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Caspase cleavage product of BAP31 induce ... chrome c release to the cytosol
Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol
5394
Stimulation of cell surface death receptors activates caspase-8, which targets a limited number of substrates including BAP31, an integral membrane protein of the endoplasmic reticulum (ER). Recently, we reported that a caspase-resistant BAP31 mutant inhibited several features of Fas-induced apoptosis, including the release of cytochrome c (cyt.c) from mitochondria (Nguyen, M., D.G. Breckenridge, A. Ducret, and G.C. Shore. 2000. Mol. Cell. Biol. 20:6731-6740), implicating ER-mitochondria crosstalk in this pathway. Here, we report that the p20 caspase cleavage fragment of BAP31 can direct pro-apoptotic signals between the ER and mitochondria. Adenoviral expression of p20 caused an early release of Ca2+ from the ER, concomitant uptake of Ca2+ into mitochondria, and mitochondrial recruitment of Drp1, a dynamin-related protein that mediates scission of the outer mitochondrial membrane, resulting in dramatic fragmentation and fission of the mitochondrial network. Inhibition of Drp1 or ER-mitochondrial Ca2+ signaling prevented p20-induced fission of mitochondria. p20 strongly sensitized mitochondria to caspase-8-induced cyt.c release, whereas prolonged expression of p20 on its own ultimately induced caspase activation and apoptosis through the mitochondrial apoptosome stress pathway. Therefore, caspase-8 cleavage of BAP31 at the ER stimulates Ca2+-dependent mitochondrial fission, enhancing the release of cyt.c in response to this initiator caspase.
Breckenridge DG, Stojanovic M, Marcellus RC, Shore GC
The Journal of cell biology
2003-03-31 00:00
160
7
1115-27
Adenoviridae,Animals,Antigens, CD95,Apoptosis,CHO Cells,Calcium,Caspases,Cell Line,Cricetinae,Cytochrome c Group,Cytoskeletal Proteins,Cytosol,Endoplasmic Reticulum,Fibroblasts,HSP20 Heat-Shock Proteins,Heat-Shock Proteins,Hela Cells,Humans,Membrane Proteins,Mitochondria,Models, Biological,Muscle Proteins,Rats,Signal Transduction,Tumor Cells, Cultured,Utrophin,Antigens, CD95,BCAP31 protein, human,Cytochrome c Group,Cytoskeletal Proteins,HSP20 Heat-Shock Proteins,Heat-Shock Proteins,Membrane Proteins,Muscle Proteins,Utrophin,HSP20 protein, rat,Calcium,Caspases
Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6.
J. Cell Biol.
0021-9525
10.1083/jcb.200212059
jcb.200212059
0
False
12668660
