ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim

Hamsa Puthalakath, Lorraine A. O'Reilly, Priscilla Gunn, Lily Lee, Priscilla N. Kelly, Nicholas D. Huntington, Peter D. Hughes, Ewa M. Michalak, Jennifer McKimm-Breschkin, Noburo Motoyama, Tomomi Gotoh, Shizuo Akira, Philippe Bouillet, Andreas Strasser

Research output: Contribution to journalArticleResearchpeer-review

974 Citations (Scopus)

Abstract

Endoplasmic reticulum (ER) stress caused by misfolded proteins or cytotoxic drugs can kill cells and although activation of this pathway has been implicated in the etiology of certain degenerative disorders its mechanism remains unresolved. Bim, a proapoptotic BH3-only member of the Bcl-2 family is required for initiation of apoptosis induced by cytokine deprivation or certain stress stimuli. Its proapoptotic activity can be regulated by several transcriptional or posttranslational mechanisms, such as ERK-mediated phosphorylation, promoting its ubiquitination and proteasomal degradation. We found that Bim is essential for ER stress-induced apoptosis in a diverse range of cell types both in culture and within the whole animal. ER stress activates Bim through two novel pathways, involving protein phosphatase 2A-mediated dephosphorylation, which prevents its ubiquitination and proteasomal degradation and CHOP-C/EBPα-mediated direct transcriptional induction. These results define the molecular mechanisms of ER stress-induced apoptosis and identify targets for therapeutic intervention in ER stress-related diseases.

Original languageEnglish
Pages (from-to)1337-1349
Number of pages13
JournalCell
Volume129
Issue number7
DOIs
Publication statusPublished - 29 Jun 2007
Externally publishedYes

Keywords

  • CELLBIO
  • SIGNALING

Cite this