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ER stress triggers apoptosis by activating BH3-only protein Bim

Hamsa Puthalakath1, Lorraine A O'Reilly, Priscilla Gunn

  • 1The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.

Cell
|July 3, 2007
PubMed

Insights

Endoplasmic reticulum (ER) stress triggers cell death by activating the Bim protein. Novel pathways involving dephosphorylation and transcriptional induction clarify ER stress-induced apoptosis mechanisms.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Endoplasmic reticulum (ER) stress, caused by misfolded proteins or drugs, can lead to cell death.
  • The precise mechanisms linking ER stress to apoptosis, particularly in degenerative diseases, are not fully understood.
  • Bim, a proapoptotic protein, plays a key role in stress-induced cell death and is regulated by various mechanisms.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which ER stress induces apoptosis.
  • To investigate the role and regulation of Bim in ER stress-induced cell death.
  • To identify potential therapeutic targets for ER stress-related diseases.

Main Methods:

  • Utilized cell culture and whole animal models to study ER stress-induced apoptosis.
  • Investigated the regulation of Bim protein levels and activity under ER stress conditions.
  • Analyzed the involvement of protein phosphatase 2A (PP2A) and CHOP-C/EBPalpha in Bim activation.

Main Results:

  • Bim is essential for ER stress-induced apoptosis across various cell types and in vivo.
  • ER stress activates Bim via two novel pathways: PP2A-mediated dephosphorylation (inhibiting degradation) and CHOP-C/EBPalpha-mediated transcriptional induction.
  • Dephosphorylation by PP2A prevents Bim ubiquitination and proteasomal degradation, while CHOP-C/EBPalpha directly increases Bim transcription.

Conclusions:

  • The study defines the molecular pathways through which ER stress triggers apoptosis via Bim.
  • These findings reveal PP2A and CHOP-C/EBPalpha as key regulators of Bim in ER stress.
  • The identified mechanisms offer potential therapeutic targets for diseases associated with ER stress.

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