. |
| GO:0000164 protein phosphatase type 1 complex | IPI PMID:26095357 Structural and Functional Analysis of the GADD34:PP1 eIF2Ξ± P... | ACCEPT | Summary: Structural and functional analysis of the GADD34:PP1 holoenzyme. Reason: Crystal structure and binding data define the GADD34-PP1 holophosphatase. Supporting Evidence: PMID:26095357 Here, we report detailed structural and functional analyses of the GADD34:PP1 holoenzyme and its recruitment of eIF2Ξ±. |
| GO:0000164 protein phosphatase type 1 complex | IPI PMID:34847777 Substrate recognition determinants of human eIF2Ξ± phosphatas... | ACCEPT | Summary: IPI (DisProt) placing PPP1R15A in the PP1 complex with PPP1CA and, per the WITH/FROM, Q9BY44. Reason: The holoenzyme claim is right; the paper defines R15A-PP1 heterodimeric eIF2alpha phosphatases. However the WITH/FROM lists UniProtKB:Q9BY44, which is EIF2A (eIF-2A, a different protein that shares the EIF2A alias), not the eIF2alpha subunit EIF2S1 (P05198) phosphorylated on Ser51 that the paper studies. Supporting Evidence: PMID:34847777 The phosphatases are composed of the catalytic subunit PP1 and one of two related non-catalytic subunits, PPP1R15A or PPP1R15B (R15A or R15B). |
| GO:0005515 protein binding | IPI PMID:11564868 Growth arrest and DNA damage-inducible protein GADD34 assemb... | REMOVE | Summary: Yeast two-hybrid interaction with PP1 inhibitor-1 (PPP1R1A). Reason: Bare protein binding is uninformative; the I-1/GADD34 interaction is a regulatory contact whose function is not captured by this term. Removal does not dispute the interaction. Supporting Evidence: PMID:11564868 The growth arrest and DNA damage-inducible protein, GADD34, was identified by its interaction with human inhibitor 1 (I-1), a protein kinase A (PKA)-activated inhibitor of type 1 protein serine/threonine phosphatase (PP1), in a yeast two-hybrid screen of a human brain cDNA library. |
| GO:0005515 protein binding | IPI PMID:15231748 Functional proteomics mapping of a human signaling pathway. | MODIFY | Summary: Two-hybrid interaction with PPP1CA in a Smad-pathway interactome. Reason: Binding to the PP1 catalytic subunit is the defining interaction of a PP1 regulatory subunit; the informative term is protein phosphatase 1 binding, which the gene already carries. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:12556489 Structure-function studies identified a bipartite C-terminal domain in GADD34 that encompassed a canonical PP1-binding motif, KVRF, and a novel RARA sequence, both of which were required for PP1 binding. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: High-throughput liver yeast two-hybrid interaction with CTBP2. Reason: Uninformative protein binding from a screen; no function identified. Supporting Evidence: PMID:21988832 we map the interactions of an unbiased selection of 5026 human liver expression proteins by yeast two-hybrid technology |
| GO:0005515 protein binding | IPI PMID:26095357 Structural and Functional Analysis of the GADD34:PP1 eIF2Ξ± P... | MODIFY | Summary: GADD34 binding to PPP1CA in the GADD34:PP1 structure paper. Reason: Specific PP1c binding is captured by protein phosphatase 1 binding. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:26095357 The data highlight independent interactions of PP1 and eIF2Ξ± with GADD34, demonstrating that GADD34 functions as a scaffold both in vitro and in cells. |
| GO:0005515 protein binding | IPI PMID:29109149 Chronic oxidative stress promotes GADD34-mediated phosphoryl... | MODIFY | Summary: GADD34 recruits PP1alpha in a study of oxidative-stress-driven TDP-43 phosphorylation. Reason: Specific PP1c binding is captured by protein phosphatase 1 binding. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:29109149 GADD34, the protein product of which recruits the Ξ±-isoform of protein phosphatase 1 catalytic subunit (PP1Ξ±) and eIF2Ξ± to assemble a phosphatase complex catalyzing eIF2Ξ± dephosphorylation and resumption of protein synthesis. |
