Lysosome is a primary organelle in B cell receptor-mediated apoptosis: an indispensable role of Syk in lysosomal function
Lysosome is a primary organelle in B cell receptor-mediated apoptosis: an indispensable role of Syk in lysosomal function
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DOI：
10.1111/j.1365-2443.2004.00811.x
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发表时间：
2005-01-01
期刊：
影响因子：
2.1
通讯作者：
Yamamura, H
中科院分区：
文献类型：
--
作者：
He, J;Tohyama, Y;Yamamura, H
为了研究B细胞受体（BCR）介导的凋亡机制，我们利用未成熟的B细胞系，DT 40和WEHI-231。在这两种细胞系中，BCR交联导致溶酶体pH值升高，伴有以染色质浓缩和磷脂酰丝氨酸暴露为特征的早期凋亡变化。在c-Abl缺陷型DT 40细胞中检测到这种增加，但在Syk缺陷型细胞中未检测到，这对应于前者细胞而非后者揭示BCR诱导的凋亡的事实。相反，BCR交联没有引起线粒体跨膜电位的明显变化。因此，溶酶体的变化可能是BCR诱导DT 40细胞凋亡的主要事件。组织蛋白酶B活性的增加和组织蛋白酶抑制剂的凋亡预防作用表明溶酶体酶在这种凋亡中起重要作用。通过显微镜研究，与携带BCR的内体融合的野生型DT 40细胞的溶酶体变大并彼此积聚。相反，这些变化的溶酶体动力学没有发生在Syk缺陷的细胞，但野生型Syk的转移恢复了溶酶体的变化和细胞凋亡。这些结果表明，伴随溶酶体酶活化的溶酶体变化是BCR交联介导的细胞凋亡的主要步骤，Syk通过携带BCR的内体与溶酶体融合负责该步骤。
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.