Endoplasmic reticulum stress-induced cell death mediated by the proteasome

Cell Death Differ. 2007 Jun;14(6):1172-80. doi: 10.1038/sj.cdd.4402125. Epub 2007 Mar 30.

Abstract

Cells exposed to sustained endoplasmic reticulum (ER) stress undergo programmed cell death and display features typical of apoptosis, such as cysteine aspartyl protease (caspase) activation, cytochrome c release, and DNA fragmentation. Here, we show that the execution of cell death induced by ER stress is mediated via the proteasome. Inhibition of the proteasome by lactacystin prevented ER stress-induced degradation of Bcl-2, release of cytochrome c, processing of effector caspase-3, and exposure of phosphatidylserine. Owing to the ability of lactacystin to inhibit cytochrome c release, we propose that the pro-apoptotic activity of the proteasome lies upstream of mitochondrial activation. Thus, the proteasome serves as a principal mediator of ER stress-induced cell death in this system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / analogs & derivatives
  • Acetylcysteine / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Blotting, Western
  • Brefeldin A / pharmacology
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Chlorhexidine / pharmacology
  • Cytochromes c / metabolism
  • DNA Fragmentation / drug effects
  • Electrophoresis, Polyacrylamide Gel
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Mitochondrial Membranes / metabolism
  • Models, Biological
  • Phosphatidylserines / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Sulfones / pharmacology
  • Temperature
  • Ubiquitin-Activating Enzymes / genetics
  • Ubiquitin-Activating Enzymes / metabolism

Substances

  • Phosphatidylserines
  • Proteasome Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfones
  • lactacystin
  • Brefeldin A
  • 4-(2-aminoethyl)benzenesulfonylfluoride
  • Cytochromes c
  • Caspase 3
  • Proteasome Endopeptidase Complex
  • Ubiquitin-Activating Enzymes
  • Chlorhexidine
  • Acetylcysteine