Tardy C, Tyynelä J, Hasilik A, Levade T, Andrieu-Abadie N
INSERM U466, Institut Louis Bugnard, Centre Hospitalier Universitaire de Rangueil, Toulouse, France.
Cell Death Differ. 2003 Sep;10(9):1090-100. doi: 10.1038/sj.cdd.4401272.
The role of cathepsin D in stress-induced cell death has been investigated by using ovine fibroblasts exhibiting a missense mutation in the active site of cathepsin D. The cathepsin D (lysosomal aspartic protease) deficiency did not protect cells against toxicity induced by doxorubicin and other cytotoxic agents, neither did it protect cells from caspase activation. Moreover, the cathepsin D inhibitor, pepstatin A, did not prevent stress-induced cell death in human fibroblasts or lymphoblasts. The possible role of lysosomal ceramide or sphingosine-mediated activation of cathepsin D in apoptosis was also excluded by using human cells either overexpressing or deficient in acid ceramidase. However, a normal lysosomal function seems to be required for efficient cell death, as indicated by the finding that fibroblasts from patients with mucolipidosis II were partially resistant to staurosporine, sphingosine and TNF-induced apoptosis, suggesting a key role of lysosomes in cell death.
通过使用在组织蛋白酶D活性位点表现出错义突变的绵羊成纤维细胞，研究了组织蛋白酶D在应激诱导的细胞死亡中的作用。组织蛋白酶D（溶酶体天冬氨酸蛋白酶）缺乏并不能保护细胞免受阿霉素和其他细胞毒性剂诱导的毒性，也不能保护细胞免受半胱天冬酶激活。此外，组织蛋白酶D抑制剂胃酶抑素A并不能预防人成纤维细胞或淋巴母细胞中应激诱导的细胞死亡。通过使用过表达或缺乏酸性神经酰胺酶的人细胞，也排除了溶酶体神经酰胺或鞘氨醇介导的组织蛋白酶D激活在细胞凋亡中的可能作用。然而，如粘脂贮积症II患者的成纤维细胞对星形孢菌素、鞘氨醇和TNF诱导的细胞凋亡具有部分抗性这一发现所示，有效的细胞死亡似乎需要正常的溶酶体功能，这表明溶酶体在细胞死亡中起关键作用。
