Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation inferred from phylogenetic analysis. While GCN-2 primarily functions in the cytosol at ribosome-associated sites, studies in other organisms show GCN2 can localize to nucleus. However, direct localization data for C. elegans GCN-2 in the nucleus was not found in retrieved literature (Tatara et al. 2024). Reason: Phylogenetic inference is reasonable given conservation of GCN2 across eukaryotes. Nuclear localization is plausible though not directly demonstrated in C. elegans. Accept as IBA represents well-curated phylogenetic evidence. Supporting Evidence: file:worm/gcn-2/gcn-2-deep-research-falcon.md model: Edison Scientific Literature
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for cytoplasmic localization. GCN-2 functions in the cytosol at ribosome-associated sites through GCN1/ABCF complexes binding to polyribosomes and collided ribosomes (Tatara et al. 2024, Altintas et al. 2024). Reason: Cytoplasmic localization is well-established for GCN2 family kinases. The protein functions at ribosomes in the cytosol to phosphorylate eIF2alpha. Supporting Evidence: doi:10.3390/ijms25052998 GCN1 is the ribosome-associated activator of GCN-2... bind polyribosomes and stalled/disome ribosomes
GO:0034198 cellular response to amino acid starvation	IBA GO_REF:0000033	ACCEPT	Summary: Core function of GCN-2. The kinase responds to amino acid limitation by phosphorylating eIF2alpha. This was directly demonstrated in C. elegans by Rousakis et al. 2013, showing GCN-2-dependent eIF2alpha phosphorylation when aminoacyl-tRNA synthetases are knocked down (PMID:23692540). Reason: This is the primary, evolutionarily conserved function of GCN2 kinases. Directly demonstrated in C. elegans with RNAi of tRNA synthetases (krs-1, lrs-1). Supporting Evidence: PMID:23692540 We found that worms grown on bacteria expressing dsRNA for krs-1 either arrested in early larval stages or became adults with low brood size
GO:0032057 negative regulation of translational initiation in response to stress	IBA GO_REF:0000033	ACCEPT	Summary: Core function of GCN-2. Phosphorylation of eIF2alpha by GCN-2 attenuates global translation initiation. Directly demonstrated in C. elegans during mitochondrial stress (Baker et al. 2012), osmotic stress (Lee & Strange 2012), and amino acid limitation (Rousakis et al. 2013). Reason: Well-established mechanism of GCN2 function across species and directly demonstrated in C. elegans. Supporting Evidence: PMID:22719267 GCN-2-dependent eIF2alpha phosphorylation is required for development as well as the lifespan extension observed in Caenorhabditis elegans PMID:23076791 Hypertonicity-induced translation inhibition is mediated by general control nonderepressible (GCN)-2 kinase signaling and eIF-2alpha phosphoryation
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for cytosolic localization. GCN-2 functions in the cytosol at ribosome-associated sites. More specific than GO:0005737 (cytoplasm). Reason: Consistent with known localization of GCN2 kinases functioning at cytosolic ribosomes. IBA represents well-curated phylogenetic evidence.
GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Core molecular function of GCN-2. Directly demonstrated in C. elegans by multiple studies showing GCN-2-dependent phosphorylation of eIF2alpha at Ser49 (Baker et al. 2012, Lee & Strange 2012, Rousakis et al. 2013). Reason: This is the defining enzymatic activity of GCN-2. Directly demonstrated in C. elegans by immunoblotting with phospho-specific antibodies. Supporting Evidence: PMID:22719267 in a deletion mutant lacking 1482 bases of gcn-2 (gcn-2(ok871)), the level of steady-state phospho-eIF2alpha was reduced relative to wild-type worms PMID:23692540 By measuring the basal levels of eIF2alpha phosphorylation in whole protein extracts of N2 worms subjected to gcn-2(RNAi)... we verified that both ok871 and ok886 are loss-of-function alleles of gcn-2
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA based on UniProt keyword mapping. GCN-2 is an ATP-dependent kinase. The protein contains ATP binding sites at positions 114-122, 154, 497-505, and 520 per UniProt annotation. Reason: Correct but generic. GCN-2 requires ATP for kinase activity. More specific annotations exist (GO:0005524 ATP binding).
GO:0004672 protein kinase activity	IEA GO_REF:0000002	ACCEPT	Summary: IEA based on InterPro domain mapping. GCN-2 belongs to the protein kinase superfamily with two protein kinase domains (positions 108-507 and 508-999). Reason: Correct but generic. More specific term GO:0004694 (eIF2alpha kinase activity) is also annotated and is more informative.
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA based on combined automated annotation. GCN-2 is a serine/threonine kinase that phosphorylates eIF2alpha on serine residue (Ser49 in C. elegans, equivalent to Ser51 in mammals). Reason: Correct. GCN-2 specifically phosphorylates serine residues. More specific term GO:0004694 is also present.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA based on combined automated annotation. GCN-2 contains an ATP binding site in its kinase domain and requires ATP for catalytic activity. Reason: Correct. GCN-2 is an ATP-dependent kinase with conserved ATP-binding sites.
GO:0006417 regulation of translation	IEA GO_REF:0000043	ACCEPT	Summary: IEA based on UniProt keyword. GCN-2 regulates translation by phosphorylating eIF2alpha, which reduces global translation while enabling preferential translation of uORF-containing mRNAs. Reason: Correct but generic. More specific annotations exist for negative regulation of translational initiation in response to stress.
GO:0006986 response to unfolded protein	IEA GO_REF:0000043	ACCEPT	Summary: IEA based on UniProt keyword. GCN-2 is involved in the integrated stress response which includes unfolded protein response. UniProt function annotation states GCN-2 is "Involved in the unfolded protein response (UPR) triggered by several stresses including mitochondrial, osmotic and oxidative stresses." Reason: Supported by UniProt annotation and consistent with GCN-2 role in ISR. However, PEK-1 (PERK) is the primary UPR-ER sensor in C. elegans. Supporting Evidence: PMID:20733002 GCN-2, which is known to suppress translation and induce an adaptive transcriptional response under conditions of UPR activation or amino acid deprivation, was required for HP
GO:0009893 positive regulation of metabolic process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: IEA based on ARBA machine learning. This is a very broad term. GCN-2 does influence metabolic processes through translational reprogramming. Reason: Too broad to be informative for this specific kinase. The more specific processes regulated by GCN-2 (translation, stress response) are annotated separately.
GO:0010468 regulation of gene expression	IEA GO_REF:0000117	ACCEPT	Summary: IEA based on ARBA machine learning. GCN-2 regulates gene expression at the translational level and indirectly at the transcriptional level through ATF-5/ATF4 induction. Reason: Correct but broad. GCN-2 regulates gene expression through translational control and induction of transcription factors like ATF-5 and PHA-4. Supporting Evidence: PMID:23692540 Phosphorylation of eIF2alpha under stress results in inhibition of global protein synthesis, which is accompanied by favored translation of specific mRNAs that adapt the organism to stress
GO:0016301 kinase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA based on UniProt keyword mapping. GCN-2 is a kinase. Very broad term. Reason: Correct but very generic. More specific kinase activity terms are annotated.
GO:0016740 transferase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA based on UniProt keyword mapping. Kinases are transferases that transfer phosphate groups. Reason: Correct but extremely generic. Acceptable as it is captured by automated hierarchy but more specific terms are more informative.
GO:0033554 cellular response to stress	IEA GO_REF:0000117	ACCEPT	Summary: IEA based on ARBA machine learning. GCN-2 is activated by multiple stresses including amino acid starvation, mitochondrial stress, osmotic stress, and oxidative stress. Reason: Correct. GCN-2 is a central kinase in cellular stress response pathways. Supporting Evidence: PMID:23692540 GCN-2 signaling positively regulates the induction of PHA-4/FoxA transcription factor under nutrient or oxidative stress, as part of the adaptive response that ensures stress survival and longevity
GO:0051246 regulation of protein metabolic process	IEA GO_REF:0000117	ACCEPT	Summary: IEA based on ARBA machine learning. GCN-2 regulates protein metabolism through translational control. Reason: Correct. GCN-2 regulates protein synthesis rates through eIF2alpha phosphorylation.
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	ACCEPT	Summary: IEA based on Rhea mapping. GCN-2 phosphorylates serine residues, specifically Ser49 of eIF2alpha. Reason: Correct. The catalytic reaction phosphorylates serine residues.
GO:0140469 GCN2-mediated signaling	IMP PMID:20733002 Protein misfolding induces hypoxic preconditioning via a sub...	ACCEPT	Summary: IMP annotation from Mao & Crowder 2010 study on hypoxic preconditioning. The study shows GCN-2 is required for hypoxic preconditioning (HP) through a mechanism involving IRE-1 but not XBP-1 or ATF-6. Reason: Direct experimental evidence that GCN-2 functions in GCN2-mediated signaling in C. elegans during hypoxic stress response. Supporting Evidence: PMID:20733002 HP also required IRE-1 but not XBP-1 or ATF-6; instead, GCN-2, which is known to suppress translation and induce an adaptive transcriptional response under conditions of UPR activation or amino acid deprivation, was required for HP
GO:0140469 GCN2-mediated signaling	IMP PMID:22719267 Protective coupling of mitochondrial function and protein sy...	ACCEPT	Summary: IMP annotation from Baker et al. 2012. Study demonstrates GCN-2 functions in the mitochondrial unfolded protein response through eIF2alpha phosphorylation, complementary to ATFS-1-mediated chaperone induction. Reason: Strong experimental evidence for GCN-2 signaling during mitochondrial stress. Uses gcn-2(ok871) deletion mutant. Supporting Evidence: PMID:22719267 GCN-2-dependent translational control acts in a mitochondrial protective signaling pathway complementary to the regulation of mitochondrial chaperone gene expression mediated by HAF-1 and ATFS-1
GO:0140469 GCN2-mediated signaling	IMP PMID:23692540 The general control nonderepressible-2 kinase mediates stres...	ACCEPT	Summary: IMP annotation from Rousakis et al. 2013. Comprehensive study establishing conserved GCN-2 function in amino acid sensing and its role in stress response and longevity. Reason: Strong experimental evidence using gcn-2 mutants (ok871 and ok886) demonstrating GCN-2 signaling in C. elegans. Supporting Evidence: PMID:23692540 we have established the conserved function of the GCN-2 kinase in C. elegans under amino acid limitation, and we showed that loss of GCN-2 activity is not required for normal lifespan, but affects the lifespan of nutrient-sensitized worms
GO:1904688 regulation of cytoplasmic translational initiation	IGI PMID:22719267 Protective coupling of mitochondrial function and protein sy...	ACCEPT	Summary: IGI annotation from Baker et al. 2012. The study shows genetic interaction between gcn-2 and gsp-1 (phosphatase) in regulating eIF2alpha phosphorylation and translation. Reason: Valid genetic interaction evidence. gsp-1(RNAi) increases phospho-eIF2alpha while gcn-2 deletion reduces it, demonstrating opposing roles in regulating cytoplasmic translation initiation. Supporting Evidence: PMID:22719267 In contrast to inhibition of GCN-2 and PEK-1, GSP-1 knockdown resulted in increased levels of phospho-eIF2alpha consistent with it acting as a constitutive eIF2alpha phosphatase
GO:1904688 regulation of cytoplasmic translational initiation	IMP PMID:23692540 The general control nonderepressible-2 kinase mediates stres...	ACCEPT	Summary: IMP annotation from Rousakis et al. 2013. Study directly demonstrates GCN-2 regulates translation initiation through eIF2alpha phosphorylation. Reason: Direct evidence from gcn-2 mutant analysis showing loss of eIF2alpha phosphorylation and translational regulation. Supporting Evidence: PMID:23692540 Inhibition of protein synthesis is attained through phosphorylation of the alpha subunit of the translation initiation factor 2 (eIF2alpha) by specific protein kinases
GO:0010628 positive regulation of gene expression	IMP PMID:23076791 GCN-2 dependent inhibition of protein synthesis activates os...	ACCEPT	Summary: IMP annotation from Lee & Strange 2012. Study shows GCN-2 positively regulates gpdh-1 transcription during osmotic stress through WNK and Ste20 kinase signaling downstream of eIF2alpha phosphorylation. Reason: Direct experimental evidence that GCN-2 activity leads to induction of osmoprotective gene transcription. Supporting Evidence: PMID:23076791 GCN-2 dependent inhibition of protein synthesis activates osmosensitive gene transcription via WNK and Ste20 kinase signaling
GO:0034514 mitochondrial unfolded protein response	IMP PMID:22719267 Protective coupling of mitochondrial function and protein sy...	ACCEPT	Summary: IMP annotation from Baker et al. 2012. This landmark study demonstrates GCN-2 functions in the UPRmt as a complementary arm to ATFS-1-mediated chaperone induction. ROS from dysfunctional mitochondria activate GCN-2-dependent eIF2alpha phosphorylation. Reason: Strong experimental evidence establishing GCN-2 role in UPRmt. Uses clk-1 and isp-1 mitochondrial mutants with gcn-2(ok871). Supporting Evidence: PMID:22719267 Reactive oxygen species (ROS) generated from dysfunctional mitochondria are required for GCN-2-dependent eIF2alpha phosphorylation but not ATFS-1 activation PMID:22719267 Simultaneous deletion of ATFS-1 and GCN-2 compounds the developmental defects associated with mitochondrial stress
GO:0034063 stress granule assembly	IMP PMID:25061667 Diverse functions of mRNA metabolism factors in stress defen...	ACCEPT	Summary: IMP annotation from Rousakis et al. 2014. The study examines stress granule formation in C. elegans and shows GCN-2-dependent stress granule formation under certain stress conditions. The study shows SG formation depends on translation inhibition pathways including GCN-2 signaling. Reason: Experimental evidence linking GCN-2 to stress granule assembly. GCN-2 inhibits translation initiation, which is required for stress granule formation. Supporting Evidence: PMID:25061667 Both complexes were accumulated in response to various stress conditions, but distinct modes of SG formation were induced, depending on the insult

