Caspase Cleavage Product of BAP31 Induces Mitochondrial Fission through Endoplasmic Reticulum Calcium Signals, Enhancing Cytochrome c Release to the Cytosol

• Published in: The Journal of cell biology Vol. 160; no. 7; pp. 1115 - 1127
• Main Authors: Breckenridge, David G., Stojanovic, Marina, Marcellus, Richard C., Shore, Gordon C.
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 31.03.2003; The Rockefeller University Press
• Subjects: Adenoviridae - genetics; Animals; Antibodies; Apoptosis; Calcium - metabolism; Caspases - metabolism; Cell Line; Cells; Cellular biology; CHO Cells; Cricetinae; Cytochrome c Group - metabolism; Cytochromes; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Cytosol - metabolism; Death domain receptors; Endoplasmic Reticulum - metabolism; fas Receptor - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; Heat-Shock Proteins; HeLa Cells; Hepatocytes; HSP20 Heat-Shock Proteins; Humans; Infections; KB cells; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membranes; Mitochondria; Mitochondria - physiology; Models, Biological; Muscle Proteins - metabolism; Organelles; Proteins; Rats; Signal Transduction; Tumor Cells, Cultured; Utrophin
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200212059

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, 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.