Baxβ: A Constitutively Active Human Bax Isoform that Is under Tight Regulatory Control by the Proteasomal Degradation Mechanism

Although mRNAs of multiple isoforms of Bax, which encodes a central regulator of apoptosis signaling, have been reported, only Bax alpha protein has been well documented and studied. Bax alpha exists in latent form and is activated upon apoptosis induction through conformational changes. Here we demonstrate that Bax beta protein is ubiquitously present among human cells, but its activity is restricted through stringent regulation by proteasomal degradation. In contrast to Bax alpha, native Bax beta spontaneously integrates into mitochondrial membrane and is highly potent in inducing cytochrome c release from mitochondria. Remarkably, Bax beta protein is upregulated by apoptotic stimuli via inhibition of its ubiquitination process, and stable expression of Bax beta in HCT116-Bax(-/-) cells restores their sensitivity to multiple stimuli. Bax beta associates with and promotes Baxa activation. Moreover, selective knockdown of Bax beta desensitizes HCT116-Bax(+/-) cells to Bax-dependent apoptosis signaling. These observations underscore the plasticity of human Bax in serving its role as a gatekeeper for apoptosis.