Core Functions

Primary function: eIF2alpha kinase activity in response to amino acid starvation. Directly demonstrated in C. elegans. GCN-2 phosphorylates eIF2alpha at Ser49 in response to amino acid starvation, mitochondrial stress, osmotic stress, and oxidative stress. Confirmed using gcn-2(ok871) and gcn-2(ok886) deletion mutants with phospho-specific antibodies (Baker et al. 2012, Lee & Strange 2012, Rousakis et al. 2013).

Molecular Function:

eukaryotic translation initiation factor 2alpha kinase activity

Directly Involved In:

cellular response to amino acid starvation

Cellular Locations:

cytosol

Secondary stress response function: eIF2alpha kinase activity during mitochondrial stress. GCN-2 mediates translational attenuation during mitochondrial stress, complementary to ATFS-1-mediated chaperone induction. ROS from dysfunctional mitochondria (clk-1, isp-1 mutants) activate GCN-2 (Baker et al. 2012).

Molecular Function:

eukaryotic translation initiation factor 2alpha kinase activity

Directly Involved In:

mitochondrial unfolded protein response

Cellular Locations:

cytosol

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GCN2 family kinases are conserved from yeast to mammals with consistent eIF2alpha kinase activity and stress response functions

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:20733002

Protein misfolding induces hypoxic preconditioning via a subset of the unfolded protein response machinery.

GCN-2 is required for hypoxic preconditioning (HP) in C. elegans

"GCN-2, which is known to suppress translation and induce an adaptive transcriptional response under conditions of UPR activation or amino acid deprivation, was required for HP"
HP requires IRE-1 and GCN-2 but not XBP-1 or ATF-6

"HP also required IRE-1 but not XBP-1 or ATF-6"
eIF2alpha phosphorylation by GCN-2 is not necessary for HP, suggesting other mechanisms

"The phosphorylation of the translation factor eIF2α, an established mechanism of GCN-2-mediated translational suppression, was not necessary for HP"

PMID:22719267

Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.

GCN-2 phosphorylates eIF2alpha in response to mitochondrial dysfunction
ROS from dysfunctional mitochondria activate GCN-2
GCN-2 acts in complementary pathway to ATFS-1 for mitochondrial protection
gcn-2 deletion slows development during mitochondrial stress
GCN-2 required for lifespan extension in clk-1(qm30) mitochondrial mutants

PMID:23076791

GCN-2 dependent inhibition of protein synthesis activates osmosensitive gene transcription via WNK and Ste20 kinase signaling.

Hypertonic stress induces GCN-2-dependent eIF2alpha phosphorylation
GCN-2 signaling activates gpdh-1 transcription via WNK-1 and GCK-3 kinases
Loss of gcn-1 or gcn-2 prevents translation inhibition during osmotic stress

PMID:23692540

The general control nonderepressible-2 kinase mediates stress response and longevity induced by target of rapamycin inactivation in Caenorhabditis elegans.

GCN-2 phosphorylates eIF2alpha in response to amino acid limitation (krs-1, lrs-1 RNAi)
atf-5 translation is induced in gcn-2-dependent manner under amino acid starvation
gcn-2 deletion suppresses lifespan extension in eat-2 dietary restriction mutants
GCN-2 required for lifespan extension by TOR (let-363) inhibition
GCN-2 positively regulates pha-4 expression under nutrient stress
gcn-2 mutants sensitive to heat shock, UV, and oxidative stress

PMID:25061667

Diverse functions of mRNA metabolism factors in stress defense and aging of Caenorhabditis elegans.