| GO:0005515 protein binding | IPI PMID:29109149 Chronic oxidative stress promotes GADD34-mediated phosphoryl... | REMOVE | Summary: Interaction with TDP-43 (TARDBP) under chronic oxidative stress. Reason: Uninformative protein binding. The functional consequence reported (GADD34-dependent TDP-43 phosphorylation) is not captured by this term, and the mechanism is not established from the cached abstract. Supporting Evidence: PMID:29109149 Chronic oxidative stress promotes GADD34-mediated phosphorylation of the TAR DNA-binding protein TDP-43, a modification linked to neurodegeneration. |
| GO:0005737 cytoplasm | IDA PMID:21518769 Association with endoplasmic reticulum promotes proteasomal ... | MODIFY | Summary: Endogenous and ectopic GADD34 found in cytoplasm (soluble) and membrane fractions. Reason: Correct but general; the soluble pool is cytosolic (the gene carries cytosol from Reactome), and the V25R mutant that cannot bind membranes is 'largely cytosolic'. Proposed replacements: cytosol Supporting Evidence: PMID:21518769 Stress-induced endogenous and ectopically expressed GADD34 proteins were present both in the cytoplasm and in membranes, with their membrane association showing similar biochemical properties. |
| GO:0005739 mitochondrion | IDA PMID:21518769 Association with endoplasmic reticulum promotes proteasomal ... | KEEP AS NON CORE | Summary: GADD34 association with mitochondria via its N-terminal amphipathic helix (Zhou et al. 2011; abstract-only). Reason: Direct experimental localization (curated by UniProt as mitochondrial outer membrane, peripheral, cytoplasmic side). The eIF2alpha-phosphatase function is assigned to the ER-associated pool, so this is peripheral; deferring to the curator on the full-text imaging. Supporting Evidence: PMID:21518769 Substitution of leucines for three arginines on the polar surface indicated that the same helix also mediated the association of GADD34 with mitochondria. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt SubCell keyword mapping to mitochondrial outer membrane. Reason: Rests on PMID:21518769 (curated UniProt location); consistent with an amphipathic helix inserting peripherally on the cytoplasmic face. Peripheral to the core function. Supporting Evidence: file:human/PPP1R15A/PPP1R15A-uniprot.txt Mitochondrion outer membrane; Peripheral membrane protein; Cytoplasmic side {ECO:0000269|PubMed:21518769}. |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN001046909) for ER, is_active_in. Reason: The phosphorylation state of eIF2alpha is set at the ER by GADD34-PP1; GADD34 localizes to the ER via its N-terminal amphipathic helix in human and the family signal is conserved. Organelle claim checked against direct human evidence. Supporting Evidence: PMID:12556489 Imaging of green fluorescent protein (GFP)-GADD34 proteins showed that the N-terminal 180 residues directed the localization of GADD34 at the ER and that GADD34 targeted the alpha isoform of PP1 to the ER. |
| GO:0005783 endoplasmic reticulum | IDA PMID:12556489 Growth arrest and DNA damage-inducible protein GADD34 target... | ACCEPT | Summary: GFP-GADD34 imaging localizes GADD34 to the ER. Reason: Direct evidence; ER is where the GADD34-PP1 eIF2alpha phosphatase acts. Supporting Evidence: PMID:12556489 Imaging of green fluorescent protein (GFP)-GADD34 proteins showed that the N-terminal 180 residues directed the localization of GADD34 at the ER and that GADD34 targeted the alpha isoform of PP1 to the ER. |
| GO:0005783 endoplasmic reticulum | IDA PMID:21518769 Association with endoplasmic reticulum promotes proteasomal ... | ACCEPT | Summary: ER localization mediated by an N-terminal amphipathic helix (V25, L29). Reason: Direct evidence for ER association. Supporting Evidence: PMID:21518769 Deletion of N-terminal sequences in GADD34-GFP proteins highlighted an amphipathic helix, whose hydrophobic surface, specifically valine 25 and leucine 29, mediated endoplasmic reticulum (ER) localization. |
