Endoplasmic Reticulum Stress-induced Cell Death Mediated by the Proteasome

Egger, L. et al. Cell Death Differ., advance online publication, 30 March 2007

Student: Wei-Ching Huang (黃薇靜)                             Time: 13:10-14:00, May 9, 2007

Commentator: Dr. Robert Anderson                               Place: Room 601

Abstract

The endoplasmic reticulum (ER), the site of protein synthesis and conformational maturation, is involved in cellular regulation by controlling correctly folded proteins. Extracellular and intracellular stimuli that lead to the accumulation of unfolded proteins result in ER stress followed by initiating a series of orchestrated events known as the unfolded protein response (UPR) to maintain the cellular homeostasis¹. One of the consequences resulting from UPR activation is proteasomal degradation of poorly folded ER-directed proteins. This process is called ER-associated degradation (ERAD)². Once a cell fails to restore homeostasis from the activation of UPR and ERAD, the cell initiates ER stress-induced programmed cell death. In this study³, the authors demonstrate that the activity of the proteasome is indispensable for triggering apoptotic signaling pathways in ER stress. Cell death was induced by three ER stress inducers, such as brefeldin A (BFA), tunicamycin, and thapsigargin combined with cycloheximide. Since the cell death is not blocked by the broad-spectrum caspase inhibitors, Z-VAD.fmk, the authors suggested that some caspase-independent mechanism may be involved. Proteasome inhibitors, lactacystin and Pefabloc (AEBSF), were applied to address the necessity of the proteasome in ER stress-induced cell death. The involvement of proteasome activity in triggering ER stress-induced cell death was further demonstrated by using cell lines harboring a temperature-sensitive E1 ubiquitin-activating enzyme. Interestingly, proteasomal inhibition blocked ER stress-induced degradation of anti-apoptotic Bcl-2 family proteins and conferred protection before mitochondrial damage followed by inhibiting cytochrome c release, caspase maturation, phosphatidylserine exposure and cell death. According to these results, the authors conclude that the proteasome is a principal mediator in the activation of ER stress-induced cell death in this system. Thus, proteasome has dual roles in protecting cells from ER stress-induced URP by ERAD and in the activation of ER stress-induced cell death.

References

1.   Bernales, S. et al. Intracellular signaling by the unfolded protein response. Annu. Rev. Cell Dev. Biol. 22, 487-508 (2006)

2.   Romisch, K. Endoplasmic reticulum-associated degradation. Annu. Rev. Cell Dev. Biol. 21, 435-456 (2005)

3.   Egger, L. et al. Endoplasmic reticulum stress-induced cell death mediated by the proteasome. Cell Death Differ. advance online publication, 30 March (2007)