Stress granules and processing bodies form in response to various stresses
GCN-2-dependent translation inhibition linked to stress granule formation

file:worm/gcn-2/gcn-2-deep-research-falcon.md

Deep research report on gcn-2

Suggested Experiments

Experiment: Direct localization studies of endogenous GCN-2 in C. elegans tissues using CRISPR-tagged GCN-2 or specific antibodies

Hypothesis: GCN-2 localizes primarily to the cytosol in association with ribosomes

Experiment: Phosphoproteomics analysis of gcn-2 mutants to identify potential non-eIF2alpha substrates of GCN-2

Hypothesis: GCN-2 may have additional substrates beyond eIF2alpha that contribute to stress responses

Experiment: Tissue-specific rescue experiments in gcn-2 mutants to determine site of action for lifespan and stress resistance phenotypes

Hypothesis: GCN-2 function in specific tissues (e.g., intestine, neurons) is critical for organismal stress responses

📚 Additional Documentation

Deep Research Falcon

(gcn-2-deep-research-falcon.md)

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organism: worm
gene_id: gcn-2
gene_symbol: gcn-2
uniprot_accession: D0Z5N4
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kinase gcn-2 {ECO:0000305|PubMed:22719267}; EC=2.7.11.1 {ECO:0000250|UniProtKB:Q19192};
AltName: Full=General control nonderepressible kinase 2 {ECO:0000312|WormBase:Y81G3A.3b};'
gene_info: Name=gcn-2 {ECO:0000312|WormBase:Y81G3A.3b}; ORFNames=Y81G3A.3 {ECO:0000312|WormBase:Y81G3A.3b};
organism_full: Caenorhabditis elegans.
protein_family: Belongs to the protein kinase superfamily. Ser/Thr protein
protein_domains: aa-tRNA-synth_II/BPL/LPL. (IPR045864); CC_SR_Kinase. (IPR050339);
Kinase-like_dom_sf. (IPR011009); Prot_kinase_dom. (IPR000719); Protein_kinase_ATP_BS.
(IPR017441)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: D0Z5N4
Protein Description: RecName: Full=Eukaryotic translation initiation factor 2-alpha kinase gcn-2 {ECO:0000305|PubMed:22719267}; EC=2.7.11.1 {ECO:0000250|UniProtKB:Q19192}; AltName: Full=General control nonderepressible kinase 2 {ECO:0000312|WormBase:Y81G3A.3b};
Gene Information: Name=gcn-2 {ECO:0000312|WormBase:Y81G3A.3b}; ORFNames=Y81G3A.3 {ECO:0000312|WormBase:Y81G3A.3b};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the protein kinase superfamily. Ser/Thr protein
Key Domains: aa-tRNA-synth_II/BPL/LPL. (IPR045864); CC_SR_Kinase. (IPR050339); Kinase-like_dom_sf. (IPR011009); Prot_kinase_dom. (IPR000719); Protein_kinase_ATP_BS. (IPR017441)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "gcn-2" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'gcn-2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene gcn-2 (gene ID: gcn-2, UniProt: D0Z5N4) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: D0Z5N4
Protein Description: RecName: Full=Eukaryotic translation initiation factor 2-alpha kinase gcn-2 {ECO:0000305|PubMed:22719267}; EC=2.7.11.1 {ECO:0000250|UniProtKB:Q19192}; AltName: Full=General control nonderepressible kinase 2 {ECO:0000312|WormBase:Y81G3A.3b};
Gene Information: Name=gcn-2 {ECO:0000312|WormBase:Y81G3A.3b}; ORFNames=Y81G3A.3 {ECO:0000312|WormBase:Y81G3A.3b};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the protein kinase superfamily. Ser/Thr protein
Key Domains: aa-tRNA-synth_II/BPL/LPL. (IPR045864); CC_SR_Kinase. (IPR050339); Kinase-like_dom_sf. (IPR011009); Prot_kinase_dom. (IPR000719); Protein_kinase_ATP_BS. (IPR017441)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "gcn-2" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene gcn-2 (gene ID: gcn-2, UniProt: D0Z5N4) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
- Identity check: The target matches Caenorhabditis elegans gcn-2 (Y81G3A.3), UniProt D0Z5N4, encoding the conserved serine/threonine eIF2α kinase GCN-2 that activates the integrated stress response (ISR). Canonical domain features (RWD regulatory region, protein kinase catalytic domain, and HisRS-like/aaRS-related domain) and activation by uncharged tRNA via the GCN1 complex are conserved and concordant with recent reviews (Frontiers in Aging, Sep 2024, https://doi.org/10.3389/fragi.2024.1447370; IJMS, Mar 2024, https://doi.org/10.3390/ijms25052998). No conflicting gene symbol usage was found for C. elegans (gcn-2) in the retrieved literature (altintas2024generalcontrolnonderepressible pages 1-2, tatara2024emergingroleof pages 17-18, tatara2024emergingroleof pages 4-5).

Key concepts and definitions
- Molecular identity and enzymatic function: C. elegans gcn-2 encodes the eIF2α kinase GCN-2, a serine/threonine protein kinase that phosphorylates eIF2α at Ser51, reducing ternary complex formation to globally attenuate translation while enabling preferential translation of uORF‑containing mRNAs (e.g., ATF‑5, the worm ATF4 homolog). Activation occurs upon amino-acid insufficiency when uncharged tRNAs bind the GCN-2 HisRS-like domain, with the ribosome-associated factor GCN-1 facilitating activation on stalled/collided ribosomes (Frontiers in Aging, Sep 2024; IJMS, Mar 2024; conceptual ISR framing also in Frontiers in Cell and Developmental Biology, Aug 2023) (altintas2024generalcontrolnonderepressible pages 1-2, tatara2024emergingroleof pages 17-18, tatara2024emergingroleof pages 4-5, rath2023pkractivationin pages 2-4).
- Domain architecture: Reviews synthesize a conserved multi-domain GCN-2 architecture: N-terminal RWD domain (interaction with GCN1/IMPACT family), a kinase/pseudokinase module, a canonical protein kinase catalytic domain, a HisRS-like domain that binds uncharged tRNA, and C-terminal regions modulating activity; this aligns with the UniProt domain annotations provided (Frontiers in Aging, Sep 2024; IJMS, Mar 2024) (altintas2024generalcontrolnonderepressible pages 1-2, tatara2024emergingroleof pages 17-18, tatara2024emergingroleof pages 4-5).
- Cellular site of action: GCN-2 functions in the cytosol at ribosome-associated sites; GCN1/ABCF complexes bind polyribosomes and stalled/disome ribosomes to couple uncharged tRNA sensing to GCN-2 activation. While worm-specific localization microscopy was not retrieved here, the ribosome-associated cytosolic localization of the GCN1–GCN2 axis is consistently described and inferred to be conserved in C. elegans (IJMS, Mar 2024; Frontiers in Aging, Sep 2024) (tatara2024emergingroleof pages 17-18, tatara2024emergingroleof pages 4-5, altintas2024generalcontrolnonderepressible pages 1-2).

Recent developments and latest research (2023–2024 prioritized)
- Dietary restriction (DR) vs ER stress: In C. elegans, DR/fasting increases eIF2α phosphorylation via GCN‑2; however, eIF2α phosphorylation is not required for DR‑associated early translational attenuation, NMD changes, or lifespan extension. In contrast, ER stress requires PERK/pek‑1 and eIF2α phosphorylation for translational attenuation and survival. Strikingly, double loss of gcn‑2 and pek‑1 abolishes DR‑mediated lifespan extension, suggesting complementary or alternative substrates or noncanonical roles of these kinases (Frontiers in Cell and Developmental Biology, Dec 2023, https://doi.org/10.3389/fcell.2023.1263344) (ma2023theintegratedstress pages 1-2, ma2023theintegratedstress pages 4-7).
- Mitochondrial stress and ISR: Multiple 2024 reviews synthesize that mitochondrial proteostatic stress (UPRmt) can engage the ISR/eIF2α phosphorylation through GCN2 and other kinases, with ROS and nucleic acid signals implicated upstream; these reviews include worm perspectives on mitochondria-to-nucleus signaling and innate immunity (J Cell Biol., Feb 2024, https://doi.org/10.1083/jcb.202310005; Frontiers in Cell and Dev. Biol., May 2024, https://doi.org/10.3389/fcell.2024.1405393; Frontiers in Cell and Dev. Biol., Aug 2023, https://doi.org/10.3389/fcell.2023.1270341) (rath2023pkractivationin pages 2-4).
- GCN1 advances: 2024 review highlights GCN1 as a hub for ribosome-collision sensing and co‑translational quality control, with relevance to GCN‑2 activation; worm data indicate GCN1 roles in apoptosis independent of GCN‑2 (IJMS, Mar 2024, https://doi.org/10.3390/ijms25052998) (tatara2024emergingroleof pages 17-18, tatara2024emergingroleof pages 4-5).