| GO:0005783 endoplasmic reticulum | IDA PMID:26742780 Targeted redox inhibition of protein phosphatase 1 by Nox4 r... | ACCEPT | Summary: Nox4 binds GADD34 at the ER and inhibits ER-localized PP1 activity. Reason: Direct evidence that the GADD34-PP1 phosphatase is active at the ER. Supporting Evidence: PMID:26742780 Here, we show that the reactive oxygen species-generating NADPH oxidase-4 (Nox4) is induced downstream of ATF4, binds to a PP1-targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2Ξ± phosphorylation and ATF4 levels. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell keyword mapping to ER membrane. Reason: Monotopic insertion of the N-terminal amphipathic helix into the cytoplasmic leaflet of the ER membrane is shown experimentally. Supporting Evidence: PMID:21518769 Fluorescence protease protection and chemical modification of cysteines substituted in the membrane-binding domain pointed to a monotopic insertion of GADD34 into the outer layer of the ER membrane. |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:21518769 Association with endoplasmic reticulum promotes proteasomal ... | ACCEPT | Summary: ER membrane (NAS) from Zhou et al. 2011. Reason: The paper's protease-protection and cysteine-modification data support peripheral insertion in the ER membrane. Supporting Evidence: PMID:21518769 Fluorescence protease protection and chemical modification of cysteines substituted in the membrane-binding domain pointed to a monotopic insertion of GADD34 into the outer layer of the ER membrane. |
| GO:0005794 Golgi apparatus | IDA PMID:21518769 Association with endoplasmic reticulum promotes proteasomal ... | UNDECIDED | Summary: Golgi apparatus (IDA) from Zhou et al. 2011; abstract-only cache does not mention Golgi. Reason: The cached abstract describes ER and mitochondrial association but not Golgi; UniProt does not list Golgi. Cannot verify the full-text observation, and the root-organelle policy needs the underlying assay to judge it. Supporting Evidence: PMID:21518769 Stress-induced endogenous and ectopically expressed GADD34 proteins were present both in the cytoplasm and in membranes |
| GO:0005829 cytosol | TAS Reactome:R-NUL-2167872 | ACCEPT | Summary: Reactome TAS cytosol (PP1-GADD34 dephosphorylation of eIF2alpha reaction). Reason: The soluble GADD34 pool and its eIF2alpha substrate are cytosolic; the phosphatase acts on the cytosolic face of the ER. Supporting Evidence: PMID:21518769 Stress-induced endogenous and ectopically expressed GADD34 proteins were present both in the cytoplasm and in membranes |
| GO:0005829 cytosol | TAS Reactome:R-NUL-2167890 | ACCEPT | Summary: Reactome TAS cytosol. Reason: As for the other Reactome cytosol row. Supporting Evidence: PMID:21518769 Stress-induced endogenous and ectopically expressed GADD34 proteins were present both in the cytoplasm and in membranes |
| GO:0006446 regulation of translational initiation | IDA PMID:11564868 Growth arrest and DNA damage-inducible protein GADD34 assemb... | MODIFY | Summary: GADD34/PP1 complexes dephosphorylate eIF-2alpha and regulate initiation of protein translation. Reason: Correct but general. GADD34 acts by targeting PP1 to phospho-eIF2alpha, so the precise process is GO:0036496 regulation of translational initiation by eIF2 alpha dephosphorylation (an is_a descendant via regulation of translational initiation in response to stress). As the regulatory subunit of the holophosphatase, GADD34 does part of the work of the dephosphorylation step. Proposed replacements: regulation of translational initiation by eIF2 alpha dephosphorylation Supporting Evidence: PMID:11564868 These studies suggested that modification of the I-1/GADD34/PP1 signaling complex regulates the initiation of protein translation in mammalian tissues. |
