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

Published

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