Llambi Fabien, Wang Yue-Ming, Victor Bernadette, Yang Mao, Schneider Desiree M, Gingras Sébastien, Parsons Melissa J, Zheng Janet H, Brown Scott A, Pelletier Stéphane, Moldoveanu Tudor, Chen Taosheng, Green Douglas R
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cell. 2016 Apr 7;165(2):421-33. doi: 10.1016/j.cell.2016.02.026. Epub 2016 Mar 3.
The mitochondrial pathway of apoptosis is initiated by mitochondrial outer membrane permeabilization (MOMP). The BCL-2 family effectors BAX and BAK are thought to be absolutely required for this process. Here, we report that BCL-2 ovarian killer (BOK) is a bona fide yet unconventional effector of MOMP that can trigger apoptosis in the absence of both BAX and BAK. However, unlike the canonical effectors, BOK appears to be constitutively active and unresponsive to antagonistic effects of the antiapoptotic BCL-2 proteins. Rather, BOK is controlled at the level of protein stability by components of the endoplasmic reticulum (ER)-associated degradation pathway. BOK is ubiquitylated by the AMFR/gp78 E3 ubiquitin ligase complex and targeted for proteasomal degradation in a VCP/p97-dependent manner, which allows survival of the cell. When proteasome function, VCP, or gp78 activity is compromised, BOK is stabilized to induce MOMP and apoptosis independently of other BCL-2 proteins.
凋亡的线粒体途径由线粒体外膜通透性改变（MOMP）启动。BCL-2家族效应蛋白BAX和BAK被认为是这一过程绝对必需的。在此，我们报道BCL-2卵巢杀手（BOK）是一种真正的但非传统的MOMP效应蛋白，在BAX和BAK均缺失的情况下可触发凋亡。然而，与经典效应蛋白不同，BOK似乎组成性激活，且对抗凋亡BCL-2蛋白的拮抗作用无反应。相反，BOK在蛋白质稳定性水平受内质网（ER）相关降解途径成分的调控。BOK被AMFR/gp78 E3泛素连接酶复合物泛素化，并以VCP/p97依赖的方式靶向蛋白酶体降解，从而使细胞存活。当蛋白酶体功能、VCP或gp78活性受损时，BOK被稳定化，以独立于其他BCL-2蛋白的方式诱导MOMP和凋亡。