| GO:0006915 apoptotic process | TAS PMID:9153226 Mammalian GADD34, an apoptosis- and DNA damage-inducible gen... | MARK AS OVER ANNOTATED | Summary: TAS from the 1997 paper describing GADD34 as an apoptosis- and DNA damage-inducible gene. Reason: The paper shows correlation of GADD34 induction with radiation-induced apoptosis and speculates on a role from viral homology; it does not show GADD34 executes apoptosis. Later work places GADD34's effect on cell death downstream of restoring translation during ER stress. Supporting Evidence: PMID:9153226 The association of GADD34 expression with certain types of apoptosis and its homology with a known apoptosis regulator suggests that GADD34 may play a role in apoptosis as well. |
| GO:0006974 DNA damage response | TAS PMID:9153226 Mammalian GADD34, an apoptosis- and DNA damage-inducible gen... | MARK AS OVER ANNOTATED | Summary: TAS for DNA damage response from the 1997 induction study. Reason: Induction by ionizing radiation and MMS is an expression response, not evidence that GADD34 functions in the DNA damage response. Supporting Evidence: PMID:9153226 Induction of the human DNA damage- and growth arrest-inducible gene, GADD34, by ionizing radiation was only seen in certain cell lines and correlated with apoptosis following ionizing radiation. |
| GO:0008157 protein phosphatase 1 binding | IDA PMID:11564868 Growth arrest and DNA damage-inducible protein GADD34 assemb... | ACCEPT | Summary: GADD34 binds PP1 near its C-terminus in cellular complexes. Reason: PP1 binding via the KVRF/RARA bipartite motif is the defining activity of a PP1 regulatory subunit. Supporting Evidence: PMID:11564868 By comparison, affinity isolation of cellular GADD34/PP1 complexes showed that PP1 bound near the C terminus of GADD34 (amino acids 483 to 619) |
| GO:0008157 protein phosphatase 1 binding | IPI PMID:12556489 Growth arrest and DNA damage-inducible protein GADD34 target... | ACCEPT | Summary: GADD34 binds PP1alpha through a bipartite KVRF/RARA C-terminal domain. Reason: Direct mapping of the PP1-binding motifs; core. Supporting Evidence: PMID:12556489 Structure-function studies identified a bipartite C-terminal domain in GADD34 that encompassed a canonical PP1-binding motif, KVRF, and a novel RARA sequence, both of which were required for PP1 binding. |
| GO:0008157 protein phosphatase 1 binding | IPI PMID:21518769 Association with endoplasmic reticulum promotes proteasomal ... | ACCEPT | Summary: WT and V25R GADD34 scaffold PP1alpha. Reason: Direct binding evidence; core. Supporting Evidence: PMID:21518769 Both WT GADD34 and the mutant, V25R, effectively scaffolded the Ξ±-isoform of protein phosphatase-1 (PP1Ξ±) and enabled eIF2Ξ± dephosphorylation. |
| GO:0008157 protein phosphatase 1 binding | IPI PMID:34847777 Substrate recognition determinants of human eIF2Ξ± phosphatas... | ACCEPT | Summary: R15A truncations containing the PP1-binding region bind PP1. Reason: Direct binding evidence; core. Supporting Evidence: PMID:34847777 Activity assays in cells showed that R15A325-674 and R15B340-713, encompassing the substrate-binding region and the PP1-binding region, exhibit wild-type activity. |
| GO:0016020 membrane | IDA PMID:21518769 Association with endoplasmic reticulum promotes proteasomal ... | MODIFY | Summary: Membrane association of GADD34 (Zhou et al. 2011). Reason: Correct but general; the membrane is the ER membrane (monotopic insertion into its cytoplasmic leaflet), already carried by the gene. Mitochondrial outer membrane association is a secondary pool. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:21518769 Fluorescence protease protection and chemical modification of cysteines substituted in the membrane-binding domain pointed to a monotopic insertion of GADD34 into the outer layer of the ER membrane. |
