Cytotoxic T-cell-derived granzyme B activates the apoptotic protease ICE-LAP3
Cytotoxic T-cell-derived granzyme B activates the apoptotic protease ICE-LAP3
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DOI：
10.1016/s0960-9822(02)00614-0
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发表时间：
1996-07-01
期刊：
影响因子：
9.2
通讯作者：
Dixit, VM
中科院分区：
文献类型：
--
作者：
Chinnaiyan, AM;Hanna, WL;Dixit, VM
细胞毒性T淋巴细胞（CTL）和自然杀伤（NK）细胞提供针对病毒和肿瘤的免疫监视，并在自身免疫性疾病、AIDS和移植排斥的发病机制中发挥核心作用[1，2]。因此，了解细胞毒性淋巴细胞破坏易感靶细胞的精确分子机制非常重要。颗粒介导的细胞毒性需要穿孔素和颗粒酶B的组合[3]。穿孔蛋白聚合以形成跨膜通道，并推测允许颗粒酶B接近靶细胞底物，这直到最近还是未知的。由颗粒酶B激活的生理底物的身份的一个线索来自其切割天冬氨酸残基后的合成底物的不寻常的特异性[4]，ICE/CED-3家族的半胱氨酸蛋白酶成员是主要候选者，因为它们是重要的凋亡效应物[5，6]并且表达为酶原，其可在特定天冬氨酸残基处裂解后加工形成活性异二聚体酶，先前的研究表明颗粒酶B蛋白水解激活细胞死亡效应子Yama/CPP 32/apain [7，8]在此，我们报告颗粒酶B也激活ICE-LAP 3/Mch 3/CMH-1（这里称为ICE-LAP 3），其与Yama和Mch 2一起沿着，形成与秀丽隐杆线虫细胞死亡基因CED-3最密切相关的ICE/CED-3半胱氨酸蛋白酶家族的一个子集[6，9]，重要的是，与颗粒酶B和亚裂解浓度的穿孔素一起孵育的Jurkat T细胞经历凋亡，其之前是内源性ICE-LAP 3的活化。因此，我们提出颗粒酶B通过直接参与靶细胞的死亡效应器机制来介导细胞凋亡，该机制可能由细胞内的CED-3样半胱氨酸蛋白酶库组成。
Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells provide immune surveillance against viruses and neoplasms, and play a central role in the pathogenesis of autoimmune disease, AIDS and graft rejection [1,2]. Thus, it is important to understand the precise molecular mechanism(s) whereby cytotoxic lymphocytes destroy susceptible target cells, Granule-mediated cytotoxicity requires a combination of both perforin and granzyme B [3]. Perforin polymerizes to form transmembrane channels and presumably allows granzyme B access to target cell substrates, which until recently, were unknown, One clue to the identity of the physiological substrate(s) activated by granzyme B comes from its unusual specificity for cleaving synthetic substrates after aspartate residues [4], Members of the ICE/CED-3 family of cysteine proteases are prime candidates as they are important apoptotic effecters [5,6] and are expressed as zymogens, which can be processed to form active heterodimeric enzymes after cleavage at specific aspartate residues, Previous studies have shown that granzyme B proteolytically activates the cell death effector Yama/CPP32/apopain [7,8] (referred to here as Yama), Here we report that granzyme B also activates ICE-LAP3/Mch3/CMH-1 (referred to here as ICE-LAP3), which, along with Yama and Mch2, forms a subset of the ICE/CED-3 family of cysteine proteases most closely related to the Caenorhabditis elegans cell death gene, CED-3 [6,9], Importantly, Jurkat T cells incubated with granzyme B and a sublytic concentration of perforin undergo apoptosis, which is preceded by the activation of endogenous ICE-LAP3, Thus, we propose that granzyme B mediates apoptosis by directly engaging the target cell's death effector machinery, which is probably composed of an arsenal of intracellular, CED-3-like cysteine proteases.