Pathways, organismal phenotypes, and genetic interactions in C. elegans
- ISR branch and DR: GCN‑2 is the eIF2α kinase induced by amino‑acid scarcity in worms. Under DR/fasting, GCN‑2‑dependent eIF2α phosphorylation occurs, yet ISR signaling via eIF2α‑P is dispensable for early translation reduction and NMD changes under DR; however, combined loss of gcn‑2 and pek‑1 eliminates DR lifespan extension, implying broader roles (Frontiers in Cell and Dev. Biol., Dec 2023) (ma2023theintegratedstress pages 1-2, ma2023theintegratedstress pages 4-7).
- ER stress interplay with PERK/pek‑1: PERK/pek‑1 is essential for eIF2α‑P and translational attenuation during ER stress in worms; eIF2α‑P is required for ER stress survival. This positions gcn‑2 as a DR/AA-sensing ISR arm and pek‑1 as the ER ISR arm, with combined function influencing longevity outcomes (Frontiers in Cell and Dev. Biol., Dec 2023) (ma2023theintegratedstress pages 1-2, ma2023theintegratedstress pages 4-7).
- Mitochondrial stress and immunity: Reviews summarize that ISR kinases, including GCN‑2, are engaged during mitochondrial proteostasis stress and can influence innate immunity and proteostasis networks in C. elegans; explicit worm experiments tying gcn‑2 to UPRmt in 2023–2024 were not detailed in the retrieved texts, but mechanistic links are established conceptually (J Cell Biol., Feb 2024; Frontiers in Cell and Dev. Biol., May 2024; Aug 2023) (rath2023pkractivationin pages 2-4).
- Genetic interactions with impt-1 (IMPACT homolog): impt‑1 is a conserved GCN2 inhibitor. In C. elegans, impt‑1+/– mutants show ~1.82× higher eIF2α phosphorylation and impt‑1 RNAi increases ATF‑5 expression by ~40%, consistent with ISR activation. impt‑1 knockdown extends lifespan (~16–21%) and enhances stress resistance in a gcn‑2‑dependent manner; lifespan extension requires gcn‑1 and atf‑5, and engages SKN‑1 (larval) and DAF‑16 (adult) in a temporal sequence (BMC Biology, Oct 2016, https://doi.org/10.1186/s12915-016-0301-2; summarized in Frontiers in Aging, Sep 2024) (ferraz2016impactisa pages 2-5, ferraz2016impactisa pages 5-7, ferraz2016impactisa pages 9-10, ferraz2016impactisa pages 7-9, ferraz2016impactisa pages 1-2, altintas2024generalcontrolnonderepressible pages 2-3).
- Genetic interactions with gcn-1/ABCF-3: GCN1 is the ribosome-associated activator of GCN‑2. In worms, GCN1 also promotes developmental and irradiation-induced apoptosis independently of GCN‑2; ABCF‑3 mutants phenocopy the apoptosis defect, whereas gcn‑2 mutants do not, indicating GCN1 has GCN‑2–independent functions in apoptosis (IJMS, Mar 2024) (tatara2024emergingroleof pages 4-5).

Catalytic reaction and substrate specificity
- Reaction: ATP-dependent phosphorylation of eIF2α on Ser51 by GCN‑2 to reduce ternary complex formation and initiate ISR translational reprogramming; this is conserved and explicitly invoked in worm ISR studies during DR/fasting (Frontiers in Cell and Dev. Biol., Dec 2023; Frontiers in Aging, Sep 2024; IJMS, Mar 2024) (ma2023theintegratedstress pages 4-7, altintas2024generalcontrolnonderepressible pages 1-2, tatara2024emergingroleof pages 17-18, tatara2024emergingroleof pages 4-5).
- Substrate specificity and potential alternatives: eIF2α is the canonical substrate. Ma et al. (2023) suggest that the loss of DR lifespan extension in gcn‑2; pek‑1 double mutants despite dispensability of eIF2α‑P for DR‑driven translation changes raises the possibility of additional substrates or noncanonical roles for these kinases in longevity, but specific alternative substrates were not identified in worms (Frontiers in Cell and Dev. Biol., Dec 2023) (ma2023theintegratedstress pages 1-2, ma2023theintegratedstress pages 4-7).

Subcellular localization where GCN-2 acts
- Evidence supports cytosolic, ribosome-associated action through GCN1/ABCF complexes binding to polyribosomes and collided ribosomes, enabling uncharged tRNA-mediated activation of GCN‑2. This mechanism is conserved and inferred to apply to C. elegans gcn‑2 (IJMS, Mar 2024; Frontiers in Aging, Sep 2024) (tatara2024emergingroleof pages 17-18, tatara2024emergingroleof pages 4-5, altintas2024generalcontrolnonderepressible pages 1-2).

Current applications and real-world implementations
- Targeting GCN2: Reviews in 2024 discuss GCN2 as a therapeutic target across age-related diseases (neurodegeneration, inflammation, cancer), with small-molecule modulators under investigation; model organisms including C. elegans are used to probe healthspan and stress-resilience effects of modulating ISR activity (Frontiers in Aging, Sep 2024, https://doi.org/10.3389/fragi.2024.1447370) (altintas2024generalcontrolnonderepressible pages 1-2).
- Worm as a platform: In C. elegans, genetic modulation of impt‑1/gcn‑2 and DR paradigms are deployed to dissect ISR-longevity crosstalk, using assays such as polysome profiling, SUnSET, eIF2α‑P immunoblotting, ATF‑5 reporter induction, and lifespan/stress survival, illustrating practical implementation of GCN‑2 pathway readouts (Frontiers in Cell and Dev. Biol., Dec 2023; BMC Biology, Oct 2016) (ma2023theintegratedstress pages 4-7, ferraz2016impactisa pages 2-5, ferraz2016impactisa pages 5-7, ferraz2016impactisa pages 1-2).

Expert opinions and analysis from authoritative sources
- 2024 and 2023 reviews converge that GCN‑2 is a conserved ISR sensor for amino-acid insufficiency, activated on ribosomes by uncharged tRNA via GCN1, culminating in eIF2α‑P and selective translation of stress-responsive mRNAs. They also highlight emerging inputs (ribosome collisions, oxidative stress, proteasome inhibition) and cross-talk with mitochondrial proteostasis and innate immunity, indicating that GCN‑2 integrates multiple stress modalities beyond amino acid starvation (Frontiers in Aging, Sep 2024; IJMS, Mar 2024; J Cell Biol., Feb 2024; Frontiers in Cell and Dev. Biol., Aug 2023/May 2024) (altintas2024generalcontrolnonderepressible pages 1-2, tatara2024emergingroleof pages 17-18, tatara2024emergingroleof pages 4-5, rath2023pkractivationin pages 2-4).

Relevant statistics and data from recent studies
- DR/fasting in C. elegans: Polysome profiling and SUnSET revealed translation attenuation upon food withdrawal that persists in gcn‑2 and eif‑2α(S49A) phospho‑null backgrounds, indicating ISR‑independent components of DR translation control. Loss of DR lifespan extension in gcn‑2;pek‑1 double mutants supports functional redundancy/parallelism (Frontiers in Cell and Dev. Biol., Dec 2023) (ma2023theintegratedstress pages 4-7).
- impt-1 genetic modulation: impt‑1+/– increases eIF2α‑P ~1.82±0.11‑fold; impt‑1 RNAi increases ATF‑5 ~40%; lifespan increases by ~16–21% depending on allele/RNAi. Longevity requires gcn‑2, gcn‑1, and atf‑5; SKN‑1 (larval) and DAF‑16 (adult) contribute temporally (BMC Biology, Oct 2016) (ferraz2016impactisa pages 2-5, ferraz2016impactisa pages 5-7, ferraz2016impactisa pages 9-10, ferraz2016impactisa pages 7-9, ferraz2016impactisa pages 1-2).
- GCN1 apoptosis roles: In worms, 12–13% survival of normally doomed pharyngeal sister cells in gcn‑1 mutants, and requirement for irradiation-induced gonadal apoptosis; these effects are not observed in gcn‑2 mutants, indicating GCN‑2–independent GCN1 functions (IJMS, Mar 2024) (tatara2024emergingroleof pages 4-5).