| GO:0019888 protein phosphatase regulator activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN001046909) protein phosphatase regulator activity. Reason: Core activity of the PPP1R15 family; GADD34 directs PP1 activity toward phospho-eIF2alpha. Supporting Evidence: PMID:11381086 GADD34 formed a complex with the catalytic subunit of protein phosphatase 1 (PP1c) that specifically promoted the dephosphorylation of eIF2alpha in vitro. |
| GO:0019888 protein phosphatase regulator activity | IDA PMID:11564868 Growth arrest and DNA damage-inducible protein GADD34 assemb... | ACCEPT | Summary: GADD34-bound PP1 is an active eIF-2alpha phosphatase but inhibited toward phosphorylase a. Reason: Direct evidence that GADD34 changes PP1 substrate specificity, i.e. regulates the phosphatase. Supporting Evidence: PMID:11564868 While GADD34 inhibited PP1-catalyzed dephosphorylation of phosphorylase a, the GADD34-bound PP1 was an active eIF-2alpha phosphatase. |
| GO:0019888 protein phosphatase regulator activity | IDA PMID:12556489 Growth arrest and DNA damage-inducible protein GADD34 target... | ACCEPT | Summary: GADD34 expression reverses eIF-2alpha phosphorylation; PP1 binding necessary but not sufficient. Reason: Direct evidence for regulator function. Supporting Evidence: PMID:12556489 In this report, we show that the expression of human GADD34 in cultured cells reversed eIF-2 alpha phosphorylation induced by thapsigargin and tunicamycin, agents that promote protein unfolding in the endoplasmic reticulum (ER). |
| GO:0019888 protein phosphatase regulator activity | IEP PMID:34847777 Substrate recognition determinants of human eIF2Ξ± phosphatas... | ACCEPT | Summary: Protein phosphatase regulator activity with IEP evidence (DisProt) from the R15 substrate-recognition study. Reason: The term is correct (R15A fragments with substrate- and PP1-binding regions show wild-type eIF2alpha phosphatase activity). IEP is an unusual code for a molecular function; the claim is supported by the paper's activity assays. Supporting Evidence: PMID:34847777 Activity assays in cells showed that R15A325-674 and R15B340-713, encompassing the substrate-binding region and the PP1-binding region, exhibit wild-type activity. |
| GO:0019888 protein phosphatase regulator activity | ISS PMID:11381086 Feedback inhibition of the unfolded protein response by GADD... | ACCEPT | Summary: ISS from hamster GADD34 (P17564) based on Novoa et al. 2001. Reason: Consistent with human experimental evidence. Supporting Evidence: PMID:11381086 Mutations that interfered with the interaction with PP1c prevented the dephosphorylation of eIF2alpha and blocked attenuation of CHOP by GADD34. |
| GO:0019901 protein kinase binding | IPI PMID:11517336 Interaction between growth arrest-DNA damage protein 34 and ... | KEEP AS NON CORE | Summary: GADD34 binds the SH3 domain of LYN and is tyrosine-phosphorylated by it. Reason: A specific, experimentally supported interaction (GADD34 is a LYN substrate) that regulates its proapoptotic activity; peripheral to the eIF2alpha phosphatase function. Supporting Evidence: PMID:11517336 The specific interaction was confirmed by in vitro association of GADD34 with glutathione S-transferase fusion proteins containing the Src Homology 3 (SH3) domain of Lyn, as well as coimmunoprecipitation of GADD34 and Lyn from mammalian cells. |
| GO:0032058 positive regulation of translational initiation in response to stress | IDA PMID:12556489 Growth arrest and DNA damage-inducible protein GADD34 target... | ACCEPT | Summary: GADD34 reverses stress-induced eIF2alpha phosphorylation, restoring initiation. Reason: Dephosphorylating eIF2alpha after stress positively regulates translational initiation; correct sign and core process. Supporting Evidence: PMID:12556489 In this report, we show that the expression of human GADD34 in cultured cells reversed eIF-2 alpha phosphorylation induced by thapsigargin and tunicamycin, agents that promote protein unfolding in the endoplasmic reticulum (ER). |
