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Molecular and Cellular Biology, August 2004, p. 6592-6607, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6592-6607.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Association of Active Caspase 8 with the Mitochondrial Membrane during Apoptosis: Potential Roles in Cleaving BAP31 and Caspase 3 and Mediating Mitochondrion-Endoplasmic Reticulum Cross Talk in Etoposide-Induced Cell Death

Dhyan Chandra,1 Grace Choy,1 Xiaodi Deng,1 Bobby Bhatia,1 Peter Daniel,2 and Dean G. Tang1*

Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957,1 Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Humboldt University of Berlin, Berlin 13125, Germany2

Received 29 December 2003/ Returned for modification 26 January 2004/ Accepted 27 April 2004

It was recently demonstrated that during apoptosis, active caspase 9 and caspase 3 rapidly accumulate in the mitochondrion-enriched membrane fraction (D. Chandra and D. G. Tang, J. Biol. Chem.278:17408-17420, 2003). We now show that active caspase 8 also becomes associated with the membranes in apoptosis caused by multiple stimuli. In MDA-MB231 breast cancer cells treated with etoposide (VP16), active caspase 8 is detected only in the membrane fraction, which contains both mitochondria and endoplasmic reticulum (ER), as revealed by fractionation studies. Immunofluorescence microscopy, however, shows that procaspase 8 and active caspase 8 predominantly colocalize with the mitochondria. Biochemical analysis demonstrates that both procaspase 8 and active caspase 8 are localized mainly on the outer mitochondrial membrane (OMM) as integral proteins. Functional analyses with dominant-negative mutants, small interfering RNAs, peptide inhibitors, and Fas-associated death domain (FADD)- and caspase 8-deficient Jurkat T cells establish that the mitochondrion-localized active caspase 8 results mainly from the FADD-dependent and tumor necrosis factor receptor-associated death domain-dependent mechanisms and that caspase 8 activation plays a causal role in VP16-induced caspase 3 activation and cell death. Finally, we present evidence that the OMM-localized active caspase 8 can activate cytosolic caspase 3 and ER-localized BAP31. Cleavage of BAP31 leads to the generation of ER- localized, proapoptotic BAP20, which may mediate mitochondrion-ER cross talk through a Ca2+-dependent mechanism.

* Corresponding author. Mailing address: Dept. of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Park Rd. 1C, Smithville, TX 78957. Phone: (512) 237-9575. Fax: (512) 237-2475. E-mail: dtang{at}sprd1.mdacc.tmc.edu.

Molecular and Cellular Biology, August 2004, p. 6592-6607, Vol. 24, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.15.6592-6607.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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