Open questions and gaps
- Alternative substrates/noncanonical roles: The DR findings (ISR dispensable for translation attenuation; double mutant abolishes longevity) suggest GCN‑2 and PERK may have substrates beyond eIF2α or scaffold roles affecting longevity; specific alternative substrates in C. elegans remain to be identified (Frontiers in Cell and Dev. Biol., Dec 2023) (ma2023theintegratedstress pages 1-2, ma2023theintegratedstress pages 4-7).
- Direct localization in worm tissues: Ribosome-associated cytosolic function is clear from mechanism, but high-resolution localization of endogenous C. elegans GCN‑2 in vivo is not provided in the retrieved 2023–2024 sources and would benefit from targeted studies (tatara2024emergingroleof pages 17-18, tatara2024emergingroleof pages 4-5, altintas2024generalcontrolnonderepressible pages 1-2).

Embedded summary table of key sources
| Year | Type (Review/Primary) | System/Model | Main finding about gcn-2/ISR | Assay/Approach | URL / DOI (citation) |
|---|---|---|---|---|---|
| 2023 | Primary | Caenorhabditis elegans | GCN-2 phosphorylates eIF2α during nutrient restriction but eIF2α phosphorylation is not required for DR-driven translational changes or lifespan; PERK required for ER stress responses; double loss (gcn-2; pek-1) abolishes DR lifespan extension | Genetic knockouts (gcn-2(ok871), pek-1(ok275)), eif-2α phospho-null allele, polysome profiling, SUnSET, lifespan assays | https://doi.org/10.3389/fcell.2023.1263344 (ma2023theintegratedstress pages 1-2) |
| 2024 | Review | Multiple (cross-species) | Summarizes GCN2 activation by uncharged tRNA via HisRS-like domain and GCN1; canonical phosphorylation of eIF2α (Ser51) and links to impt-1/GCN-2 dependence in worms | Review of structural, biochemical and genetic literature | https://doi.org/10.3389/fragi.2024.1447370 (altintas2024generalcontrolnonderepressible pages 1-2) |
| 2024 | Review | Multiple (incl. C. elegans notes) | Reviews GCN1 role in activating GCN2 on stalled/collided ribosomes; notes GCN1/ABCF-3 functions and GCN1-dependent and -independent effects in worms | Review and synthesis of recent molecular studies | https://doi.org/10.3390/ijms25052998 (tatara2024emergingroleof pages 17-18) |
| 2023 | Commentary/Review | Multiple (mtUPR context) | Highlights eIF2α kinases (GCN2, PERK, HRI, PKR) in mtUPR signaling; describes ROS/mtRNA as inputs and eIF2α phosphorylation as ISR hallmark | Review/commentary integrating mitochondrial stress literature | https://doi.org/10.3389/fcell.2023.1270341 (rath2023pkractivationin pages 2-4) |
| 2024 | Review | Caenorhabditis elegans / Mammals | Reviews mitochondria→nucleus communication and notes ISR engagement via eIF2α kinases including GCN2 in proteostasis and innate immunity contexts | Review of signaling pathways and cell-nonautonomous responses | https://doi.org/10.1083/jcb.202310005 (rath2023pkractivationin pages 2-4) |
| 2024 | Mini-review | Multiple (incl. C. elegans) | Summarizes UPRmt mechanisms and notes cases where GCN2 mediates eIF2α phosphorylation during mitochondrial stress | Minireview of UPRmt components and signaling | https://doi.org/10.3389/fcell.2024.1405393 (rath2023pkractivationin pages 2-4) |
| 2016 | Primary | Caenorhabditis elegans | IMPACT homolog impt-1 inhibits GCN-2; impt-1 knockdown activates ISR and extends lifespan in a gcn-2- and atf-5-dependent manner | RNAi knockdown (impt-1), lifespan and stress-resistance assays, genetic epistasis with gcn-2 and atf-5 | https://doi.org/10.1186/s12915-016-0301-2 (altintas2024generalcontrolnonderepressible pages 2-3) |

Table: Concise table of primary and review studies (2016–2024) reporting molecular roles, regulatory interactions, and organismal phenotypes for C. elegans GCN-2/ISR; includes assay types and DOIs with supporting context citations for traceability.

References (with URLs and publication dates embedded above); citations by context IDs: (altintas2024generalcontrolnonderepressible pages 1-2, tatara2024emergingroleof pages 17-18, tatara2024emergingroleof pages 4-5, ma2023theintegratedstress pages 1-2, ma2023theintegratedstress pages 4-7, rath2023pkractivationin pages 2-4, ferraz2016impactisa pages 2-5, ferraz2016impactisa pages 5-7, ferraz2016impactisa pages 9-10, ferraz2016impactisa pages 7-9, ferraz2016impactisa pages 1-2, altintas2024generalcontrolnonderepressible pages 2-3).

References

(altintas2024generalcontrolnonderepressible pages 1-2): Ozlem Altintas and Michael R. MacArthur. General control nonderepressible 2 (gcn2) as a therapeutic target in age-related diseases. Frontiers in Aging, Sep 2024. URL: https://doi.org/10.3389/fragi.2024.1447370, doi:10.3389/fragi.2024.1447370. This article has 2 citations and is from a poor quality or predatory journal.
(tatara2024emergingroleof pages 17-18): Yota Tatara, Shuya Kasai, Daichi Kokubu, Tadayuki Tsujita, Junsei Mimura, and Ken Itoh. Emerging role of gcn1 in disease and homeostasis. International Journal of Molecular Sciences, 25:2998, Mar 2024. URL: https://doi.org/10.3390/ijms25052998, doi:10.3390/ijms25052998. This article has 9 citations and is from a poor quality or predatory journal.
(tatara2024emergingroleof pages 4-5): Yota Tatara, Shuya Kasai, Daichi Kokubu, Tadayuki Tsujita, Junsei Mimura, and Ken Itoh. Emerging role of gcn1 in disease and homeostasis. International Journal of Molecular Sciences, 25:2998, Mar 2024. URL: https://doi.org/10.3390/ijms25052998, doi:10.3390/ijms25052998. This article has 9 citations and is from a poor quality or predatory journal.
(rath2023pkractivationin pages 2-4): Eva Rath. Pkr activation in mitochondrial unfolded protein response-mitochondrial dsrna might do the trick. Frontiers in Cell and Developmental Biology, Aug 2023. URL: https://doi.org/10.3389/fcell.2023.1270341, doi:10.3389/fcell.2023.1270341. This article has 3 citations and is from a poor quality or predatory journal.
(ma2023theintegratedstress pages 1-2): Zhengxin Ma, Jordan Horrocks, Dilawar A. Mir, Matthew Cox, Marissa Ruzga, Jarod Rollins, and Aric N. Rogers. The integrated stress response protects against er stress but is not required for altered translation and lifespan from dietary restriction in caenorhabditis elegans. Frontiers in Cell and Developmental Biology, Dec 2023. URL: https://doi.org/10.3389/fcell.2023.1263344, doi:10.3389/fcell.2023.1263344. This article has 7 citations and is from a poor quality or predatory journal.
(ma2023theintegratedstress pages 4-7): Zhengxin Ma, Jordan Horrocks, Dilawar A. Mir, Matthew Cox, Marissa Ruzga, Jarod Rollins, and Aric N. Rogers. The integrated stress response protects against er stress but is not required for altered translation and lifespan from dietary restriction in caenorhabditis elegans. Frontiers in Cell and Developmental Biology, Dec 2023. URL: https://doi.org/10.3389/fcell.2023.1263344, doi:10.3389/fcell.2023.1263344. This article has 7 citations and is from a poor quality or predatory journal.
(ferraz2016impactisa pages 2-5): Rafael C. Ferraz, Henrique Camara, Evandro A. De-Souza, Silas Pinto, Ana Paula F. Pinca, Richard C. Silva, Vitor N. Sato, Beatriz A. Castilho, and Marcelo A. Mori. Impact is a gcn2 inhibitor that limits lifespan in caenorhabditis elegans. BMC Biology, Oct 2016. URL: https://doi.org/10.1186/s12915-016-0301-2, doi:10.1186/s12915-016-0301-2. This article has 27 citations and is from a domain leading peer-reviewed journal.
(ferraz2016impactisa pages 5-7): Rafael C. Ferraz, Henrique Camara, Evandro A. De-Souza, Silas Pinto, Ana Paula F. Pinca, Richard C. Silva, Vitor N. Sato, Beatriz A. Castilho, and Marcelo A. Mori. Impact is a gcn2 inhibitor that limits lifespan in caenorhabditis elegans. BMC Biology, Oct 2016. URL: https://doi.org/10.1186/s12915-016-0301-2, doi:10.1186/s12915-016-0301-2. This article has 27 citations and is from a domain leading peer-reviewed journal.
(ferraz2016impactisa pages 9-10): Rafael C. Ferraz, Henrique Camara, Evandro A. De-Souza, Silas Pinto, Ana Paula F. Pinca, Richard C. Silva, Vitor N. Sato, Beatriz A. Castilho, and Marcelo A. Mori. Impact is a gcn2 inhibitor that limits lifespan in caenorhabditis elegans. BMC Biology, Oct 2016. URL: https://doi.org/10.1186/s12915-016-0301-2, doi:10.1186/s12915-016-0301-2. This article has 27 citations and is from a domain leading peer-reviewed journal.
(ferraz2016impactisa pages 7-9): Rafael C. Ferraz, Henrique Camara, Evandro A. De-Souza, Silas Pinto, Ana Paula F. Pinca, Richard C. Silva, Vitor N. Sato, Beatriz A. Castilho, and Marcelo A. Mori. Impact is a gcn2 inhibitor that limits lifespan in caenorhabditis elegans. BMC Biology, Oct 2016. URL: https://doi.org/10.1186/s12915-016-0301-2, doi:10.1186/s12915-016-0301-2. This article has 27 citations and is from a domain leading peer-reviewed journal.
(ferraz2016impactisa pages 1-2): Rafael C. Ferraz, Henrique Camara, Evandro A. De-Souza, Silas Pinto, Ana Paula F. Pinca, Richard C. Silva, Vitor N. Sato, Beatriz A. Castilho, and Marcelo A. Mori. Impact is a gcn2 inhibitor that limits lifespan in caenorhabditis elegans. BMC Biology, Oct 2016. URL: https://doi.org/10.1186/s12915-016-0301-2, doi:10.1186/s12915-016-0301-2. This article has 27 citations and is from a domain leading peer-reviewed journal.
(altintas2024generalcontrolnonderepressible pages 2-3): Ozlem Altintas and Michael R. MacArthur. General control nonderepressible 2 (gcn2) as a therapeutic target in age-related diseases. Frontiers in Aging, Sep 2024. URL: https://doi.org/10.3389/fragi.2024.1447370, doi:10.3389/fragi.2024.1447370. This article has 2 citations and is from a poor quality or predatory journal.

