Parkin promotes proteasomal degradation of misregulated BAX

Abstract

The pro-apoptotic BCL-2 protein BAX commits human cells to apoptosis by permeabilizing the outer mitochondrial membrane. BAX activation has been suggested to require the separation of helix α5 from α6 and thus the ‘latch’ from the ‘core’ domain among other conformational changes. Here we show that conformational changes in this region impair BAX translocation to the mitochondria and retrotranslocation back into the cytosol and therefore BAX inhibition, but not activation. Redirecting misregulated BAX to the mitochondria revealed an alternative mechanism of BAX inhibition. The E3 ligase Parkin, known to trigger mitochondria-specific autophagy, ubiquitinates BAX K128 and targets the pro-apoptotic BCL-2 protein for proteasomal degradation. Retrotranslocation-deficient BAX is completely degraded in a Parkin-dependent manner. Although only a minor pool of endogenous BAX escapes retrotranslocation into the cytosol, Parkin-dependent targeting of misregulated BAX on the mitochondria provides substantial protection against BAX apoptotic activity.