Apoptosis via the B cell antigen receptor requires Bax translocation and involves mitochondrial depolarization, cytochrome C release, and caspase‐9 activation

Various routes to apoptosis can be active during B cell development. In a model system of mature B cells, differences in caspase‐3 processing have suggested that antigen receptor (BCR)‐mediated apoptosis may involve a zVAD‐insensitive initiator protease(s). In search of the events leading to caspase...

Full description

Saved in:
Bibliographic Details
Published in:European Journal of Immunology 2004-07, Vol.34 (7), p.1950-1960
Main Authors: Eldering, Eric, Mackus, Wendelina J. M., Derks, Ingrid A. M., Evers, Ludo M., Beuling, Esther, Teeling, Peter, Lens, Susanne M. A., van Oers, Marinus H. J., van Lier, René A. W.
Format: Article
Language:English
Subjects:
Antigens - immunology
Apoptosis - drug effects
B cell receptor
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
bcl-2-Associated X Protein
Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology
Caspase
Caspase 3
Caspase 9
Caspases - chemistry
Caspases - genetics
Caspases - metabolism
CD95
Cell Line
Cytochromes c - metabolism
Enzyme Activation
fas Receptor - metabolism
Genes, Dominant - genetics
Humans
Membrane Potentials
Mitochondria - metabolism
Protein Transport
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-bcl-2
Receptors, Antigen, B-Cell - immunology
Receptors, Antigen, B-Cell - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Various routes to apoptosis can be active during B cell development. In a model system of mature B cells, differences in caspase‐3 processing have suggested that antigen receptor (BCR)‐mediated apoptosis may involve a zVAD‐insensitive initiator protease(s). In search of the events leading to caspase‐3 activation, we now establish that both CD95‐ and BCR‐mediated apoptosis depend on Bax activation and cytochrome C (cytC) release. Nevertheless, the timing and caspase‐dependence of mitochondrial membrane depolarization differed considerably after CD95‐ or BCR‐triggering. To delineate events subsequent to cytC release, we compared apoptosis induced via BCR triggering and via direct mitochondrial depolarization by CCCP. In both cases, partial processing of caspase‐3 was observed in the presence of zVAD. By expression in 293 cells we addressed the potential of candidate initiator caspases to function in the presence of zVAD, and found that caspase‐9 efficiently processed caspase‐3, while caspase‐2 or –8 were inactive. Finally, retroviral expression of dominant‐negative caspase‐9 inhibited both CD95‐ and BCR‐mediated apoptosis. In conclusion, we obtained no evidence for involvement of a BCR‐specific protease. Instead, our data show for the first time that the BCR‐signal causes Bax translocation, followed by mitochondrial depolarization, and cytC release. Subsequent caspase‐9 activation can solely account for events further downstream.
ISSN:0014-2980
1521-4141
1365-2567
DOI:10.1002/eji.200324817