| GO:0034976 response to endoplasmic reticulum stress | IBA GO_REF:0000033 | ACCEPT | Summary: IBA response to ER stress (PTN001046909). Reason: GADD34 is induced by ER stress and terminates its translational arm; inherited family-wide role. Supporting Evidence: PMID:11381086 Phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) on serine 51 integrates general translation repression with activation of stress-inducible genes such as ATF4, CHOP, and BiP in the unfolded protein response. |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:12556489 Growth arrest and DNA damage-inducible protein GADD34 target... | ACCEPT | Summary: GADD34 reverses thapsigargin/tunicamycin-induced eIF2alpha phosphorylation. Reason: Direct evidence. Supporting Evidence: PMID:12556489 In this report, we show that the expression of human GADD34 in cultured cells reversed eIF-2 alpha phosphorylation induced by thapsigargin and tunicamycin, agents that promote protein unfolding in the endoplasmic reticulum (ER). |
| GO:0036490 regulation of translation in response to endoplasmic reticulum stress | IDA PMID:21518769 Association with endoplasmic reticulum promotes proteasomal ... | ACCEPT | Summary: WT GADD34 scaffolds PP1alpha and enables eIF2alpha dephosphorylation (ER stress context). Reason: Regulation of translation in response to ER stress by eIF2alpha dephosphorylation is the core GADD34 role. Supporting Evidence: PMID:21518769 Both WT GADD34 and the mutant, V25R, effectively scaffolded the Ξ±-isoform of protein phosphatase-1 (PP1Ξ±) and enabled eIF2Ξ± dephosphorylation. |
| GO:0043558 regulation of translational initiation in response to stress | IDA PMID:11564868 Growth arrest and DNA damage-inducible protein GADD34 assemb... | MODIFY | Summary: Regulation of translational initiation in response to stress (Connor et al. 2001). Reason: Correct but general; refined to its is_a descendant GO:0036496 regulation of translational initiation by eIF2 alpha dephosphorylation, the specific mechanism. Proposed replacements: regulation of translational initiation by eIF2 alpha dephosphorylation Supporting Evidence: PMID:11564868 In contrast, the I-1/GADD34 and PP1/GADD34 interactions were disrupted in brain from hibernating animals, in which eIF-2alpha was highly phosphorylated at serine-51 and protein synthesis was inhibited. |
| GO:0043558 regulation of translational initiation in response to stress | ISS PMID:11381086 Feedback inhibition of the unfolded protein response by GADD... | MODIFY | Summary: ISS from hamster GADD34 (regulation of translational initiation in response to stress). Reason: As for the IDA row; refined to GO:0036496. Proposed replacements: regulation of translational initiation by eIF2 alpha dephosphorylation Supporting Evidence: PMID:11381086 GADD34 formed a complex with the catalytic subunit of protein phosphatase 1 (PP1c) that specifically promoted the dephosphorylation of eIF2alpha in vitro. |
| GO:0044828 host-mediated suppression of viral genome replication | IDA PMID:41747053 STING-NF-ΞΊB signaling builds an influenza spillover barrier. | KEEP AS NON CORE | Summary: STING-NF-kappaB-induced GADD34 restricts influenza A virus (abstract-only, 2026). Reason: The abstract states GADD34 is crucial for IAV restriction downstream of STING-NF-kappaB; UniProt curates this as inhibition of the viral RNA polymerase. A real but context-specific antiviral role; deferring to the curator for full-text details. Supporting Evidence: PMID:41747053 Among these NSGs, growth arrest and DNA damage-inducible protein 34 (GADD34) was crucial for IAV restriction. |
