Component

Mouse GCN2 / Eif2ak4

Context-specific entity; species, compartment and exposure are stated on each claim.

8 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What it acts on

  1. GCN2 loss prevented induction of stress-target genes such as CHOP even though amino-acid-limited CD8 cells still arrested.

    Mouse GCN2 / Eif2ak4 → Mouse CHOP / Ddit3 source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary abstract
    experimental_model
    Mouse Gcn2-deficient CD8 T-cell experiments.
    limitations
    Does not make GCN2 dispensable for T-cell fitness; proliferation and trafficking defects were also observed.
    nutrient_topic
    Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
    plain_language
    A stress gene response and the division checkpoint could be separated.
    primary_references
    Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27880901/ · DOI 10.1016/j.celrep.2016.10.079
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 386–392

    AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse Gcn2-deficient CD8 T-cell experiments. · source_derived_draft · unverified_draft

    ## tryptophan-gcn2-chop A stress gene response and the division checkpoint could be separated. GCN2 loss prevented induction of stress-target genes such as CHOP even though amino-acid-limited CD8 cells still arrested. Model: Mouse Gcn2-deficient CD8 T-cell experiments. Limitations: Does not make GCN2 dispensable for T-cell fitness; proliferation and trafficking defects were also observed. Evidence access: Primary abstract Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27880901/ · DOI 10.1016/j.celrep.2016.10.079
    Complete structured claim and evidence

  2. Donor mouse T cells lacking GCN2 still responded to IDO-mediated suppression in graft-versus-host disease experiments.

    Mouse GCN2 / Eif2ak4 → Mouse T-cell proliferation under tryptophan limitation or IDO exposure source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary abstract
    experimental_model
    Mouse allogeneic transplantation and donor T-cell genetics.
    limitations
    The authors favor metabolite-mediated suppression; it does not prove which single metabolite explains all models.
    nutrient_topic
    Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
    plain_language
    In a transplant model, IDO suppression also persisted without GCN2.
    primary_references
    Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19828695/ · DOI 10.1182/blood-2009-06-227587

    Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 394–400

    AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse allogeneic transplantation and donor T-cell genetics. · source_derived_draft · unverified_draft

    ## tryptophan-gcn2-gvhd In a transplant model, IDO suppression also persisted without GCN2. Donor mouse T cells lacking GCN2 still responded to IDO-mediated suppression in graft-versus-host disease experiments. Model: Mouse allogeneic transplantation and donor T-cell genetics. Limitations: The authors favor metabolite-mediated suppression; it does not prove which single metabolite explains all models. Evidence access: Primary abstract Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19828695/ · DOI 10.1182/blood-2009-06-227587
    Complete structured claim and evidence

  3. GCN2-deficient mouse CD8 T cells still failed to proliferate under limiting tryptophan, arginine, leucine, lysine or asparagine in the 2016 study.

    Mouse GCN2 / Eif2ak4 → Mouse T-cell proliferation under tryptophan limitation or IDO exposure source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary abstract
    experimental_model
    Gcn2-deficient mice crossed to TCR-transgenic backgrounds; defined amino-acid limitation.
    limitations
    Not identical to every IDO-dendritic-cell preparation; the authors explicitly challenge the earlier necessity model.
    nutrient_topic
    Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
    plain_language
    Another study found the division block persisted without that sensor.
    primary_references
    Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27880901/ · DOI 10.1016/j.celrep.2016.10.079
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 378–384

    AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Gcn2-deficient mice crossed to TCR-transgenic backgrounds; defined amino-acid limitation. · source_derived_draft · unverified_draft

    ## tryptophan-gcn2-not-required Another study found the division block persisted without that sensor. GCN2-deficient mouse CD8 T cells still failed to proliferate under limiting tryptophan, arginine, leucine, lysine or asparagine in the 2016 study. Model: Gcn2-deficient mice crossed to TCR-transgenic backgrounds; defined amino-acid limitation. Limitations: Not identical to every IDO-dendritic-cell preparation; the authors explicitly challenge the earlier necessity model. Evidence access: Primary abstract Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27880901/ · DOI 10.1016/j.celrep.2016.10.079
    Complete structured claim and evidence

  4. GCN2-deficient mouse T cells resisted suppression and anergy imposed by IDO-expressing dendritic cells in the 2005 study.

    Mouse GCN2 / Eif2ak4 → Mouse T-cell proliferation under tryptophan limitation or IDO exposure source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary abstract
    experimental_model
    Mouse Gcn2 knockout, IDO-positive plasmacytoid/tumor-draining dendritic-cell experiments.
    limitations
    A later genetic study reports arrest without GCN2; necessity is not universal across the available evidence.
    nutrient_topic
    Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
    plain_language
    One study found this nutrient-stress sensor necessary for suppression.
    primary_references
    GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15894280/ · DOI 10.1016/j.immuni.2005.03.013
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 370–376

    AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse Gcn2 knockout, IDO-positive plasmacytoid/tumor-draining dendritic-cell experiments. · source_derived_draft · unverified_draft

    ## tryptophan-gcn2-required One study found this nutrient-stress sensor necessary for suppression. GCN2-deficient mouse T cells resisted suppression and anergy imposed by IDO-expressing dendritic cells in the 2005 study. Model: Mouse Gcn2 knockout, IDO-positive plasmacytoid/tumor-draining dendritic-cell experiments. Limitations: A later genetic study reports arrest without GCN2; necessity is not universal across the available evidence. Evidence access: Primary abstract GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15894280/ · DOI 10.1016/j.immuni.2005.03.013
    Complete structured claim and evidence

What acts on it

  1. Liver-specific Gcn2 deletion did not prevent low-isoleucine improvements in glucose tolerance or body-composition measures.

