A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

Cell Death and Differentiation
Michael BoyceJunying Yuan

Abstract

Apoptosis triggered by endoplasmic reticulum (ER) stress has been implicated in many diseases but its cellular regulation remains poorly understood. Previously, we identified salubrinal (sal), a small molecule that protects cells from ER stress-induced apoptosis by selectively activating a subset of endogenous ER stress-signaling events. Here, we use sal as a probe in a proteomic approach to discover new information about the endogenous cellular response to ER stress. We show that sal induces phosphorylation of the translation elongation factor eukaryotic translation elongation factor 2 (eEF-2), an event that depends on eEF-2 kinase (eEF-2K). ER stress itself also induces eEF-2K-dependent eEF-2 phosphorylation, and this pathway promotes translational arrest and cell death in this context, identifying eEF-2K as a hitherto unknown regulator of ER stress-induced apoptosis. Finally, we use both sal and ER stress models to show that eEF-2 phosphorylation can be activated by at least two signaling mechanisms. Our work identifies eEF-2K as a new component of the ER stress response and underlines the utility of novel small molecules in discovering new cell biology.

References

Nov 26, 1990·FEBS Letters·L P OvchinnikovB Hardesty
Aug 17, 1990·European Journal of Biochemistry·U CarlbergO Nygård
Oct 6, 1997·Progress in Nucleic Acid Research and Molecular Biology·C O Brostrom, M A Brostrom
Dec 8, 1998·The Biochemical Journal·T A DiggleR M Denton
Jul 8, 1999·Nature Medicine·M Aridor, W E Balch
Apr 5, 2000·The Journal of Biological Chemistry·C CaspersenM Treiman
Jul 13, 2001·The Journal of Biological Chemistry·R V RaoD E Bredesen
Jul 19, 2001·Physiological Genomics·F KernecA P Koretsky
Oct 12, 2001·Toxicon : Official Journal of the International Society on Toxinology·R J Collier
Jan 10, 2002·Cell·Y Ma, L M Hendershot
Mar 21, 2002·FEBS Letters·Alexey G Ryazanov
May 8, 2002·Nature Reviews. Molecular Cell Biology·Billy TsaiTom A Rapoport
Jul 27, 2002·Annual Review of Cell and Developmental Biology·Heather P HardingDavid Ron
Oct 17, 2002·Cell Stress & Chaperones·Yanjun Ma, Linda M Hendershot
Oct 18, 2002·Traffic·Meir Aridor, Lisa A Hannan
Oct 18, 2002·Current Opinion in Cell Biology·Randolph Y Hampton
Nov 6, 2002·Biochemistry·Maxim V DorovkovAlexey G Ryazanov
Nov 25, 2003·Oncogene·David G BreckenridgeGordon C Shore
Jan 20, 2004·Trends in Cell Biology·D Thomas Rutkowski, Randal J Kaufman
Feb 7, 2004·Cell Death and Differentiation·R V RaoD E Bredesen
Dec 18, 2004·Mutation Research·Martin Schröder, Randal J Kaufman
Dec 21, 2004·Molecular and Cellular Neurosciences·Laura KorhonenDan Lindholm

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Citations

Jul 2, 2010·Cancer Chemotherapy and Pharmacology·Haibin XiTheodore J Lampidis
Mar 21, 2009·Annual Review of Biochemistry·Evan T PowersWilliam E Balch
Sep 10, 2013·PloS One·Robert D JunkinsTong-Jun Lin
Jun 4, 2014·PloS One·Christiane NeuberThomas Eschenhagen
May 28, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Elena Nosyreva, Ege T Kavalali
Jul 19, 2011·Nature Chemical Biology·Ting ChenBertal H Aktas
Jul 4, 2012·Biochemical and Biophysical Research Communications·Kathryn J Huber-KeenerJin-Ming Yang
Mar 19, 2011·Science China. Life Sciences·Lishun Wang, Guoqiang Chen
Jan 17, 2012·Proteomics·Li-Shun WangGuo-Qiang Chen
Aug 17, 2010·Molecular and Cellular Neurosciences·Racheli KaryoHagit Eldar-Finkelman
Jan 31, 2012·Experimental Cell Research·Yue ZhangBin Cong
Jan 17, 2015·Frontiers in Medicine·Luca Ulianich, Luigi Insabato
Jul 26, 2014·BioMed Research International·Dmitry A ChistiakovYuri V Bobryshev
Oct 19, 2016·Acta Neuropathologica·Asad JanPoul H Sorensen
Apr 28, 2018·Journal of Cell Science·Rafael J ArgüelloPhilippe Pierre
Oct 30, 2010·Circulation Research·Tetsuo MinaminoMasafumi Kitakaze
Jan 4, 2019·Circulation Research·Helena C Kenny, E Dale Abel
Jun 17, 2008·Cell Death and Differentiation·G KroemerZ Zakeri
Jul 29, 2016·The Journal of Biological Chemistry·Yi LiaoAlexey G Ryazanov
Apr 6, 2019·Advances in Pharmacological Sciences·Adaze Bijou EnogieruOkobi Eko Ekpo
May 26, 2017·BioMed Research International·Lorenzo Romero-RamírezM Asunción Barreda-Manso
Sep 6, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Pavlo V ZadorozhniiAleksandr V Kharchenko
Oct 15, 2010·Journal of Proteome Research·Michael MarisChantal Mathieu

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis