Distinct roles of mitochondria- and ER-localized Bcl-xL in apoptosis resistance and Ca2+ homeostasis

被引:42
作者
Eno, Colins O. [1 ,2 ,3 ,4 ]
Eckenrode, Emily F. [5 ]
Olberding, Kristen E. [1 ,2 ,3 ,4 ]
Zhao, Guoping [1 ,2 ,3 ,4 ]
White, Carl [5 ]
Li, Chi [1 ,2 ,3 ,4 ]
机构
[1] Univ Louisville, James Graham Brown Canc Ctr, Mol Targets Program, Louisville, KY 40202 USA
[2] Univ Louisville, Dept Med, Louisville, KY 40202 USA
[3] Univ Louisville, Dept Pharmacol, Louisville, KY 40202 USA
[4] Univ Louisville, Dept Toxicol, Louisville, KY 40202 USA
[5] Rosalind Franklin Univ Med & Sci, Dept Physiol & Biophys, N Chicago, IL 60064 USA
基金
美国国家卫生研究院;
关键词
INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS; BCL-X-L; ENDOPLASMIC-RETICULUM; CELL-DEATH; FAMILY-MEMBERS; PROTEINS; MODULATION; SURVIVAL; BAX; REGULATORS;
D O I
10.1091/mbc.E12-02-0090
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Bcl-2 proteins are major regulators of cellular responses to intrinsic and extrinsic apoptotic stimuli. Among them, overexpression of the antiapoptotic protein Bcl-x(L) modulates intracellular Ca2+ homeostasis and organelle-specific apoptotic signaling pathways. However, the specific activities of Bcl-x(L) at mitochondria and the endoplasmic reticulum (ER) have not been fully defined. To further explore this, we generated mouse embryonic fibroblast (MEF) cell lines deficient in Bcl-x(L) expression (Bcl-x-KO). Deficiency in Bcl-x(L) expression did not induce compensatory changes in the expression of other Bcl-2 proteins, and Bcl-x-KO MEF cells showed increased sensitivity to various apoptotic stimuli compared with wild-type MEF cells. Targeting Bcl-x(L) at mitochondria but not at the ER restored apoptosis protection in Bcl-x-KO MEF cells to the degree observed in wild-type MEF cells. However, expression of ER-targeted Bcl-x(L) but not mitochondrially targeted Bcl-x(L) was required to restore Ca2+ homeostasis in Bcl-x-KO MEF cells. Of importance, ER-targeted Bcl-x(L) was able to protect cells against death stimuli in the presence of endogenous Bcl-x(L). These data indicate that mitochondrial Bcl-x(L) can regulate apoptosis independently of ER Bcl-x(L) and that when localized exclusively at the ER, Bcl-x(L) impinges on Ca2+ homeostasis but does not affect apoptosis unless Bcl-x(L) is present in additional cellular compartments.
引用
收藏
页码:2605 / 2618
页数:14
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