id: Q92616
gene_symbol: GCN1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: GCN1 (stalled ribosome sensor GCN1, formerly GCN1L1) is a very large cytoplasmic HEAT-repeat/alpha-solenoid protein that binds directly to ribosomes and acts as a sentinel for stalled and collided ribosomes. Through its RWD-binding domain it engages RWD-domain proteins and serves two intertwined ribosome-surveillance functions. First, GCN1 activates the eIF2alpha kinase GCN2 (EIF2AK4) on translating ribosomes, stimulating GCN2 to phosphorylate eIF2alpha (EIF2S1) and thereby triggering the integrated stress response and the cellular response to amino-acid starvation (the GCN2-mediated signaling axis conserved from yeast GCN1/GCN20). Second, GCN1 is the collision sensor of the RNF14-RNF25 translation quality-control pathway, where it is required for ubiquitination and degradation of translation factors (eEF1A/eEF1A1, eRF1/ETF1) and ribosomal proteins on stalled ribosomes, including resolution of formaldehyde-induced mRNA RNA-protein crosslinks. GCN1 binding by IMPACT antagonizes GCN2 activation. GCN1 is ribosome/polysome-associated in the cytosol.
existing_annotations:
- term:
    id: GO:0006417
    label: regulation of translation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Broad phylogenetically inferred process term. GCN1's specific roles are activation of the GCN2/ISR pathway and collided-ribosome quality control; these down-regulate translation, but the broad term is non-specific.
    action: KEEP_AS_NON_CORE
    reason: Correct in direction but too general; the informative core roles (GCN2 activation/ISR and RQC) are captured by more specific terms.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-goa.tsv
      supporting_text: GO:0006417 regulation of translation biological_process ECO:0000318 IBA
- term:
    id: GO:0019887
    label: protein kinase regulator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: GCN1 regulates (activates) the protein kinase GCN2/EIF2AK4. This is a core molecular function, though the more specific protein serine/threonine kinase activator activity term is preferable.
    action: KEEP_AS_NON_CORE
    reason: Accurate but less specific than the protein serine/threonine kinase activator activity term that more precisely captures GCN1's activation of GCN2; retained as a valid parent.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: stimulates EIF2AK4/GCN2 kinase activity, leading to phosphorylation of eukaryotic translation initiation factor 2
- term:
    id: GO:0034198
    label: cellular response to amino acid starvation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: GCN1 mediates activation of GCN2 in response to amino-acid starvation, a conserved role (yeast GCN1/GCN20 -> GCN2 -> eIF2alpha -> GCN4/ATF4). This is a core biological process for GCN1.
    action: ACCEPT
    reason: Well-supported, conserved core role of GCN1 in the amino-acid starvation response via GCN2 activation.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: positive activator of the integrated stress response (ISR) by mediating activation of EIF2AK4/GCN2 in response to amino acid starvation
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: GCN1 acts in the cytosol, associated with ribosomes/polysomes. Phylogenetically inferred and experimentally supported.
    action: ACCEPT
    reason: Correct site of action for this cytosolic ribosome-associated sensor.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation of cytoplasmic localization, consistent with the documented cytoplasmic/ribosome-associated location of GCN1.
    action: ACCEPT
    reason: Correct compartment, corroborated by experimental and similarity evidence.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17314511
  qualifier: enables
  review:
    summary: c-MYC interactome (TAP/MudPIT) screen capturing a GCN1-MYC (P01106) interaction. GCN1 is a very large, abundant ribosome-associated protein; this isolated high-throughput interaction does not inform its core function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from a single large-scale affinity screen with a partner (MYC) unrelated to GCN1's ribosome-surveillance function; uninformative and not core.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:17314511 UniProtKB:P01106
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20936779
  qualifier: enables
  review:
    summary: Human MAP kinase interactome screen capturing a GCN1-MYC (P01106) interaction. Isolated high-throughput interaction unrelated to GCN1's core function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from a high-throughput interactome with an unrelated partner; uninformative and not core.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20936779 UniProtKB:P01106
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38884001
  qualifier: enables
  review:
    summary: Adipocyte HaloTag-enrichment mass-spectrometry interactome capturing a GCN1-MYC (P01106) interaction. Isolated high-throughput interaction unrelated to GCN1's core function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from a high-throughput proteomic screen with an unrelated partner; uninformative and not core.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:38884001 UniProtKB:P01106
- term:
    id: GO:0034198
    label: cellular response to amino acid starvation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic annotation of the amino-acid starvation response, consistent with GCN1's conserved role in GCN2 activation.
