A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death.
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.
Boyce
M
M
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Py
B F
BF
Ryazanov
A G
AG
Minden
J S
JS
Long
K
K
Ma
D
D
Yuan
J
J
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology*; D054736:Elongation Factor 2 Kinase / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D051379:Mice; D016716:PC12 Cells; D020652:Peptide Elongation Factor 2 / Q000378:metabolism*; D040901:Proteomics; D051381:Rats; D015398:Signal Transduction; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D020652:Peptide Elongation Factor 2; C496827:salubrinal; D054736:Elongation Factor 2 Kinase; D013890:Thiourea