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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Boyce, M; Py, BF; Ryazanov, AG; Minden, JS; Long, K; Ma, D; Yuan, J

Published Date

  • March 2008

Published In

Volume / Issue

  • 15 / 3

Start / End Page

  • 589 - 599

PubMed ID

  • 18188169

Pubmed Central ID

  • 18188169

International Standard Serial Number (ISSN)

  • 1350-9047

Digital Object Identifier (DOI)

  • 10.1038/sj.cdd.4402296

Language

  • eng

Conference Location

  • England