Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis
Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis
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DOI：
10.1038/380723a0
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发表时间：
1996-04-25
期刊：
影响因子：
64.8
通讯作者：
Nagata, S
中科院分区：
文献类型：
--
作者：
Enari, M;Talanian, RV;Nagata, S
与Fas配体或激动性抗Fas抗体结合可诱导携带Fas的细胞凋亡（1）。白细胞介素-1 β转化酶（ICE）是一种半胱氨酸蛋白酶（2），参与各种刺激诱导的细胞凋亡，包括Fas介导的细胞凋亡（3-8）。已经鉴定了几种ICE同源物，并且这些同源物被细分为三组（ICE-、CPP 32-和Ich-1-样蛋白酶）（9-18）。我们在这里表明，ICE或CPP 32样蛋白酶的特异性抑制剂可以抑制Fas介导的细胞凋亡。短暂的ICE样活性被发现在Fas激活的细胞的胞质部分，而ICE依赖性，CPP 32样活性逐渐积累在胞质中。补充有重组ICE或CPP 32的小鼠淋巴瘤细胞裂解物诱导细胞核凋亡。CPP 32抑制剂抑制ICE或CPP 32诱导的无细胞系统中的细胞凋亡，而ICE抑制剂仅抑制ICE诱导的细胞凋亡。ICE-null小鼠胸腺细胞的细胞提取物在无细胞系统中补充CPP 32时诱导细胞凋亡。这些结果表明Fas依次激活ICE样蛋白酶和CPP 32样蛋白酶，并且下游CPP 32与细胞质中的组分一起引起细胞核的凋亡。
BINDING of Fas ligand or an agonistic anti-Fas antibody induces apoptosis in Fas-bearing cells(1). The interleukin-1 beta-converting enzyme (ICE) is a cysteine protease(2) that is involved in apoptosis induced by various stimuli, including Fas-mediated apoptosis(3-8). Several ICE homologues have been identified, and these are subdivided into three groups (ICE-, CPP32- and Ich-1-like proteases)(9-18). We show here that specific inhibitors of ICE- or CPP32-like proteases can inhibit Fas-mediated apoptosis. Transient ICE-like activity was found in the cytosolic fraction of Fas-activated cells, whereas ICE-dependent, CPP32-like activity gradually accumulated in the cytosol. Cell lysates from mouse lymphoma supplemented with either recombinant ICE or CPP32 induced apoptosis of nuclei. The CPP32 inhibitor inhibited ICE- or CPP32-induced apoptosis in the cell-free system, whereas the ICE-inhibitor only inhibited ICE-induced apoptosis. Cell extracts from thymocytes from ICE-null mice induced apoptosis in the cell-free system when it was supplemented with CPP32. These results indicate that Fas sequentially activates ICE- and CPP32-like proteases, and that downstream CPP32, together with a component(s) in the cytoplasm, causes apoptosis of nuclei.