    action: ACCEPT
    reason: Correct core biological process, corroborated by experimental/ISS evidence.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: positive activator of the integrated stress response (ISR) by mediating activation of EIF2AK4/GCN2 in response to amino acid starvation
- term:
    id: GO:0043539
    label: protein serine/threonine kinase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: GCN1 activates the serine/threonine kinase GCN2/EIF2AK4 on translating ribosomes, stimulating eIF2alpha phosphorylation. This is a core molecular function.
    action: ACCEPT
    reason: Precisely captures GCN1's core activity as an activator of the GCN2 protein serine/threonine kinase.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: stimulates EIF2AK4/GCN2 kinase activity, leading to phosphorylation of eukaryotic translation initiation factor 2
- term:
    id: GO:0140469
    label: GCN2-mediated signaling
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: GCN1 is upstream activator of GCN2-mediated signaling. Core biological process capturing the ISR-activation role.
    action: ACCEPT
    reason: Directly reflects GCN1's role in stimulating GCN2 signaling; core process.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: Interaction with EIF2AK4/GCN2 on translating ribosomes stimulates EIF2AK4/GCN2 kinase activity
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for cytosolic localization, consistent with GCN1's ribosome-associated cytosolic location.
    action: ACCEPT
    reason: IDA-supported cytosolic localization matching the documented site of action.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000314 IDA GO_REF:0000052
- term:
    id: GO:0022626
    label: cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: is_active_in
  review:
    summary: GCN1 is active on the cytosolic ribosome, where it senses collided ribosomes and engages RNF14. Direct experimental evidence.
    action: ACCEPT
    reason: Core cellular component/site of action; GCN1 binds and acts on cytosolic ribosomes.
    supported_by:
    - reference_id: PMID:36638793
      supporting_text: GCN1 is a conserved ribosome-associated scaffolding protein that binds the RWD domain of the integrated stress response kinase, GCN2
- term:
    id: GO:0170011
    label: stalled ribosome sensor activity
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: enables
  review:
    summary: GCN1 directly senses stalled/collided ribosomes (occluded A site) and recruits RNF14, triggering degradation of translation factors. This is the core molecular function of GCN1.
    action: ACCEPT
    reason: Directly demonstrated core MF; GCN1 is the ribosome collision sensor of the RNF14-RNF25 quality-control pathway.
    supported_by:
    - reference_id: PMID:36638793
      supporting_text: The ribosome collision sensor GCN1 plays an
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: acts as a sentinel for colliding ribosomes
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based annotation of cytoplasmic localization, consistent with experimental evidence.
    action: ACCEPT
    reason: Correct compartment, corroborated by IDA evidence.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0160127
    label: protein-RNA covalent cross-linking repair
  evidence_type: IDA
  original_reference_id: PMID:37951215
  qualifier: involved_in
  review:
    summary: GCN1 is required for translation-coupled resolution of formaldehyde-induced mRNA RNA-protein crosslinks that stall ribosomes (RNF14/RNF25 pathway). A specific RQC-adjacent biological process.
    action: ACCEPT
    reason: GCN1's collision-sensing role is required for resolving ribosome stalls at RNA-protein crosslinks; supported by the companion RNF14 crosslink-resolution studies.
    supported_by:
    - reference_id: PMID:37951216
      supporting_text: which also requires the ribosome collision sensor GCN1
    - reference_id: file:human/GCN1/GCN1-goa.tsv
      supporting_text: GO:0160127 protein-RNA covalent cross-linking repair biological_process ECO:0000314 IDA PMID:37951215
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37651229
  qualifier: involved_in
  review:
    summary: GCN1 functions in a branch of ribosome-associated quality control that rescues stalled ribosomes via RNF14/RNF25-mediated degradation of A-site-blocking factors (here eRF1). Core RQC biological process.
    action: ACCEPT
    reason: Directly supported role of GCN1 in stalled-ribosome rescue through the RNF14/RNF25 pathway.
    supported_by:
    - reference_id: PMID:37651229
      supporting_text: activating a branch of the ribosome-associated quality control network, which involves the translational stress sensor GCN1 and the catalytic activity of the E3 ubiquitin ligases RNF14 and RNF25
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37951215
  qualifier: involved_in
  review:
    summary: GCN1 is required for resolution of ribosomes stalled at formaldehyde-induced RNA-protein crosslinks (RNF14 pathway). Core RQC biological process.
