Lysosome is a primary organelle in B cell receptor‐mediated apoptosis: an indispensable role of Syk in lysosomal function

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 exposur...

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Published in:Genes to cells : devoted to molecular & cellular mechanisms 2005-01, Vol.10 (1), p.23-35
Main Authors: He, Jinsong, Tohyama, Yumi, Yamamoto, Ken‐ichi, Kobayashi, Masahiko, Shi, Yuhong, Takano, Tomoko, Noda, Chiseko, Tohyama, Kaoru, Yamamura, Hirohei
Format: Article
Language:English
Subjects:
Animals
Apoptosis - physiology
Cell Line
Cell Nucleus - ultrastructure
Chickens
Cytochromes c - metabolism
Enzyme Activation
Enzyme Precursors - genetics
Enzyme Precursors - metabolism
Fluorescent Dyes - metabolism
Humans
Hydrogen-Ion Concentration
Intracellular Signaling Peptides and Proteins
Lymphocyte Activation
Lysosomes - metabolism
Lysosomes - ultrastructure
Mutagenesis, Site-Directed
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins c-abl - genetics
Proto-Oncogene Proteins c-abl - metabolism
Receptors, Antigen, B-Cell - metabolism
Syk Kinase
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Summary: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.
ISSN:1356-9597
1365-2443
DOI:10.1111/j.1365-2443.2004.00811.x