ER-Targeted Bcl-2 Mitigates Ethanol Toxicity More Significantly than Wildtype or Mitochondria-Targeted Bcl-2
Balan, Andreea G.
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The Bcl-2 family of proteins, which includes both pro- and anti-apoptotic members, is responsible for the regulation of apoptosis through control of caspase activity. Bcl-2 protects cells from apoptosis by inhibiting Bax and Bak (both pro-apoptotic members) from releasing cytochrome c, an important co-factor for caspase activation, from mitochondria. Previously, Bcl-2 was thought to be subcellularly localized only to the mitochondria, however recent work suggests that Bcl-2 is distributed in the endoplasmic reticulum as well. Prior in vivo studies have shown that overexpression of wildtype Bcl-2 is protective against ethanol toxicity, a known inducer of apoptosis; nonetheless, it is unclear whether protection is mediated through the mitochondria or the ER. Chinese hamster ovary cells (CH0695) were transiently transfected with GFP: Bcl-2 wildtype, GFP: Bcl-2 MAOB (mitochondria target) or GFP: Bcl-2 CbS (ER target) in order to confirm the subcellular localization of overexpressed Bcl-2 and to determine differential rescue from ethanol toxicity. GFP: Bcl-2 fusion proteins were appropriately localized, indicating successful organelle-targeting. MTI apoptosis assay was used to measure cell viability in response to ethanol in cells overexpressing wildtype and organelle-targeted Bcl-2. We found that the ER-targeted Bcl-2 significantly rescued CH0695 cells from ethanol toxicity even at normally toxic concentrations, whereas wildtype and mitochondria-targeted Bcl-2 offered more limited protection. Therefore, the present study indicates that Bcl-2's known amelioration of ethanol toxicity is likely mediated through the ER. Future work should clarify the role of the ER in ethanol toxicity.
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