Moderate endoplasmic reticulum stress activates a PERK and p38-dependent apoptosis

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• The endoplasmic reticulum (ER) signals dysfunction through the unfolded protein response (UPR).
• Understanding dose-dependent ER stress responses is crucial for cell fate determination.

Purpose of the Study:

• To compare cellular responses to moderate versus severe ER stress.
• To elucidate the signaling pathways involved in ER stress-induced apoptosis.

Main Methods:

• Utilized tunicamycin (Tm) and temperature shift (TS) to induce varying levels of ER stress in hamster fibroblast cells.
• Investigated key ER stress mediators like inositol-requiring enzyme 1 (IRE1) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK).
• Analyzed kinase activation (p38, Erk1/2) and the role of ER calcium release inhibitors (2-APB, XeC) and specific pathway inhibitors (PERK, p38, Jnk1, Erk1/2).

Main Results:

• Moderate ER stress (20-40 nM Tm) activated ER stress signaling similarly to TS treatment, distinct from high Tm doses (500-1000 nM).
• Inhibition of ER calcium release protected against apoptosis at moderate, but not high, Tm doses.
• PERK and p38 signaling were critical for apoptosis induction at moderate ER stress levels and for the decline of anti-apoptotic proteins Mcl-1 and survivin.

Conclusions:

• ER stress signaling functions as a dose-dependent rheostat, with distinct molecular events at moderate versus severe stress levels.
• Apoptosis during moderate ER stress is dependent on PERK and p38 kinase activation.
• The findings emphasize the need to consider dose-dependent effects in ER stress research.