Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol.
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
David G
DG
Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6.
Stojanovic
Marina
M
Marcellus
Richard C
RC
Shore
Gordon C
GC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D003574:Cytochrome c Group / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D050886:HSP20 Heat-Shock Proteins; D006367:HeLa Cells; D006360:Heat-Shock Proteins; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology*; D008954:Models, Biological; D009124:Muscle Proteins / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D049411:Utrophin; D019014:fas Receptor / Q000378:metabolism
C091247:BCAP31 protein, human; D003574:Cytochrome c Group; D003598:Cytoskeletal Proteins; D050886:HSP20 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D049411:Utrophin; D019014:fas Receptor; C087458:Hspb6 protein, rat; D020169:Caspases; D002118:Calcium