Intracellular localization of the BCL-2 family member BOK and functional implications
Intracellular localization of the BCL-2 family member BOK and functional implications
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DOI：
10.1038/cdd.2013.10
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发表时间：
2013-06-01
影响因子：
12.4
通讯作者：
Kaufmann, T.
中科院分区：
文献类型：
--
作者：
Echeverry, N.;Bachmann, D.;Kaufmann, T.
促凋亡BCL-2家族成员BOK广泛表达，并且基于其氨基酸序列类似于多BH结构域蛋白BAX和巴克。据报道，编码BOK的基因组区域在人类癌症中频繁缺失，因此推测BOK起肿瘤抑制剂的作用。然而，人们对BOK的分子功能知之甚少。我们发现，BOK的强制表达激活BAX/BAK-精通细胞的内在（线粒体）凋亡途径，但未能杀死缺乏BAX和巴克的细胞或使它们对细胞毒性损伤敏感。有趣的是，内源性BOK的主要部分定位于并部分插入高尔基体的膜以及内质网（ER）和相关膜。因此，BOK的C-末端跨膜结构域构成特异性靶向高尔基体和ER的“尾锚”。全长BOK的过度表达导致ER和高尔基体区室的早期片段化。Bok缺陷细胞对高尔基体/ER应激因子布雷菲德菌素A的异常反应支持了Bok对高尔基体和ER的作用。基于这些结果，我们提出，BOK的主要功能是在高尔基体和ER膜和BOK诱导细胞凋亡的方式依赖于BAX和BAK。
The pro-apoptotic BCL-2 family member BOK is widely expressed and resembles the multi-BH domain proteins BAX and BAK based on its amino acid sequence. The genomic region encoding BOK was reported to be frequently deleted in human cancer and it has therefore been hypothesized that BOK functions as a tumor suppressor. However, little is known about the molecular functions of BOK. We show that enforced expression of BOK activates the intrinsic (mitochondrial) apoptotic pathway in BAX/BAK-proficient cells but fails to kill cells lacking both BAX and BAK or sensitize them to cytotoxic insults. Interestingly, major portions of endogenous BOK are localized to and partially inserted into the membranes of the Golgi apparatus as well as the endoplasmic reticulum (ER) and associated membranes. The C-terminal transmembrane domain of BOK thereby constitutes a 'tail-anchor' specific for targeting to the Golgi and ER. Overexpression of full-length BOK causes early fragmentation of ER and Golgi compartments. A role for BOK on the Golgi apparatus and the ER is supported by an abnormal response of Bok-deficient cells to the Golgi/ER stressor brefeldin A. Based on these results, we propose that major functions of BOK are exerted at the Golgi and ER membranes and that BOK induces apoptosis in a manner dependent on BAX and BAK.