| GO:0051246 regulation of protein metabolic process | IEA GO_REF:0000117 | TOO GENERAL | Summary: ARBA-based IEA for regulation of protein metabolic process. Reason: True (GADD34 regulates protein synthesis) but uninformative beside the accepted regulation of translational initiation by eIF2 alpha dephosphorylation and positive regulation of translational initiation in response to stress. Supporting Evidence: PMID:11564868 These studies suggested that modification of the I-1/GADD34/PP1 signaling complex regulates the initiation of protein translation in mammalian tissues. |
| GO:0051726 regulation of cell cycle | TAS PMID:9153226 Mammalian GADD34, an apoptosis- and DNA damage-inducible gen... | MARK AS OVER ANNOTATED | Summary: TAS regulation of cell cycle from the 1997 induction paper. Reason: The 'growth arrest' name reflects co-induction with DNA damage, not a demonstrated cell-cycle function; the paper does not test cell-cycle regulation. Supporting Evidence: PMID:9153226 Induction of the human DNA damage- and growth arrest-inducible gene, GADD34, by ionizing radiation was only seen in certain cell lines and correlated with apoptosis following ionizing radiation. |
| GO:0060090 molecular adaptor activity | IDA PMID:26095357 Structural and Functional Analysis of the GADD34:PP1 eIF2Ξ± P... | MODIFY | Summary: GADD34 binds PP1 and eIF2alpha independently and functions as a scaffold. Reason: The adaptor function is specifically recruitment of the substrate (eIF2alpha) to the enzyme (PP1), which is GO:0140767 enzyme-substrate adaptor activity, an is_a descendant of molecular adaptor activity. Supported by independent binding sites and by substrate-trapping fragments. Proposed replacements: enzyme-substrate adaptor activity Supporting Evidence: PMID:26095357 The data highlight independent interactions of PP1 and eIF2Ξ± with GADD34, demonstrating that GADD34 functions as a scaffold both in vitro and in cells. PMID:34847777 In this minimal system, composed of R15, PP1 and the amino-terminal fragment of eIF2Ξ±, R15s recruit the substrate, providing substrate selectivity to the holoenzyme [18]. |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | TAS PMID:22934019 The endoplasmic reticulum stress response in aging and age-r... | KEEP AS NON CORE | Summary: Review (NAS/TAS) linking GADD34 to ER-stress-induced apoptosis. Reason: By restoring translation, GADD34 permits synthesis of pro-apoptotic CHOP targets under prolonged ER stress; an indirect, context-dependent contribution, non-core. Supporting Evidence: PMID:22934019 Suppression of the translational block by GADD34 allows for the synthesis of pro-apoptotic proteins like CHOP. |
| GO:0070972 protein localization to endoplasmic reticulum | IMP PMID:12556489 Growth arrest and DNA damage-inducible protein GADD34 target... | KEEP AS NON CORE | Summary: GADD34 N-terminus targets PP1alpha to the ER. Reason: GADD34 itself directs PP1alpha to the ER membrane, so it does the work of this localization; supportive of, but secondary to, the phosphatase-regulator role. Supporting Evidence: PMID:12556489 Imaging of green fluorescent protein (GFP)-GADD34 proteins showed that the N-terminal 180 residues directed the localization of GADD34 at the ER and that GADD34 targeted the alpha isoform of PP1 to the ER. |
| GO:0071074 eukaryotic initiation factor eIF2 binding | IPI PMID:34847777 Substrate recognition determinants of human eIF2Ξ± phosphatas... | ACCEPT | Summary: IPI (DisProt) for eIF2 binding via the conserved R15A substrate-recruitment region; WITH/FROM lists Q9BY44. Reason: Substrate recruitment of phospho-eIF2alpha is core to GADD34 function. The WITH/FROM UniProtKB:Q9BY44 is EIF2A (eIF-2A), not eIF2alpha/EIF2S1 (P05198), the Ser51 substrate studied. Supporting Evidence: PMID:34847777 Fragments containing the substrate-binding regions but lacking the PP1-binding motif trapped the phospho-substrate and caused accumulation of phosphorylated eIF2Ξ± in unstressed cells. |