Citations

rath2023pkractivationin pages 2-4
tatara2024emergingroleof pages 4-5
altintas2024generalcontrolnonderepressible pages 1-2
ma2023theintegratedstress pages 4-7
ma2023theintegratedstress pages 1-2
tatara2024emergingroleof pages 17-18
altintas2024generalcontrolnonderepressible pages 2-3
ferraz2016impactisa pages 2-5
ferraz2016impactisa pages 5-7
ferraz2016impactisa pages 9-10
ferraz2016impactisa pages 7-9
ferraz2016impactisa pages 1-2
https://doi.org/10.3389/fragi.2024.1447370;
https://doi.org/10.3390/ijms25052998
https://doi.org/10.3389/fcell.2023.1263344
https://doi.org/10.1083/jcb.202310005;
https://doi.org/10.3389/fcell.2024.1405393;
https://doi.org/10.3389/fcell.2023.1270341
https://doi.org/10.1186/s12915-016-0301-2;
https://doi.org/10.3389/fragi.2024.1447370
https://doi.org/10.1083/jcb.202310005
https://doi.org/10.3389/fcell.2024.1405393
https://doi.org/10.1186/s12915-016-0301-2
https://doi.org/10.3389/fragi.2024.1447370,
https://doi.org/10.3390/ijms25052998,
https://doi.org/10.3389/fcell.2023.1270341,
https://doi.org/10.3389/fcell.2023.1263344,
https://doi.org/10.1186/s12915-016-0301-2,

