Baxbeta: 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 Baxalpha protein has been well documented and studied. Baxalpha exists in latent form and is activated upon apoptosis induction through conformational changes. Here we demonstrate that Baxbeta protein is ubiquitously present among human cells, but its activity is restricted through stringent regulation by proteasomal degradation. In contrast to Baxalpha, native Baxbeta spontaneously integrates into mitochondrial membrane and is highly potent in inducing cytochrome c release from mitochondria. Remarkably, Baxbeta protein is upregulated by apoptotic stimuli via inhibition of its ubiquitination process, and stable expression of Baxbeta in HCT116-Bax(-/-) cells restores their sensitivity to multiple stimuli. Baxbeta associates with and promotes Baxalpha activation. Moreover, selective knockdown of Baxbeta 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.
Fu
Nai Yang
NY
Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore.
Sukumaran
Sunil K
SK
Kerk
Sze Yen
SY
Yu
Victor C
VC
D017209:Apoptosis / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D008970:Molecular Weight; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D020033:Protein Isoforms / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*
D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D020033:Protein Isoforms; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D046988:Proteasome Endopeptidase Complex