Emerging Role of GCN1 in Disease and Homeostasis
Abstract
:1. The GCN1–GCN2 Pathway Regulates the Amino Acid Starvation Branch of the Integrated Stress Response
2. Molecular Structure of GCN1 and Its Role in ISR Activation
3. Emerging Role of GCN1 through GCN2-Independent Pathways
3.1. Identification of an Alternative Amino Acid Deprivation Response Distinct from the Canonical GCN2 Pathway in Mammalian Cells
3.2. Role of GCN1-Dependent and GCN2-Independent Mechanisms in Mammalian Development
3.3. GCN2-Independent Pathway in Species Other Than Mammals
4. Function and Structure of the GCN1-Interacting RWD-Domain-Containing Proteins
4.1. GCN2/EIF2AK4
4.2. IMPACT
4.3. DFRP2/RWDD1
4.4. RNF14 and RNF25
4.5. RESUME/RWDD3
5. Emerging Role of GCN1 in Co-Translational Protein Quality Control
5.1. Quality Control Mechanisms for Stalled Ribosomes
5.2. GCN2 Branch of the ISR
5.3. RSR
6. Function of GCN1 in Basal-State Translational Regulation
7. Role of GCN1-Mediated Responses in Energy Homeostasis
7.1. Role of the GCN1–GCN2 Pathway in the Regulation of Insulin Secretion and Sensitivity
7.2. GCN1 Regulates Energy Storage and Usage
8. Potential Role of GCN1 in Aging and Disease
8.1. Potential Role of GCN1 in Aging
8.2. Potential Role of GCN1 in Neurodegenerative Diseases
9. Future Perspectives
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AAS | Amino acid starvation |
ABC | ATP-binding cassette |
ABCE1 | ATP-binding cassette sub-family E member 1 |
ABCF1 | ATP-binding cassette sub-family F member 1 |
ABCF2 | ATP-binding cassette sub-family F member 2 |
ATF4 | Cyclic AMP-dependent transcription factor ATF-4 |
CCR4/NOT | CCR4-Not complex 3’-5’-exoribonuclease subunit Ccr4 |
Cdk1 | Cyclin-dependent kinase 1 |
CHOP | CCAAT/Enhancer-binding protein homologous protein |
DELE1 | DAP3-binding cell death enhancer 1 |
DFRP2 | RWD domain-containing protein 1 |
DRG2 | Developmentally regulated GTP-binding protein 2 |
EDF1 | Endothelial differentiation-related factor 1 |
eEF1α | Eukaryotic elongation factor-1α |
eEF3 | Eukaryotic translation elongation factor 3 |
EIF4E2 | Eukaryotic translation initiation factor 4E type 2 |
eIF5A | Eukaryotic translation initiation factor 5A-1 |
elF2α | Eukaryotic initiation factor 2 alpha |
eRF1 | Eukaryotic release factor 1 |
eRF3 | Eukaryotic release factor 3 |
GCN1 | General control nonderepressible 1 |
GCN2 | General control nonderepressible 2 |
GIGYF2 | GRB10-interacting GYF protein 2 |
Hbs1 | Elongation factor 1 alpha-like protein |
Hel2 | E3 ubiquitin-protein ligase HEL2 |
HIF1A | Hypoxia-inducible factor 1-alpha |
HisRS | Histidyl-tRNA synthetase |
HRI | Eukaryotic translation initiation factor 2-alpha kinase 1 |
ISR | Integrated stress response |
LOX | Lipoxygenase |
Ltn1 | E3 ubiquitin-protein ligase listerin |
Mbf1 | Multiprotein-bridging factor 1 |
mTOR | Mechanistic target of rapamycin |
NEMF | Nuclear export mediator factor |
NFKBIA | NF-kappa-B inhibitor alpha |
NGD | No-go decay |
NMD | Nonsense-mediated decay |
NPC | Nascent polypeptide chain |
NR3C1 | Glucocorticoid receptor |
NRLP1 | Nod-like receptor 1 |
NSD | Nonstop decay |
OMA1 | Metalloendopeptidase OMA1, mitochondrial |
PERK | Eukaryotic translation initiation factor 2-alpha kinase 3 |
PIAS | Protein inhibitor of activated STAT 1 |
PKR | Interferon-induced, double-stranded RNA-activated protein kinase |
Rbg2 | Ribosome-interacting GTPase 2 |
Rli1 | RNase L inhibitor 1 |
RNF14 | Ring finger protein 14 |
RNF25 | Ring finger protein 25 |
RPS10 | Small ribosomal subunit protein eS10 |
RQC | Ribosome-associated quality control |
RWDBD | RWD-binding domain |
RWDD2A | RWD domain-containing protein 2A |
RWDD2B | RWD domain-containing protein 2B |
RWDD3 | RWD domain-containing protein 3 |
RWDD4 | RWD domain-containing protein 4 |
SUMO | Small ubiquitin-related modifier |
TOP1 | DNA topoisomerase 1 |
UBC9 | Ubiquitin-conjugating enzyme E2I (UBC9 homolog, yeast) |
uS10 | Small ribosomal subunit protein uS10 |
WDR59 | WD repeat-containing protein 59 |
ZAKα | Mitogen-activated protein kinase kinase kinase AZK long isoform |
ZNF598 | Zinc finger protein 598 |
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RWD-Domain-Containing Proteins | Gene Symbol | Amino Acids | RWD Domain Region |
---|---|---|---|
eIF-2-alpha kinase GCN2 | EIF2AK4 (GCN2) | 1649 | 25–137 |
Protein IMPACT | IMPACT | 320 | 14–116 |
Ring finger protein 14 | RNF14 | 474 | 11–137 |
Ring finger protein 25 | RNF25 | 459 | 18–128 |
RWD domain-containing protein 1 | RWDD1 (DFRP2) | 243 | 10–114 |
RWD domain-containing protein 2A | RWDD2A | 292 | 14–134 |
RWD domain-containing protein 2B | RWDD2B | 319 | 41–165 |
RWD domain-containing protein 3 | RWDD3 (RESUME) | 267 | 7–114 |
RWD domain-containing protein 4 | RWDD4 | 188 | 9–111 |
WD repeat-containing protein 59 | WDR59 | 974 | 393–494 |
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Tatara, Y.; Kasai, S.; Kokubu, D.; Tsujita, T.; Mimura, J.; Itoh, K. Emerging Role of GCN1 in Disease and Homeostasis. Int. J. Mol. Sci. 2024, 25, 2998. https://doi.org/10.3390/ijms25052998
Tatara Y, Kasai S, Kokubu D, Tsujita T, Mimura J, Itoh K. Emerging Role of GCN1 in Disease and Homeostasis. International Journal of Molecular Sciences. 2024; 25(5):2998. https://doi.org/10.3390/ijms25052998
Chicago/Turabian StyleTatara, Yota, Shuya Kasai, Daichi Kokubu, Tadayuki Tsujita, Junsei Mimura, and Ken Itoh. 2024. "Emerging Role of GCN1 in Disease and Homeostasis" International Journal of Molecular Sciences 25, no. 5: 2998. https://doi.org/10.3390/ijms25052998