📄 View Raw YAML

id: D0Z5N4
gene_symbol: gcn-2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: GCN-2 is the sole C. elegans homolog of yeast/mammalian GCN2, a 
  serine/threonine protein kinase that phosphorylates eIF2alpha at Ser49 in 
  response to amino acid deprivation, mitochondrial stress, osmotic stress, and 
  oxidative stress. It is the primary sensor for the integrated stress response 
  (ISR) in C. elegans alongside PEK-1 (PERK homolog). GCN-2 functions to 
  attenuate global translation while enabling selective translation of 
  stress-responsive mRNAs such as atf-5, pha-4, and gpdh-1. It is required for 
  lifespan extension associated with dietary restriction and TOR inhibition, and
  protects against mitochondrial dysfunction through translational control 
  complementary to ATFS-1-mediated chaperone induction.
existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation inferred from phylogenetic analysis. While GCN-2 
        primarily functions in the cytosol at ribosome-associated sites, studies
        in other organisms show GCN2 can localize to nucleus. However, direct 
        localization data for C. elegans GCN-2 in the nucleus was not found in 
        retrieved literature (Tatara et al. 2024).
      action: ACCEPT
      reason: Phylogenetic inference is reasonable given conservation of GCN2 
        across eukaryotes. Nuclear localization is plausible though not directly
        demonstrated in C. elegans. Accept as IBA represents well-curated 
        phylogenetic evidence.
      supported_by:
        - reference_id: file:worm/gcn-2/gcn-2-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation for cytoplasmic localization. GCN-2 functions in 
        the cytosol at ribosome-associated sites through GCN1/ABCF complexes 
        binding to polyribosomes and collided ribosomes (Tatara et al. 2024, 
        Altintas et al. 2024).
      action: ACCEPT
      reason: Cytoplasmic localization is well-established for GCN2 family 
        kinases. The protein functions at ribosomes in the cytosol to 
        phosphorylate eIF2alpha.
      supported_by:
        - reference_id: doi:10.3390/ijms25052998
          supporting_text: GCN1 is the ribosome-associated activator of GCN-2...
            bind polyribosomes and stalled/disome ribosomes
  - term:
      id: GO:0034198
      label: cellular response to amino acid starvation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Core function of GCN-2. The kinase responds to amino acid 
        limitation by phosphorylating eIF2alpha. This was directly demonstrated 
        in C. elegans by Rousakis et al. 2013, showing GCN-2-dependent eIF2alpha
        phosphorylation when aminoacyl-tRNA synthetases are knocked down 
        (PMID:23692540).
      action: ACCEPT
      reason: This is the primary, evolutionarily conserved function of GCN2 
        kinases. Directly demonstrated in C. elegans with RNAi of tRNA 
        synthetases (krs-1, lrs-1).
      supported_by:
        - reference_id: PMID:23692540
          supporting_text: We found that worms grown on bacteria expressing 
            dsRNA for krs-1 either arrested in early larval stages or became 
            adults with low brood size
  - term:
      id: GO:0032057
      label: negative regulation of translational initiation in response to 
        stress
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Core function of GCN-2. Phosphorylation of eIF2alpha by GCN-2 
        attenuates global translation initiation. Directly demonstrated in C. 
        elegans during mitochondrial stress (Baker et al. 2012), osmotic stress 
        (Lee & Strange 2012), and amino acid limitation (Rousakis et al. 2013).
      action: ACCEPT
      reason: Well-established mechanism of GCN2 function across species and 
        directly demonstrated in C. elegans.
      supported_by:
        - reference_id: PMID:22719267
          supporting_text: GCN-2-dependent eIF2alpha phosphorylation is required
            for development as well as the lifespan extension observed in 
            Caenorhabditis elegans
        - reference_id: PMID:23076791
          supporting_text: Hypertonicity-induced translation inhibition is 
            mediated by general control nonderepressible (GCN)-2 kinase 
            signaling and eIF-2alpha phosphoryation
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation for cytosolic localization. GCN-2 functions in the
        cytosol at ribosome-associated sites. More specific than GO:0005737 
        (cytoplasm).
      action: ACCEPT
      reason: Consistent with known localization of GCN2 kinases functioning at 
        cytosolic ribosomes. IBA represents well-curated phylogenetic evidence.
  - term:
      id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Core molecular function of GCN-2. Directly demonstrated in C. 
        elegans by multiple studies showing GCN-2-dependent phosphorylation of 
        eIF2alpha at Ser49 (Baker et al. 2012, Lee & Strange 2012, Rousakis et 
        al. 2013).
      action: ACCEPT
      reason: This is the defining enzymatic activity of GCN-2. Directly 
        demonstrated in C. elegans by immunoblotting with phospho-specific 
        antibodies.
      supported_by:
        - reference_id: PMID:22719267
          supporting_text: in a deletion mutant lacking 1482 bases of gcn-2 
            (gcn-2(ok871)), the level of steady-state phospho-eIF2alpha was 
            reduced relative to wild-type worms
        - reference_id: PMID:23692540
          supporting_text: By measuring the basal levels of eIF2alpha 
            phosphorylation in whole protein extracts of N2 worms subjected to 
            gcn-2(RNAi)... we verified that both ok871 and ok886 are 
            loss-of-function alleles of gcn-2
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA based on UniProt keyword mapping. GCN-2 is an ATP-dependent 
        kinase. The protein contains ATP binding sites at positions 114-122, 
        154, 497-505, and 520 per UniProt annotation.
      action: ACCEPT
      reason: Correct but generic. GCN-2 requires ATP for kinase activity. More 
        specific annotations exist (GO:0005524 ATP binding).
  - term:
      id: GO:0004672
      label: protein kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA based on InterPro domain mapping. GCN-2 belongs to the 
        protein kinase superfamily with two protein kinase domains (positions 
        108-507 and 508-999).
      action: ACCEPT
      reason: Correct but generic. More specific term GO:0004694 (eIF2alpha 
        kinase activity) is also annotated and is more informative.
  - term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA based on combined automated annotation. GCN-2 is a 
        serine/threonine kinase that phosphorylates eIF2alpha on serine residue 
        (Ser49 in C. elegans, equivalent to Ser51 in mammals).
      action: ACCEPT
      reason: Correct. GCN-2 specifically phosphorylates serine residues. More 
        specific term GO:0004694 is also present.
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA based on combined automated annotation. GCN-2 contains an ATP
        binding site in its kinase domain and requires ATP for catalytic 
        activity.
      action: ACCEPT
      reason: Correct. GCN-2 is an ATP-dependent kinase with conserved 
        ATP-binding sites.
  - term:
      id: GO:0006417
      label: regulation of translation
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA based on UniProt keyword. GCN-2 regulates translation by 
        phosphorylating eIF2alpha, which reduces global translation while 
        enabling preferential translation of uORF-containing mRNAs.
      action: ACCEPT
      reason: Correct but generic. More specific annotations exist for negative 
        regulation of translational initiation in response to stress.
  - term:
      id: GO:0006986
      label: response to unfolded protein
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA based on UniProt keyword. GCN-2 is involved in the integrated
        stress response which includes unfolded protein response. UniProt 
        function annotation states GCN-2 is "Involved in the unfolded protein 
        response (UPR) triggered by several stresses including mitochondrial, 
        osmotic and oxidative stresses."
      action: ACCEPT
      reason: Supported by UniProt annotation and consistent with GCN-2 role in 
        ISR. However, PEK-1 (PERK) is the primary UPR-ER sensor in C. elegans.
      supported_by:
        - reference_id: PMID:20733002
          supporting_text: GCN-2, which is known to suppress translation and 
            induce an adaptive transcriptional response under conditions of UPR 
            activation or amino acid deprivation, was required for HP
  - term:
      id: GO:0009893
      label: positive regulation of metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: IEA based on ARBA machine learning. This is a very broad term. 
        GCN-2 does influence metabolic processes through translational 
        reprogramming.
      action: MARK_AS_OVER_ANNOTATED
      reason: Too broad to be informative for this specific kinase. The more 
        specific processes regulated by GCN-2 (translation, stress response) are
        annotated separately.
  - term:
      id: GO:0010468
      label: regulation of gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: IEA based on ARBA machine learning. GCN-2 regulates gene 
        expression at the translational level and indirectly at the 
        transcriptional level through ATF-5/ATF4 induction.
      action: ACCEPT
      reason: Correct but broad. GCN-2 regulates gene expression through 
        translational control and induction of transcription factors like ATF-5 
        and PHA-4.
      supported_by:
        - reference_id: PMID:23692540
          supporting_text: Phosphorylation of eIF2alpha under stress results in 
            inhibition of global protein synthesis, which is accompanied by 
            favored translation of specific mRNAs that adapt the organism to 
            stress
  - term:
      id: GO:0016301
      label: kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA based on UniProt keyword mapping. GCN-2 is a kinase. Very 
        broad term.
      action: ACCEPT
      reason: Correct but very generic. More specific kinase activity terms are 
        annotated.
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA based on UniProt keyword mapping. Kinases are transferases 
        that transfer phosphate groups.
      action: ACCEPT
      reason: Correct but extremely generic. Acceptable as it is captured by 
        automated hierarchy but more specific terms are more informative.
  - term:
      id: GO:0033554
      label: cellular response to stress
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: IEA based on ARBA machine learning. GCN-2 is activated by 
        multiple stresses including amino acid starvation, mitochondrial stress,
        osmotic stress, and oxidative stress.
      action: ACCEPT
      reason: Correct. GCN-2 is a central kinase in cellular stress response 
        pathways.
      supported_by:
        - reference_id: PMID:23692540
          supporting_text: GCN-2 signaling positively regulates the induction of
            PHA-4/FoxA transcription factor under nutrient or oxidative stress, 
            as part of the adaptive response that ensures stress survival and 
            longevity
  - term:
      id: GO:0051246
      label: regulation of protein metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: IEA based on ARBA machine learning. GCN-2 regulates protein 
        metabolism through translational control.
      action: ACCEPT
      reason: Correct. GCN-2 regulates protein synthesis rates through eIF2alpha
        phosphorylation.
  - term:
      id: GO:0106310
      label: protein serine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000116
    review:
      summary: IEA based on Rhea mapping. GCN-2 phosphorylates serine residues, 
        specifically Ser49 of eIF2alpha.
      action: ACCEPT
      reason: Correct. The catalytic reaction phosphorylates serine residues.
  - term:
      id: GO:0140469
      label: GCN2-mediated signaling
    evidence_type: IMP
    original_reference_id: PMID:20733002
    review:
      summary: IMP annotation from Mao & Crowder 2010 study on hypoxic 
        preconditioning. The study shows GCN-2 is required for hypoxic 
        preconditioning (HP) through a mechanism involving IRE-1 but not XBP-1 
        or ATF-6.
      action: ACCEPT
      reason: Direct experimental evidence that GCN-2 functions in GCN2-mediated
        signaling in C. elegans during hypoxic stress response.
      supported_by:
        - reference_id: PMID:20733002
          supporting_text: HP also required IRE-1 but not XBP-1 or ATF-6; 
