Inhibition of ubiquitin-mediated degradation of MOAP-1 by apoptotic stimuli promotes Bax function in mitochondria.
The multidomain proapoptotic protein Bax of the Bcl-2 family is a central regulator for controlling the release of apoptogenic factors from mitochondria. Recent evidence suggests that the Bax-associating protein MOAP-1 may act as an effector for promoting Bax function in mitochondria. Here, we report that MOAP-1 protein is rapidly up-regulated by multiple apoptotic stimuli in mammalian cells. MOAP-1 is a short-lived protein (t(1/2) approximately 25 min) that is constitutively degraded by the ubiquitin-proteasome system. Induction of MOAP-1 by apoptotic stimuli ensues through inhibition of its polyubiquitination process. Elevation of MOAP-1 levels sensitizes cells to apoptotic stimuli and promotes recombinant Bax-mediated cytochrome c release from isolated mitochondria. Mitochondria depleted of short-lived proteins by cycloheximide (CHX) become resistant to Bax-mediated cytochrome c release. Remarkably, incubation of these mitochondria with in vitro-translated MOAP-1 effectively restores the cytochrome c releasing effect of recombinant Bax. We propose that apoptotic stimuli can facilitate the proapoptotic function of Bax in mitochondria through stabilization of MOAP-1.
Fu
Nai Yang
NY
Institute of Molecular and Cell Biology, 61 Biopolis Drive (Proteos), Singapore 138673.
Sukumaran
Sunil K
SK
Yu
Victor C
VC
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D045325:HCT116 Cells; D006207:Half-Life; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000037:antagonists & inhibitors*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C428449:MOAP1 protein, human; D011994:Recombinant Proteins; D025801:Ubiquitin; D051028:bcl-2-Associated X Protein; D046988:Proteasome Endopeptidase Complex