Granzyme B directly and efficiently cleaves several downstream caspase substrates: Implications for CTL-induced apoptosis
Granzyme B directly and efficiently cleaves several downstream caspase substrates: Implications for CTL-induced apoptosis
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DOI：
10.1016/s1074-7613(00)80550-6
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发表时间：
1998-04-01
期刊：
影响因子：
32.4
通讯作者：
Casciola-Rosen, L
中科院分区：
文献类型：
--
作者：
Andrade, F;Roy, S;Casciola-Rosen, L
caspase介导的下游底物的蛋白水解是迄今为止研究的所有形式的细胞凋亡共同的执行途径的关键因素。虽然这种caspase依赖性途径在细胞毒性淋巴细胞颗粒诱导的细胞死亡过程中被激活，但最近的研究也提供了caspase非依赖性途径的证据。然而，介导这些额外途径的机制尚未明确。目前的研究表明，DNA-PKcs和NuMA在体外和体内都能被颗粒酶B直接有效地切割，产生在其他形式的细胞凋亡中没有观察到的独特的底物片段。这种直接的、不依赖于caspase的颗粒酶B切割下游死亡底物的能力构成了一种凋亡效应机制，对内源性凋亡级联的信号传导或执行成分的抑制剂不敏感。
Caspase-mediated proteolysis of downstream substrates is a critical element of the execution pathway common to all forms of apoptosis studied to date. While this caspase-dependent pathway is activated during cytotoxic lymphocyte granule-induced cell death, recent studies have also provided evidence for caspase-independent pathways. However, the mechanisms mediating these additional pathways have not been defined. The current study demonstrates that DNA-PKcs, and NuMA are directly and efficiently cleaved by granzyme B in vitro and in vivo, generating unique substrate fragments not observed during other forms of apoptosis. This direct, caspase-independent ability of granzyme B to cleave downstream death substrates constitutes an apoptotic effector mechanism that is insensitive to inhibitors of the signaling or execution components of the endogenous apoptotic cascade.