期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：23
页码：7201-7206
DOI：10.1073/pnas.1421063112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe role of B-cell lymphoma-2 (BCL-2) ovarian killer (BOK) in apoptosis regulation has been a long-standing enigma. Despite the homology to BAX and BAK, BOK has yet to be linked to a definitive physiologic function in the classical apoptotic pathway. Here, we report a selective role for BOK in promoting mitochondrial apoptosis in response to endoplasmic reticulum stress. B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) is a BCL-2 family protein with high homology to the multidomain proapoptotic proteins BAX and BAK, yet Bok-/- and even Bax-/-Bok-/- and Bak-/-Bok-/- mice were reported to have no overt phenotype or apoptotic defects in response to a host of classical stress stimuli. These surprising findings were interpreted to reflect functional compensation among the BAX, BAK, and BOK proteins. However, BOK cannot compensate for the severe apoptotic defects of Bax-/-Bak-/- mice despite its widespread expression. Here, we independently developed Bok-/- mice and found that Bok-/- cells are selectively defective in their response to endoplasmic reticulum (ER) stress stimuli, consistent with the predominant subcellular localization of BOK at the ER. Whereas Bok-/- mouse embryonic fibroblasts exposed to thapsigargin, A23187, brefeldin A, DTT, geldanamycin, or bortezomib manifested reduced activation of the mitochondrial apoptotic pathway, the death response to other stimuli such as etoposide, staurosporine, or UV remained fully intact. Multiple organs in Bok-/- mice exhibited resistance to thapsigargin-induced apoptosis in vivo. Although the ER stress agents activated the unfolded protein response, both ATF4 and CHOP activation were diminished in Bok-/- cells and mice. Importantly, BAX and BAK were unable to compensate for the defective apoptotic response to ER stress observed in SV40-transformed and primary Bok-/- cells, and in vivo. These findings support a selective and distinguishing role for BOK in regulating the apoptotic response to ER stress, revealing--to our knowledge--the first bona fide apoptotic defect linked to Bok deletion.
关键词：BOK ; apoptosis ; BCL-2 family ; endoplasmic reticulum stress ; unfolded protein response