            instead, GCN-2, which is known to suppress translation and induce an
            adaptive transcriptional response under conditions of UPR activation
            or amino acid deprivation, was required for HP
  - term:
      id: GO:0140469
      label: GCN2-mediated signaling
    evidence_type: IMP
    original_reference_id: PMID:22719267
    review:
      summary: IMP annotation from Baker et al. 2012. Study demonstrates GCN-2 
        functions in the mitochondrial unfolded protein response through 
        eIF2alpha phosphorylation, complementary to ATFS-1-mediated chaperone 
        induction.
      action: ACCEPT
      reason: Strong experimental evidence for GCN-2 signaling during 
        mitochondrial stress. Uses gcn-2(ok871) deletion mutant.
      supported_by:
        - reference_id: PMID:22719267
          supporting_text: GCN-2-dependent translational control acts in a 
            mitochondrial protective signaling pathway complementary to the 
            regulation of mitochondrial chaperone gene expression mediated by 
            HAF-1 and ATFS-1
  - term:
      id: GO:0140469
      label: GCN2-mediated signaling
    evidence_type: IMP
    original_reference_id: PMID:23692540
    review:
      summary: IMP annotation from Rousakis et al. 2013. Comprehensive study 
        establishing conserved GCN-2 function in amino acid sensing and its role
        in stress response and longevity.
      action: ACCEPT
      reason: Strong experimental evidence using gcn-2 mutants (ok871 and ok886)
        demonstrating GCN-2 signaling in C. elegans.
      supported_by:
        - reference_id: PMID:23692540
          supporting_text: we have established the conserved function of the 
            GCN-2 kinase in C. elegans under amino acid limitation, and we 
            showed that loss of GCN-2 activity is not required for normal 
            lifespan, but affects the lifespan of nutrient-sensitized worms
  - term:
      id: GO:1904688
      label: regulation of cytoplasmic translational initiation
    evidence_type: IGI
    original_reference_id: PMID:22719267
    review:
      summary: IGI annotation from Baker et al. 2012. The study shows genetic 
        interaction between gcn-2 and gsp-1 (phosphatase) in regulating 
        eIF2alpha phosphorylation and translation.
      action: ACCEPT
      reason: Valid genetic interaction evidence. gsp-1(RNAi) increases 
        phospho-eIF2alpha while gcn-2 deletion reduces it, demonstrating 
        opposing roles in regulating cytoplasmic translation initiation.
      supported_by:
        - reference_id: PMID:22719267
          supporting_text: In contrast to inhibition of GCN-2 and PEK-1, GSP-1 
            knockdown resulted in increased levels of phospho-eIF2alpha 
            consistent with it acting as a constitutive eIF2alpha phosphatase
  - term:
      id: GO:1904688
      label: regulation of cytoplasmic translational initiation
    evidence_type: IMP
    original_reference_id: PMID:23692540
    review:
      summary: IMP annotation from Rousakis et al. 2013. Study directly 
        demonstrates GCN-2 regulates translation initiation through eIF2alpha 
        phosphorylation.
      action: ACCEPT
      reason: Direct evidence from gcn-2 mutant analysis showing loss of 
        eIF2alpha phosphorylation and translational regulation.
      supported_by:
        - reference_id: PMID:23692540
          supporting_text: Inhibition of protein synthesis is attained through 
            phosphorylation of the alpha subunit of the translation initiation 
            factor 2 (eIF2alpha) by specific protein kinases
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:23076791
    review:
      summary: IMP annotation from Lee & Strange 2012. Study shows GCN-2 
        positively regulates gpdh-1 transcription during osmotic stress through 
        WNK and Ste20 kinase signaling downstream of eIF2alpha phosphorylation.
      action: ACCEPT
      reason: Direct experimental evidence that GCN-2 activity leads to 
        induction of osmoprotective gene transcription.
      supported_by:
        - reference_id: PMID:23076791
          supporting_text: GCN-2 dependent inhibition of protein synthesis 
            activates osmosensitive gene transcription via WNK and Ste20 kinase 
            signaling
  - term:
      id: GO:0034514
      label: mitochondrial unfolded protein response
    evidence_type: IMP
    original_reference_id: PMID:22719267
    review:
      summary: IMP annotation from Baker et al. 2012. This landmark study 
        demonstrates GCN-2 functions in the UPRmt as a complementary arm to 
        ATFS-1-mediated chaperone induction. ROS from dysfunctional mitochondria
        activate GCN-2-dependent eIF2alpha phosphorylation.
      action: ACCEPT
      reason: Strong experimental evidence establishing GCN-2 role in UPRmt. 
        Uses clk-1 and isp-1 mitochondrial mutants with gcn-2(ok871).
      supported_by:
        - reference_id: PMID:22719267
          supporting_text: Reactive oxygen species (ROS) generated from 
            dysfunctional mitochondria are required for GCN-2-dependent 
            eIF2alpha phosphorylation but not ATFS-1 activation
        - reference_id: PMID:22719267
          supporting_text: Simultaneous deletion of ATFS-1 and GCN-2 compounds 
            the developmental defects associated with mitochondrial stress
  - term:
      id: GO:0034063
      label: stress granule assembly
    evidence_type: IMP
    original_reference_id: PMID:25061667
    review:
      summary: IMP annotation from Rousakis et al. 2014. The study examines 
        stress granule formation in C. elegans and shows GCN-2-dependent stress 
        granule formation under certain stress conditions. The study shows SG 
        formation depends on translation inhibition pathways including GCN-2 
        signaling.
      action: ACCEPT
      reason: Experimental evidence linking GCN-2 to stress granule assembly. 
        GCN-2 inhibits translation initiation, which is required for stress 
        granule formation.
      supported_by:
        - reference_id: PMID:25061667
          supporting_text: Both complexes were accumulated in response to 
            various stress conditions, but distinct modes of SG formation were 
            induced, depending on the insult
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings:
      - statement: GCN2 family kinases are conserved from yeast to mammals with 
          consistent eIF2alpha kinase activity and stress response functions
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000116
    title: Automatic Gene Ontology annotation based on Rhea mapping
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:20733002
    title: Protein misfolding induces hypoxic preconditioning via a subset of 
      the unfolded protein response machinery.
    findings:
      - statement: GCN-2 is required for hypoxic preconditioning (HP) in C. 
          elegans
        supporting_text: GCN-2, which is known to suppress translation and 
          induce an adaptive transcriptional response under conditions of UPR 
          activation or amino acid deprivation, was required for HP
      - statement: HP requires IRE-1 and GCN-2 but not XBP-1 or ATF-6
        supporting_text: HP also required IRE-1 but not XBP-1 or ATF-6
      - statement: eIF2alpha phosphorylation by GCN-2 is not necessary for HP, 
          suggesting other mechanisms
        supporting_text: "The phosphorylation of the translation factor eIF2α, an
          established mechanism of GCN-2-mediated translational suppression, was not
          necessary for HP"
  - id: PMID:22719267
    title: "Protective coupling of mitochondrial function and protein synthesis via
      the eIF2α kinase GCN-2."
    findings:
      - statement: GCN-2 phosphorylates eIF2alpha in response to mitochondrial 
          dysfunction
      - statement: ROS from dysfunctional mitochondria activate GCN-2
      - statement: GCN-2 acts in complementary pathway to ATFS-1 for 
          mitochondrial protection
      - statement: gcn-2 deletion slows development during mitochondrial stress
      - statement: GCN-2 required for lifespan extension in clk-1(qm30) 
          mitochondrial mutants
  - id: PMID:23076791
    title: GCN-2 dependent inhibition of protein synthesis activates 
      osmosensitive gene transcription via WNK and Ste20 kinase signaling.
    findings:
      - statement: Hypertonic stress induces GCN-2-dependent eIF2alpha 
          phosphorylation
      - statement: GCN-2 signaling activates gpdh-1 transcription via WNK-1 and 
          GCK-3 kinases
      - statement: Loss of gcn-1 or gcn-2 prevents translation inhibition during
          osmotic stress
  - id: PMID:23692540
    title: The general control nonderepressible-2 kinase mediates stress 
      response and longevity induced by target of rapamycin inactivation in 
      Caenorhabditis elegans.
    findings:
      - statement: GCN-2 phosphorylates eIF2alpha in response to amino acid 
          limitation (krs-1, lrs-1 RNAi)
      - statement: atf-5 translation is induced in gcn-2-dependent manner under 
          amino acid starvation
      - statement: gcn-2 deletion suppresses lifespan extension in eat-2 dietary
          restriction mutants
      - statement: GCN-2 required for lifespan extension by TOR (let-363) 
          inhibition
      - statement: GCN-2 positively regulates pha-4 expression under nutrient 
          stress
      - statement: gcn-2 mutants sensitive to heat shock, UV, and oxidative 
          stress
  - id: PMID:25061667
    title: Diverse functions of mRNA metabolism factors in stress defense and 
      aging of Caenorhabditis elegans.
    findings:
      - statement: Stress granules and processing bodies form in response to 
          various stresses
      - statement: GCN-2-dependent translation inhibition linked to stress 
          granule formation
  - id: file:worm/gcn-2/gcn-2-deep-research-falcon.md
    title: Deep research report on gcn-2
    findings: []
core_functions:
  - description: 'Primary function: eIF2alpha kinase activity in response to amino
      acid starvation. Directly demonstrated in C. elegans. GCN-2 phosphorylates eIF2alpha
      at Ser49 in response to amino acid starvation, mitochondrial stress, osmotic
      stress, and oxidative stress. Confirmed using gcn-2(ok871) and gcn-2(ok886)
      deletion mutants with phospho-specific antibodies (Baker et al. 2012, Lee &
      Strange 2012, Rousakis et al. 2013).'
    molecular_function:
      id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
    directly_involved_in:
      - id: GO:0034198
        label: cellular response to amino acid starvation
    locations:
      - id: GO:0005829
        label: cytosol
  - description: 'Secondary stress response function: eIF2alpha kinase activity during
      mitochondrial stress. GCN-2 mediates translational attenuation during mitochondrial
      stress, complementary to ATFS-1-mediated chaperone induction. ROS from dysfunctional
      mitochondria (clk-1, isp-1 mutants) activate GCN-2 (Baker et al. 2012).'
    molecular_function:
      id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
    directly_involved_in:
      - id: GO:0034514
        label: mitochondrial unfolded protein response
    locations:
      - id: GO:0005829
        label: cytosol
proposed_new_terms: []
suggested_questions:
  - question: Does C. elegans GCN-2 have substrates other than eIF2alpha that 
      contribute to dietary restriction-induced lifespan extension?
  - question: What is the mechanism by which ROS activate GCN-2 in C. elegans?
  - question: Is there tissue-specific expression or function of GCN-2 in C. 
      elegans?
suggested_experiments:
  - description: Direct localization studies of endogenous GCN-2 in C. elegans 
      tissues using CRISPR-tagged GCN-2 or specific antibodies
    hypothesis: GCN-2 localizes primarily to the cytosol in association with 
      ribosomes
  - description: Phosphoproteomics analysis of gcn-2 mutants to identify 
      potential non-eIF2alpha substrates of GCN-2
    hypothesis: GCN-2 may have additional substrates beyond eIF2alpha that 
      contribute to stress responses
  - description: Tissue-specific rescue experiments in gcn-2 mutants to 
      determine site of action for lifespan and stress resistance phenotypes
    hypothesis: GCN-2 function in specific tissues (e.g., intestine, neurons) is
      critical for organismal stress responses
tags:
  - caeel-upr-stress

gcn-2

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Gene Research for Functional Annotation

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Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

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