Cathepsins as effector proteases in hepatocyte apoptosis
Cathepsins as effector proteases in hepatocyte apoptosis
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DOI：
10.1007/bf02737885
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发表时间：
1999-01-01
影响因子：
2.6
通讯作者：
Gores, Gregory J.
中科院分区：
文献类型：
--
作者：
Roberts, Lewis R.;Adjei, Philip N.;Gores, Gregory J.
结论组织蛋白酶B和D在胆盐诱导的肝癌细胞凋亡和CPT诱导的肝癌细胞凋亡中均参与了肝细胞凋亡的效应蛋白酶级联反应。值得注意的是，这些蛋白酶似乎并不参与迄今为止研究的许多细胞凋亡模型;事实上，组织蛋白酶抑制剂已被用作阴性对照，以显示除半胱天冬酶以外的酶不参与细胞凋亡。特别是，已经表明组织蛋白酶B抑制剂不能阻止淋巴细胞中的许多细胞凋亡模型（43）。此外，我们的实验表明，并不是所有的肝细胞凋亡模型是由组织蛋白酶介导的。例如，在原代肝细胞或用组织蛋白酶B反义构建体稳定转染的细胞系中，星形孢菌素诱导的细胞凋亡不被组织蛋白酶B抑制剂抑制。虽然在肝细胞凋亡中导致组织蛋白酶B和D活化的信号通路尚未完全了解，但我们假设在组织蛋白酶D和B附近可能涉及半胱天冬酶8样蛋白（图6）。组织蛋白酶B从溶酶体转移到“凋亡靶点”的确切机制目前正在我们的实验室进行研究。由于组织蛋白酶B作为蛋白酶的相对混杂性，它很可能参与凋亡小体中的非特异性蛋白质降解;然而，组织蛋白酶B也被证明降解某些特定的蛋白质，如组蛋白，其可能与凋亡过程直接相关。组织蛋白酶B和D在细胞凋亡中的作用的进一步评价应包括确定导致细胞凋亡的生化和形态学表现的特异性蛋白水解靶点。
ConclusionCathepsins B and D appear to act as part of the effector protease cascade in hepatocyte apoptosis, both in bile salt-induced apoptosis and CPT-induced apoptosis of hepatocellular cancer cell lines. It is important to note that these proteases do not appear to participate in many models of apoptosis studied to date; in fact, cathepsin inhibitors have been used as negative controls to show that enzymes other than caspases are not involved in apoptosis. In particular, it has been shown that cathepsin B inhibitors do not prevent many models of apoptosis in lymphocytes (43). Further, our experiments have shown that not all models of hepatocyte apoptosis are mediated by cathepsins. For example, staurosporine-induced apoptosis is not inhibited by cathepsin B inhibitors in primary hepatocytes or in cell lines stably transfected with the cathepsin B antisense construct. Although the signaling pathways leading to activation of cathepsins B and D in hepatocyte apoptosis are not completely understood, we hypothesize that a caspase 8-like protein may be involved proximal to cathepsins D and B (Fig. 6). The precise mechanism by which cathepsin B is translocated from lysosomes to “apoptotic targets” is currently under investigation in our laboratory. Because of the relative promiscuity of cathepsin B as protease, it is likely that it is involved in nonspecific protein degradation in apoptotic bodies; however, cathepsin B has also been shown to degrade certain specific proteins, such as histones, which may be directly relevant to the apoptotic process. Further evaluation of the role of cathepsins B and D in apoptosis should include the determination of specific proteolytic targets that result in the biochemical and morphologic manifestations of apoptosis.