    action: ACCEPT
    reason: Supported by the RNF14 crosslink-resolution studies that require the collision sensor GCN1.
    supported_by:
    - reference_id: PMID:37951216
      supporting_text: which also requires the ribosome collision sensor GCN1
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37951216
  qualifier: involved_in
  review:
    summary: RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks and requires the ribosome collision sensor GCN1. Core RQC biological process.
    action: ACCEPT
    reason: Directly supported; GCN1 is required for RNF14/RNF25-mediated resolution of stalled ribosomes.
    supported_by:
    - reference_id: PMID:37951216
      supporting_text: which also requires the ribosome collision sensor GCN1
- term:
    id: GO:0170011
    label: stalled ribosome sensor activity
  evidence_type: IDA
  original_reference_id: PMID:37651229
  qualifier: enables
  review:
    summary: GCN1 senses stalled ribosomes (here induced by eRF1 depletion/readthrough) to engage the RNF14/RNF25 RQC branch. Core molecular function.
    action: ACCEPT
    reason: Directly demonstrated core sensor MF in a second independent stalling context.
    supported_by:
    - reference_id: PMID:37651229
      supporting_text: activating a branch of the ribosome-associated quality control network, which involves the translational stress sensor GCN1 and the catalytic activity of the E3 ubiquitin ligases RNF14 and RNF25
- term:
    id: GO:0170011
    label: stalled ribosome sensor activity
  evidence_type: IDA
  original_reference_id: PMID:37951215
  qualifier: enables
  review:
    summary: GCN1 senses ribosomes stalled at formaldehyde-induced RNA-protein crosslinks. Core molecular function.
    action: ACCEPT
    reason: Directly supported core sensor MF in the RNA-protein crosslink stalling context.
    supported_by:
    - reference_id: PMID:37951216
      supporting_text: which also requires the ribosome collision sensor GCN1
- term:
    id: GO:0170011
    label: stalled ribosome sensor activity
  evidence_type: IDA
  original_reference_id: PMID:37951216
  qualifier: enables
  review:
    summary: GCN1 senses stalled/collided ribosomes in the RNF14-dependent crosslink-resolution pathway. Core molecular function.
    action: ACCEPT
    reason: Directly supported core sensor MF.
    supported_by:
    - reference_id: PMID:37951216
      supporting_text: which also requires the ribosome collision sensor GCN1
- term:
    id: GO:0043539
    label: protein serine/threonine kinase activator activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity-based annotation of GCN2 (serine/threonine kinase) activator activity, consistent with the conserved GCN1->GCN2 activation role.
    action: ACCEPT
    reason: Core MF, corroborated by experimental and ortholog evidence.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: stimulates EIF2AK4/GCN2 kinase activity, leading to phosphorylation of eukaryotic translation initiation factor 2
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: enables
  review:
    summary: GCN1 acts as a ribosome-associated scaffold/adaptor that, via its RWD-binding domain, brings RWD-domain partners (GCN2, RNF14, IMPACT) to stalled ribosomes. A reasonable molecular-function description of its scaffolding role.
    action: ACCEPT
    reason: GCN1 is described as a scaffolding protein that recruits RWD-domain effectors to the ribosome; adaptor activity captures this bridging function.
    supported_by:
    - reference_id: PMID:36638793
      supporting_text: GCN1 is a conserved ribosome-associated scaffolding protein that binds the RWD domain of the integrated stress response kinase, GCN2
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: involved_in
  review:
    summary: GCN1 senses stalled ribosomes and recruits RNF14 to ubiquitinate and degrade A-site-blocking translation factors (eEF1A), a stalled-ribosome rescue process. Core RQC biological process.
    action: ACCEPT
    reason: Directly demonstrated; GCN1 is essential for RNF14/RNF25-mediated rescue of stalled ribosomes.
    supported_by:
    - reference_id: PMID:36638793
      supporting_text: interacts with RNF14 and is also essential for eEF1A degradation
- term:
    id: GO:0140469
    label: GCN2-mediated signaling
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity-based annotation of GCN1's role in GCN2-mediated signaling, consistent with experimental evidence.
