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Heat shock preconditioning protects against ER stress-induced apoptosis through the regulation of the BH3-only protein BIM

Donna C Kennedy,K. Mnich,Afshin Samali

Published 2014 in FEBS Open Bio

ABSTRACT

A mild heat shock (HS) preconditioning and acquisition of thermotolerance protects cells against a variety of cytotoxic agents that otherwise induce apoptosis. Here we tested whether there is a molecular link between HS preconditioning and endoplasmic reticulum (ER) stress‐induced apoptosis. ER stress results from a loss of ER lumen homeostasis, culminating in an accumulation of unfolded/misfolded proteins in the ER and activation of unfolded protein response (UPR). Unresolved, ER stress leads to activation of BH3‐only proteins, mitochondrial membrane permeabilization, caspase activation and apoptotic cell death. HS preconditioning (1 h at 42 °C) induced a rapid increase in HSPA1 (HSP70) levels which remained elevated for at least 48 h post‐HS. HS preconditioning significantly reduced BAX, caspase activation and apoptosis in cell cultures treated with the ER stress‐inducing agents thapsigargin (TG) and tunicamycin (TM). HS‐mediated protection was found to be due to regulation of the BH3‐only protein BIM. Further, overexpression of HSPA1 could not mimic the effect of HS on BIM expression, suggesting that other HS factors may play a role in inhibiting ER stress‐induced apoptosis by regulating BIM.

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