Emerging Role of GCN1 in Disease and Homeostasis

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Mar 13

PMID 38474243

Authors

Yota Tatara

Shuya Kasai

Daichi Kokubu

Tadayuki Tsujita

Junsei Mimura

Ken Itoh

Affiliations

Soon will be listed here.

Abstract

GCN1 is recognized as a factor that is essential for the activation of GCN2, which is a sensor of amino acid starvation. This function is evolutionarily conserved from yeast to higher eukaryotes. However, recent studies have revealed non-canonical functions of GCN1 that are independent of GCN2, such as its participation in cell proliferation, apoptosis, and the immune response, beyond the borders of species. Although it is known that GCN1 and GCN2 interact with ribosomes to accomplish amino acid starvation sensing, recent studies have reported that GCN1 binds to disomes (i.e., ribosomes that collide each other), thereby regulating both the co-translational quality control and stress response. We propose that GCN1 regulates ribosome-mediated signaling by dynamically changing its partners among RWD domain-possessing proteins via unknown mechanisms. We recently demonstrated that GCN1 is essential for cell proliferation and whole-body energy regulation in mice. However, the manner in which ribosome-initiated signaling via GCN1 is related to various physiological functions warrants clarification. GCN1-mediated mechanisms and its interaction with other quality control and stress response signals should be important for proteostasis during aging and neurodegenerative diseases, and may be targeted for drug development.

Citing Articles

Regulatory Role of eIF2αK4 in Amino Acid Transporter Expression in Mouse Brain Capillary Endothelial Cells.

Hamada Y, Masuda T, Ito S, Ohtsuki S Pharm Res. 2024; 41(11):2213-2223.

PMID: 39532778 DOI: 10.1007/s11095-024-03793-0.

References

Sinha N, Ordureau A, Best K, Saba J, Zinshteyn B, Sundaramoorthy E . EDF1 coordinates cellular responses to ribosome collisions. Elife. 2020; 9. PMC: 7486125. DOI: 10.7554/eLife.58828. View

Ryder L, Arendrup F, Martinez J, Snieckute G, Pecorari C, Shah R . Nitric oxide-induced ribosome collision activates ribosomal surveillance mechanisms. Cell Death Dis. 2023; 14(7):467. PMC: 10372077. DOI: 10.1038/s41419-023-05997-5. View

Iordanov M, Pribnow D, Magun J, Dinh T, Pearson J, Chen S . Ribotoxic stress response: activation of the stress-activated protein kinase JNK1 by inhibitors of the peptidyl transferase reaction and by sequence-specific RNA damage to the alpha-sarcin/ricin loop in the 28S rRNA. Mol Cell Biol. 1997; 17(6):3373-81. PMC: 232190. DOI: 10.1128/MCB.17.6.3373. View

Costa-Mattioli M, Gobert D, Harding H, Herdy B, Azzi M, Bruno M . Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature. 2005; 436(7054):1166-73. PMC: 1464117. DOI: 10.1038/nature03897. View

Ye J, Kumanova M, Hart L, Sloane K, Zhang H, De Panis D . The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 2010; 29(12):2082-96. PMC: 2892366. DOI: 10.1038/emboj.2010.81. View

Szabat M, Page M, Panzhinskiy E, Skovso S, Mojibian M, Fernandez-Tajes J . Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces β Cell Proliferation. Cell Metab. 2015; 23(1):179-93. DOI: 10.1016/j.cmet.2015.10.016. View

Kanno A, Asahara S, Masuda K, Matsuda T, Kimura-Koyanagi M, Seino S . Compensatory hyperinsulinemia in high-fat diet-induced obese mice is associated with enhanced insulin translation in islets. Biochem Biophys Res Commun. 2015; 458(3):681-686. DOI: 10.1016/j.bbrc.2015.02.024. View

Palmisano I, Della Chiara G, DAmbrosio R, Huichalaf C, Brambilla P, Corbetta S . Amino acid starvation induces reactivation of silenced transgenes and latent HIV-1 provirus via down-regulation of histone deacetylase 4 (HDAC4). Proc Natl Acad Sci U S A. 2012; 109(34):E2284-93. PMC: 3427085. DOI: 10.1073/pnas.1202174109. View

Kriachkov V, Ormsby A, Kusnadi E, McWilliam H, Mintern J, Amarasinghe S . Arginine-rich C9ORF72 ALS proteins stall ribosomes in a manner distinct from a canonical ribosome-associated quality control substrate. J Biol Chem. 2022; 299(1):102774. PMC: 9830226. DOI: 10.1016/j.jbc.2022.102774. View

10.

Takahashi N, Wei F, Watanabe S, Hirayama M, Ohuchi Y, Fujimura A . Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion. Nucleic Acids Res. 2016; 45(1):435-445. PMC: 5224495. DOI: 10.1093/nar/gkw745. View

11.

Wang S, Chen M, Chou Y, Ueng Y, Yin P, Yeh T . Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α-ATF4-xCT pathway. Oncotarget. 2016; 7(45):74132-74151. PMC: 5342041. DOI: 10.18632/oncotarget.12356. View

12.

Deng J, Harding H, Raught B, Gingras A, Berlanga J, Scheuner D . Activation of GCN2 in UV-irradiated cells inhibits translation. Curr Biol. 2002; 12(15):1279-86. DOI: 10.1016/s0960-9822(02)01037-0. View

13.

Brown A, Fernandez I, Gordiyenko Y, Ramakrishnan V . Ribosome-dependent activation of stringent control. Nature. 2016; 534(7606):277-280. PMC: 4900451. DOI: 10.1038/nature17675. View

14.

Sekine Y, Houston R, Eckl E, Fessler E, Narendra D, Jae L . A mitochondrial iron-responsive pathway regulated by DELE1. Mol Cell. 2023; 83(12):2059-2076.e6. PMC: 10329284. DOI: 10.1016/j.molcel.2023.05.031. View

15.

Ishimura R, Nagy G, Dotu I, Chuang J, Ackerman S . Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation. Elife. 2016; 5. PMC: 4917338. DOI: 10.7554/eLife.14295. View

16.

Martin P, Kigoshi-Tansho Y, Sher R, Ravenscroft G, Stauffer J, Kumar R . NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease. Nat Commun. 2020; 11(1):4625. PMC: 7494853. DOI: 10.1038/s41467-020-18327-6. View

17.

Pitale P, Gorbatyuk O, Gorbatyuk M . Neurodegeneration: Keeping ATF4 on a Tight Leash. Front Cell Neurosci. 2018; 11:410. PMC: 5736573. DOI: 10.3389/fncel.2017.00410. View

18.

Sattlegger E, Swanson M, Ashcraft E, Jennings J, Fekete R, Link A . YIH1 is an actin-binding protein that inhibits protein kinase GCN2 and impairs general amino acid control when overexpressed. J Biol Chem. 2004; 279(29):29952-62. DOI: 10.1074/jbc.M404009200. View

19.

Tesina P, Ebine S, Buschauer R, Thoms M, Matsuo Y, Inada T . Molecular basis of eIF5A-dependent CAT tailing in eukaryotic ribosome-associated quality control. Mol Cell. 2023; 83(4):607-621.e4. DOI: 10.1016/j.molcel.2023.01.020. View

20.

De Vito A, Lazzaro M, Palmisano I, Cittaro D, Riba M, Lazarevic D . Amino acid deprivation triggers a novel GCN2-independent response leading to the transcriptional reactivation of non-native DNA sequences. PLoS One. 2018; 13(7):e0200783. PMC: 6051655. DOI: 10.1371/journal.pone.0200783. View