    Experimentally reduced-isoleucine mouse diet → Mouse GCN2 / Eif2ak4 source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary full text
    experimental_model
    Mouse liver-specific Gcn2 knockout, twelve-day and three-week glucose tests.
    limitations
    Not equivalent to complete cellular starvation or loss of GCN2 in every tissue.
    nutrient_topic
    L-Isoleucine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Isoleucine
    plain_language
    A common amino-acid stress sensor was dispensable in this liver/diet experiment.
    primary_references
    The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33887198/ · DOI 10.1016/j.cmet.2021.03.025
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 402–408

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse liver-specific Gcn2 knockout, twelve-day and three-week glucose tests. · source_derived_draft · unverified_draft

    ## isoleucine-restriction-gcn2-boundary A common amino-acid stress sensor was dispensable in this liver/diet experiment. Liver-specific Gcn2 deletion did not prevent low-isoleucine improvements in glucose tolerance or body-composition measures. Model: Mouse liver-specific Gcn2 knockout, twelve-day and three-week glucose tests. Limitations: Not equivalent to complete cellular starvation or loss of GCN2 in every tissue. Evidence access: Primary full text The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33887198/ · DOI 10.1016/j.cmet.2021.03.025
    Complete structured claim and evidence

  2. Gcn2-null mice retained the methionine-restriction changes in adiposity, energy expenditure, insulin sensitivity and FGF21 induction.

    Experimentally methionine-restricted diet → Mouse GCN2 / Eif2ak4 source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary abstract
    experimental_model
    Wild-type and Gcn2-knockout mice under the study diet.
    limitations
    Not a universal statement about GCN2 during total starvation or other amino-acid deficiencies.
    nutrient_topic
    L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
    plain_language
    This dietary response did not require the usual amino-acid stress sensor.
    primary_references
    Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26936965/ · DOI 10.2337/db15-1324
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 380–386

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Wild-type and Gcn2-knockout mice under the study diet. · source_derived_draft · unverified_draft

    ## methionine-gcn2-dispensability This dietary response did not require the usual amino-acid stress sensor. Gcn2-null mice retained the methionine-restriction changes in adiposity, energy expenditure, insulin sensitivity and FGF21 induction. Model: Wild-type and Gcn2-knockout mice under the study diet. Limitations: Not a universal statement about GCN2 during total starvation or other amino-acid deficiencies. Evidence access: Primary abstract Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26936965/ · DOI 10.2337/db15-1324
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. Methionine restriction activated hepatic PERK and an antioxidant/ISR program in wild-type and Gcn2-null mice, without the measured ER-stress pattern.

    Experimentally methionine-restricted diet → Mouse PERK / Eif2ak3 source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary abstract
    experimental_model
    Mouse liver signaling and dietary experiments.
    limitations
    The proposed glutathione-sensing mechanism is not evidence of direct methionine binding to PERK.
    nutrient_topic
    L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
    plain_language
    Dietary sulfur status engaged an alternative stress-response route.
    primary_references
    Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26936965/ · DOI 10.2337/db15-1324

    L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 388–394

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse liver signaling and dietary experiments. · source_derived_draft · unverified_draft

    ## methionine-perk-redox-response Dietary sulfur status engaged an alternative stress-response route. Methionine restriction activated hepatic PERK and an antioxidant/ISR program in wild-type and Gcn2-null mice, without the measured ER-stress pattern. Model: Mouse liver signaling and dietary experiments. Limitations: The proposed glutathione-sensing mechanism is not evidence of direct methionine binding to PERK. Evidence access: Primary abstract Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26936965/ · DOI 10.2337/db15-1324
    Complete structured claim and evidence

  2. Exogenous proline reversed halofuginone-induced amino-acid response signaling and selected cellular effects in the study, consistent with competition at the prolyl-tRNA synthetase step.

    L-Proline → Mouse-cell amino acid response during halofuginone exposure source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary full text
    experimental_model
    Mouse embryonic fibroblast and immune-cell experiments with halofuginone; model and assay-specific concentrations.
    limitations
    Not every proline-processing defect is competitively reversible, and this is not a clinical drug-interaction dose recommendation.
    nutrient_topic
    L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline
    plain_language
    Restoring access to a blocked loading step can turn off a shortage-like signal.
    primary_references
    Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22327401/ · DOI 10.1038/nchembio.790
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 238–244

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse embryonic fibroblast and immune-cell experiments with halofuginone; model and assay-specific concentrations. · source_derived_draft · unverified_draft

    ## l-proline-eprs-stress-rescue Restoring access to a blocked loading step can turn off a shortage-like signal. Exogenous proline reversed halofuginone-induced amino-acid response signaling and selected cellular effects in the study, consistent with competition at the prolyl-tRNA synthetase step. Model: Mouse embryonic fibroblast and immune-cell experiments with halofuginone; model and assay-specific concentrations. Limitations: Not every proline-processing defect is competitively reversible, and this is not a clinical drug-interaction dose recommendation. Evidence access: Primary full text Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22327401/ · DOI 10.1038/nchembio.790
    Complete structured claim and evidence

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

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