| GO:0072542 protein phosphatase activator activity | IDA PMID:21518769 Association with endoplasmic reticulum promotes proteasomal ... | MODIFY | Summary: Protein phosphatase activator activity (IDA) from Zhou et al. 2011. Reason: Overly specific. GADD34 does not activate PP1 generally; it redirects PP1 toward eIF2alpha while inhibiting PP1 activity toward other substrates such as phosphorylase a. The supported term is the parent GO:0019888 protein phosphatase regulator activity. Proposed replacements: protein phosphatase regulator activity Supporting Evidence: PMID:11564868 While GADD34 inhibited PP1-catalyzed dephosphorylation of phosphorylase a, the GADD34-bound PP1 was an active eIF-2alpha phosphatase. |
| GO:0140870 RNA polymerase inhibitor activity | IDA PMID:41747053 STING-NF-ΞΊB signaling builds an influenza spillover barrier. | UNDECIDED | Summary: RNA polymerase inhibitor activity (IDA) for influenza A RNA polymerase, from an abstract-only 2026 paper. Reason: UniProt curates that GADD34 mediates inhibition of influenza A virus RNA polymerase, but the cached abstract only states GADD34 is crucial for IAV restriction; whether GADD34 inhibits the polymerase directly (as this molecular-function term asserts) or indirectly (e.g. via its PP1 phosphatase activity) cannot be checked without the full text. Supporting Evidence: file:human/PPP1R15A/PPP1R15A-uniprot.txt Mediates the inhibition of influenza A virus RNA polymerase (PubMed:41747053). |
| GO:1901798 positive regulation of signal transduction by p53 class mediator | ISS PMID:14635196 GADD34 induces p53 phosphorylation and p21/WAF1 transcriptio... | MARK AS OVER ANNOTATED | Summary: ISS from hamster for positive regulation of p53 signal transduction, based on a human overexpression study (Yagi et al. 2003). Reason: Overexpression of GADD34 increased p53 Ser15 phosphorylation and p21 promoter activity; no mechanism, and UniProt hedges ('May promote apoptosis'). Over-interpretation of an overexpression phenotype. Supporting Evidence: PMID:14635196 Transfected Myc-tagged p53 was dose-dependently phosphorylated at Ser15 by increasing the amount of GADD34. |
| GO:1903898 negative regulation of PERK-mediated unfolded protein response | TAS PMID:22013210 The unfolded protein response: integrating stress signals th... | ACCEPT | Summary: TAS from an IRE1 review for negative regulation of PERK-mediated UPR. Reason: GADD34-mediated eIF2alpha dephosphorylation is the feedback that terminates the PERK translational arm; shown directly in Novoa et al. 2001. Supporting Evidence: PMID:11381086 Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. |
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Download this section (compressed HTML)Q: Does GADD34 inhibit influenza A virus RNA polymerase directly, or does restriction depend on its PP1-targeting activity toward eIF2alpha or another substrate?
Q: Several IPI rows (DisProt) for PPP1R15A and PPP1R15B list UniProtKB:Q9BY44 (EIF2A, eIF-2A) as the eIF2 partner; should these be repointed to EIF2S1 (P05198)?
Experiment: Test PP1-binding-deficient (KVRF/RARA) and substrate-binding-deficient GADD34 mutants for influenza A restriction and polymerase activity in minigenome assays.
Hypothesis: GADD34 restricts influenza through PP1-mediated dephosphorylation of a specific substrate rather than by binding the viral polymerase.
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The mechanism by which GADD34 restricts influenza A virus replication (direct polymerase inhibition versus PP1-dependent dephosphorylation of a host or viral substrate) is unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
Provenance (the field's own admissions):
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