    action: ACCEPT
    reason: Core process; GCN1 is the upstream activator of GCN2 signaling.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: Interaction with EIF2AK4/GCN2 on translating ribosomes stimulates EIF2AK4/GCN2 kinase activity
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: HDA
  original_reference_id: PMID:25468996
  qualifier: enables
  review:
    summary: High-throughput quantitative proteomics of the E-cadherin interactome capturing GCN1. GCN1 is a very large, abundant ribosome-associated protein; this is a non-specific proximity/affinity capture, not a genuine cadherin-binding function.
    action: MARK_AS_OVER_ANNOTATED
    reason: HDA proteomic capture inconsistent with GCN1's known cytosolic ribosome-surveillance function; likely a non-specific co-purification.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-goa.tsv
      supporting_text: GO:0045296 cadherin binding molecular_function ECO:0007005 HDA PMID:25468996
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput NK-cell membrane proteome capture. GCN1 is a cytosolic ribosome-associated protein; membrane localization is inconsistent with its established biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: HDA membrane-proteome capture conflicts with the well-documented cytosolic/ribosomal localization of GCN1; likely a contaminant in the membrane fraction.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-goa.tsv
      supporting_text: GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  qualifier: enables
  review:
    summary: mRNA-interactome capture identifying GCN1 as an RNA-associated protein. GCN1 associates with ribosomes/rRNA and senses mRNA-bound stalled ribosomes, so some RNA association is expected, but the bare RNA binding term is non-specific and not the informative core function.
    action: KEEP_AS_NON_CORE
    reason: Plausible given ribosome/mRNA association, but uninformative relative to GCN1's core sensor/scaffold and kinase-activator roles.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-goa.tsv
      supporting_text: GO:0003723 RNA binding molecular_function ECO:0007005 HDA PMID:22681889
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: NAS
  original_reference_id: PMID:9234705
  qualifier: located_in
  review:
    summary: Non-traceable author statement of cytoplasmic localization from the classic yeast GCN1/GCN20 study, consistent with the documented cytoplasmic location.
    action: ACCEPT
    reason: Consistent with experimental and similarity evidence for cytoplasmic localization.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005840
    label: ribosome
  evidence_type: NAS
  original_reference_id: PMID:9234705
  qualifier: located_in
  review:
    summary: Author statement that GCN1 (with GCN20) co-sediments with polysomes/80S ribosomes and functions on elongating ribosomes. Consistent with GCN1's ribosome-associated role.
    action: ACCEPT
    reason: Correct ribosome-associated localization, consistent with the cytosolic ribosome IDA annotation and GCN1's mechanism.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: Associates with ribosomes
- term:
    id: GO:0008135
    label: translation factor activity, RNA binding
  evidence_type: NAS
  original_reference_id: PMID:9234705
  qualifier: enables
  review:
    summary: Outdated framing of GCN1 as a translation factor from the 1997 yeast study. GCN1 is now understood as a ribosome collision sensor and scaffold/activator of GCN2, not a canonical translation factor.
    action: MARK_AS_OVER_ANNOTATED
    reason: GCN1's molecular function is better captured by stalled ribosome sensor activity and kinase activator activity; the generic translation-factor MF is a legacy over-annotation.
    supported_by:
    - reference_id: file:human/GCN1/GCN1-uniprot.txt
      supporting_text: acts as a sentinel for colliding ribosomes
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:9234705
  title: Evidence that GCN1 and GCN20, translational regulators of GCN4, function on elongating ribosomes in activation of eIF2alpha kinase GCN2.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_9234705.md title matches YAML; foundational
      (yeast) evidence that GCN1 stimulates the eIF2alpha kinase GCN2 on ribosomes,
      supporting the core kinase-activator function. GOA anchors this PMID to GO:0008135
      (NAS) and ribosome localization."
  findings:
  - statement: GCN1 and GCN20 form a complex required for stimulation of GCN2 kinase activity under amino-acid starvation; they co-sediment with polysomes and 80S ribosomes and function on elongating ribosomes.
    reference_section_type: ABSTRACT
- id: PMID:17314511
  title: Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20936779
  title: A human MAP kinase interactome.
  findings: []
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
  findings: []
- id: PMID:25468996
  title: E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
  findings: []
- id: PMID:36638793
  title: An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_36638793.md title matches YAML; establishes
      the human core functions — GCN1 as a ribosome-collision sensor and RNF14 adaptor.
