Thomas D A, Du C, Xu M, Wang X, Ley T J
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Immunity. 2000 Jun;12(6):621-32. doi: 10.1016/s1074-7613(00)80213-7.
Granzyme B (GzmB) is a component of cytotoxic lymphocyte granules that can rapidly initiate apoptosis in target cells. While several procaspases are cleaved and activated by GzmB, the absolute requirement of caspase activation for GzmB-induced apoptosis is controversial. In this report, we demonstrate that GzmB can initiate apoptosis in the absence of caspase-3 activity by directly cleaving DFF45/ICAD to liberate activated DFF40/CAD. DFF45/ICAD cleavage occurs less efficiently in cells that lack caspase-3 activity, suggesting that the caspases normally amplify the GzmB death signal. DFF45/ICAD-deficient mouse embryo fibroblasts are partially resistant to GzmB-induced death, demonstrating the biological importance of DFF45/ICAD for GzmB-mediated apoptosis.
颗粒酶B（GzmB）是细胞毒性淋巴细胞颗粒的一个组成部分，可迅速启动靶细胞的凋亡。虽然几种半胱天冬酶原被GzmB切割并激活，但半胱天冬酶激活对于GzmB诱导的凋亡的绝对必要性存在争议。在本报告中，我们证明GzmB可在缺乏半胱天冬酶-3活性的情况下，通过直接切割DFF45/ICAD以释放激活的DFF40/CAD来启动凋亡。在缺乏半胱天冬酶-3活性的细胞中，DFF45/ICAD切割的效率较低，这表明半胱天冬酶通常会放大GzmB死亡信号。缺乏DFF45/ICAD的小鼠胚胎成纤维细胞对GzmB诱导的死亡具有部分抗性，这证明了DFF45/ICAD对于GzmB介导的凋亡的生物学重要性。
