Molecular Targets Group, James Graham Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
Cell Death Differ. 2011 Jan;18(1):38-47. doi: 10.1038/cdd.2010.68. Epub 2010 Jun 11.
Endoplasmic reticulum (ER) stress-induced apoptosis may arise from multiple environmental and pharmacological causes, but the precise mechanism(s) involved are not completely known. Members of Bcl-2 protein family are important regulators of apoptosis. In this study, we report that in a process dependent on the proapoptotic Bcl-2 members Bax and Bak, exogenously expressed fluorescent protein localized to the ER lumen is released into the cytosol in cells undergoing ER stress. Upon ER stress induction, endogenous ER luminal proteins are also released into the cytosol in a similar manner accompanied by translocation and anchorage of Bax to the ER membrane. In addition, Bax and truncated-Bid (tBid) mediate a global increase in ER membrane permeability to ER luminal proteins in vitro. Importantly, antiapoptotic Bcl-X(L) antagonizes the effects of proapoptotic Bcl-2 proteins on ER membrane permeability. Consistent with Bax translocation to the ER membrane in whole apoptotic cells, there is also increased tight association of Bax with the ER membrane correlated with the increase in ER membrane permeability in vitro. Overall, these data suggest that the regulation of ER membrane permeability by Bcl-2 proteins could be an important molecular mechanism of ER stress-induced apoptosis.
内质网（ER）应激诱导的细胞凋亡可能由多种环境和药物因素引起，但具体的机制尚不完全清楚。Bcl-2 蛋白家族成员是细胞凋亡的重要调节因子。在这项研究中，我们报告说，在一个依赖于促凋亡的 Bcl-2 成员 Bax 和 Bak 的过程中，细胞发生内质网应激时，胞外表达的荧光蛋白定位到内质网腔并释放到细胞质中。内质网应激诱导后，内源性内质网腔蛋白也以类似的方式被释放到细胞质中，同时 Bax 易位并锚定到内质网膜上。此外，Bax 和截断的 Bid（tBid）介导内质网腔蛋白对 ER 膜通透性的全面增加。重要的是，抗凋亡的 Bcl-X(L) 拮抗促凋亡 Bcl-2 蛋白对 ER 膜通透性的影响。与 Bax 在整个凋亡细胞中易位到内质网膜一致，体外 ER 膜通透性增加时，Bax 与 ER 膜的紧密结合也增加。总的来说，这些数据表明 Bcl-2 蛋白对 ER 膜通透性的调节可能是 ER 应激诱导细胞凋亡的一个重要分子机制。
