1. Lysosome is a primary organelle in B cell receptor-mediated apoptosis: an indispensable role of Syk in lysosomal function.
- Author
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He J, Tohyama Y, Yamamoto K, Kobayashi M, Shi Y, Takano T, Noda C, Tohyama K, and Yamamura H
- Subjects
- Animals, Cell Line, Cell Nucleus ultrastructure, Chickens, Cytochromes c metabolism, Enzyme Activation, Enzyme Precursors genetics, Fluorescent Dyes metabolism, Humans, Hydrogen-Ion Concentration, Intracellular Signaling Peptides and Proteins, Lymphocyte Activation, Lysosomes ultrastructure, Mutagenesis, Site-Directed, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins c-abl genetics, Proto-Oncogene Proteins c-abl metabolism, Syk Kinase, Apoptosis physiology, Enzyme Precursors metabolism, Lysosomes metabolism, Protein-Tyrosine Kinases metabolism, Receptors, Antigen, B-Cell metabolism
- Abstract
To investigate the mechanism of B cell receptor (BCR)-mediated apoptosis, we utilized immature B cell lines, DT40 and WEHI-231. In both cell lines, BCR-crosslinking caused the increase in lysosomal pH with early apoptotic changes characterized by chromatin condensation and phosphatidylserine exposure. This increase was detected in c-Abl-deficient DT40 cells but not in Syk-deficient cells, which corresponded to the fact that the former cells but not the latter revealed BCR-induced apoptosis. In contrast, BCR-crosslinking caused no apparent change in mitochondrial transmembrane potential. Therefore, the lysosomal change might be a primary event in BCR-induced apoptosis in DT40 cells. The increased activity of cathepsin B and apoptosis-preventing effect of a cathepsin inhibitor suggested a significant role of lysosomal enzymes in this apoptosis. By microscopic studies, lysosomes of wild-type DT40 cells fused to BCR-carrying endosomes became enlarged and accumulated one another. In contrast, these changes of lysosomal dynamics did not occur in Syk-deficient cells but transfer of wild-type Syk restored the lysosomal changes and apoptosis. These results demonstrated that the lysosomal change accompanied with the activation of lysosomal enzymes is a primary step in BCR-crosslinking-mediated apoptosis and Syk is responsible for this step through the fusion of BCR-carrying endosomes to lysosomes.
- Published
- 2005
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