Role of EIF2α Kinases in Translational Control and Adaptation to Cellular Stress

Overview

Journal Cold Spring Harb Perspect Biol

Specialties Biology
Molecular Biology

Date 2018 Feb 15

PMID 29440070

Citations 238

Authors

Ronald C Wek

Affiliations

Soon will be listed here.

Abstract

A central mechanism regulating translation initiation in response to environmental stress involves phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Phosphorylation of eIF2α causes inhibition of global translation, which conserves energy and facilitates reprogramming of gene expression and signaling pathways that help to restore protein homeostasis. Coincident with repression of protein synthesis, many gene transcripts involved in the stress response are not affected or are even preferentially translated in response to increased eIF2α phosphorylation by mechanisms involving upstream open reading frames (uORFs). This review highlights the mechanisms regulating eIF2α kinases, the role that uORFs play in translational control, and the impact that alteration of eIF2α phosphorylation by gene mutations or small molecule inhibitors can have on health and disease.

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References

Munn D, Sharma M, Baban B, Harding H, Zhang Y, Ron D . GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005; 22(5):633-42. DOI: 10.1016/j.immuni.2005.03.013. View

Richardson J, Mohammad S, Pavitt G . Mutations causing childhood ataxia with central nervous system hypomyelination reduce eukaryotic initiation factor 2B complex formation and activity. Mol Cell Biol. 2004; 24(6):2352-63. PMC: 355856. DOI: 10.1128/MCB.24.6.2352-2363.2004. View

Jennings M, Zhou Y, Mohammad-Qureshi S, Bennett D, Pavitt G . eIF2B promotes eIF5 dissociation from eIF2*GDP to facilitate guanine nucleotide exchange for translation initiation. Genes Dev. 2013; 27(24):2696-707. PMC: 3877758. DOI: 10.1101/gad.231514.113. View

Shi Y, Vattem K, Sood R, An J, Liang J, Stramm L . Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol. 1998; 18(12):7499-509. PMC: 109330. DOI: 10.1128/MCB.18.12.7499. View

Krishnamoorthy J, Rajesh K, Mirzajani F, Kesoglidou P, Papadakis A, Koromilas A . Evidence for eIF2α phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERK with clinical implications. Cell Cycle. 2014; 13(5):801-6. PMC: 3979916. DOI: 10.4161/cc.27726. View

Lehman S, Cerniglia G, Johannes G, Ye J, Ryeom S, Koumenis C . Translational Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress. PLoS Genet. 2015; 11(6):e1005212. PMC: 4477940. DOI: 10.1371/journal.pgen.1005212. View

Boyce M, Bryant K, Jousse C, Long K, Harding H, Scheuner D . A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 2005; 307(5711):935-9. DOI: 10.1126/science.1101902. View

Abdulkarim B, Nicolino M, Igoillo-Esteve M, Daures M, Romero S, Philippi A . A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly. Diabetes. 2015; 64(11):3951-62. PMC: 4713904. DOI: 10.2337/db15-0477. View

Reijonen S, Putkonen N, Norremolle A, Lindholm D, Korhonen L . Inhibition of endoplasmic reticulum stress counteracts neuronal cell death and protein aggregation caused by N-terminal mutant huntingtin proteins. Exp Cell Res. 2008; 314(5):950-60. DOI: 10.1016/j.yexcr.2007.12.025. View

10.

Watatani Y, Ichikawa K, Nakanishi N, Fujimoto M, Takeda H, Kimura N . Stress-induced translation of ATF5 mRNA is regulated by the 5'-untranslated region. J Biol Chem. 2007; 283(5):2543-53. DOI: 10.1074/jbc.M707781200. View

11.

Axten J, Romeril S, Shu A, Ralph J, Medina J, Feng Y . Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development. ACS Med Chem Lett. 2014; 4(10):964-8. PMC: 4027568. DOI: 10.1021/ml400228e. View

12.

Young S, Baird T, Wek R . Translation Regulation of the Glutamyl-prolyl-tRNA Synthetase Gene EPRS through Bypass of Upstream Open Reading Frames with Noncanonical Initiation Codons. J Biol Chem. 2016; 291(20):10824-35. PMC: 4865927. DOI: 10.1074/jbc.M116.722256. View

13.

Starck S, Tsai J, Chen K, Shodiya M, Wang L, Yahiro K . Translation from the 5' untranslated region shapes the integrated stress response. Science. 2016; 351(6272):aad3867. PMC: 4882168. DOI: 10.1126/science.aad3867. View

14.

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

15.

Abastado J, Miller P, Jackson B, Hinnebusch A . Suppression of ribosomal reinitiation at upstream open reading frames in amino acid-starved cells forms the basis for GCN4 translational control. Mol Cell Biol. 1991; 11(1):486-96. PMC: 359655. DOI: 10.1128/mcb.11.1.486-496.1991. View

16.

Rojas-Rivera D, Delvaeye T, Roelandt R, Nerinckx W, Augustyns K, Vandenabeele P . When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157. Cell Death Differ. 2017; 24(6):1100-1110. PMC: 5442476. DOI: 10.1038/cdd.2017.58. View

17.

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

18.

Reid D, Chen Q, Tay A, Shenolikar S, Nicchitta C . The unfolded protein response triggers selective mRNA release from the endoplasmic reticulum. Cell. 2014; 158(6):1362-1374. PMC: 4163055. DOI: 10.1016/j.cell.2014.08.012. View

19.

van der Knaap M, Leegwater P, Konst A, Visser A, Naidu S, Oudejans C . Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol. 2002; 51(2):264-70. DOI: 10.1002/ana.10112. View

20.

Silva R, Sattlegger E, Castilho B . Perturbations in actin dynamics reconfigure protein complexes that modulate GCN2 activity and promote an eIF2 response. J Cell Sci. 2016; 129(24):4521-4533. DOI: 10.1242/jcs.194738. View