      GOA anchors this PMID to GO:0170011 (stalled ribosome sensor activity), GO:0060090
      (molecular adaptor activity) and GO:0072344 (rescue of stalled ribosome), all IDA."
  findings:
  - statement: GCN1 is a ribosome collision sensor that interacts with RNF14 and is essential for ubiquitination and degradation of eEF1A (and other translation factors/ribosomal proteins) on stalled ribosomes with an occluded A site.
    reference_section_type: ABSTRACT
  - statement: GCN1 is a conserved ribosome-associated scaffolding protein that binds the RWD domain of the GCN2 kinase; IMPACT competes for this interaction.
    reference_section_type: RESULTS
- id: PMID:37651229
  title: Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control.
  findings:
  - statement: Drug-induced stalling triggers a branch of ribosome-associated quality control involving the translational stress sensor GCN1 and the E3 ligases RNF14 and RNF25, leading to eRF1 degradation.
    reference_section_type: ABSTRACT
- id: PMID:37951215
  title: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution.
  findings:
  - statement: Formaldehyde-induced RNA-protein crosslinks in mRNA stall ribosomes and are marked by RNF14-catalyzed K6-linked ubiquitylation and resolved by VCP; GCN1 acts as the collision sensor in this pathway.
    reference_section_type: ABSTRACT
- id: PMID:37951216
  title: RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks.
  findings:
  - statement: RNF14/RNF25-dependent ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks and requires the ribosome collision sensor GCN1.
    reference_section_type: RESULTS
- id: PMID:38884001
  title: Mapping adipocyte interactome networks by HaloTag-enrichment-mass spectrometry.
  findings: []
core_functions:
- description: Ribosome collision/stall sensor that binds the ribosome and recognizes stalled and collided ribosomes (occluded A site), serving as the trigger for downstream quality-control and stress-response effectors via its RWD-binding domain.
  molecular_function:
    id: GO:0170011
    label: stalled ribosome sensor activity
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: file:human/GCN1/GCN1-uniprot.txt
    supporting_text: acts as a sentinel for colliding ribosomes
  - reference_id: PMID:36638793
    supporting_text: GCN1 is a conserved ribosome-associated scaffolding protein that binds the RWD domain of the integrated stress response kinase, GCN2
- description: Activator of the eIF2alpha kinase GCN2 (EIF2AK4) on translating ribosomes, stimulating GCN2 to phosphorylate eIF2alpha and thereby triggering the integrated stress response and the cellular response to amino-acid starvation.
  molecular_function:
    id: GO:0043539
    label: protein serine/threonine kinase activator activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/GCN1/GCN1-uniprot.txt
    supporting_text: stimulates EIF2AK4/GCN2 kinase activity, leading to phosphorylation of eukaryotic translation initiation factor 2
- description: Essential scaffold of the RNF14-RNF25 translation quality-control pathway, recruiting the E3 ligase RNF14 to stalled ribosomes to promote ubiquitination and degradation of A-site-blocking translation factors (eEF1A, eRF1) and rescue of stalled ribosomes.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: PMID:36638793
    supporting_text: interacts with RNF14 and is also essential for eEF1A degradation
proposed_new_terms: []
suggested_questions:
- question: What structural features distinguish GCN1's recognition of collided ribosomes that activate GCN2/ISR versus those that engage the RNF14-RNF25 degradation branch?
- question: How is the choice between GCN2-mediated ISR signaling and RNF14/RNF25-mediated factor degradation coordinated on the same stalled-ribosome substrate, and what determines the balance?
- question: Does IMPACT-mediated antagonism of GCN1-GCN2 binding also modulate the RNF14 quality-control branch?
suggested_experiments:
- description: Cryo-EM of GCN1 bound to collided (disome) ribosomes with and without GCN2, RNF14 or IMPACT to define how the HEAT-repeat solenoid and RWD-binding domain discriminate substrates and effectors.
- description: Degron/ubiquitination kinetics (eEF1A, eRF1) on stalled-ribosome reporters in GCN1-knockout versus wild-type cells to quantify GCN1's requirement across distinct stalling stimuli (poly(A), ternatin-4, formaldehyde RPCs, eRF1 depletion).
- description: Phospho-eIF2alpha and ATF4 reporter assays in GCN1-knockout cells under amino-acid starvation versus collision stress to dissect the GCN2-activation versus RQC functions of GCN1.