BOK Is a Non-canonical BCL-2 Family Effector of Apoptosis Regulated by ER-Associated Degradation

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. [Display omitted] •BOK induces mitochondrial apoptosis in the absence of BAX and BAK•The proapoptotic activity of BOK is independent of other BCL-2 family proteins•BOK activity is regulated via endoplasmic-reticulum-associated degradation (ERAD)•ERAD components AMFR/gp78 and VCP/p97 and the proteasome carry out BOK degradation The BCL-2 family member BOK offers a path to mitochondrial outer membrane permeabilization and apoptosis that can be executed in the absence of BAX and BAK and that is controlled at the level of protein stability by ER-associated degradation.