Loeb Carly R K, Harris Jennifer L, Craik Charles S
Department of Biochemistry and Biophysics, Tetrad Graduate Program, University of California, San Francisco, 94131, USA.
J Biol Chem. 2006 Sep 22;281(38):28326-35. doi: 10.1074/jbc.M604544200. Epub 2006 Jun 23.
Granzyme B is critical to the ability of natural killer cells and cytotoxic T lymphocytes to induce efficient cell death of virally infected or tumor cell targets. Although granzyme B can cleave and activate caspases to induce apoptosis, granzyme B can also cause caspase-independent cell death. Thirteen prospective granzyme B substrates were identified from a cDNA expression-cleavage screen, including Hsp70, Notch1, fibroblast growth factor receptor-1 (FGFR1), poly-A-binding protein, cAbl, heterogeneous nuclear ribonucleoprotein H', Br140, and intersectin-1. Validation revealed that Notch1 is a substrate of both granzyme B and caspases, whereas FGFR1 is a caspase-independent substrate of granzyme B. Proteolysis of FGFR1 in prostate cancer cells has functionally relevant consequences that indicate its cleavage may be advantageous for granzyme B to kill prostate cancer cells. Therefore, granzyme B not only activates pro-death functions within a target, but also has a previously unidentified role in inactivating pro-growth signals to cause cell death.
颗粒酶B对于自然杀伤细胞和细胞毒性T淋巴细胞诱导病毒感染或肿瘤细胞靶标有效细胞死亡的能力至关重要。尽管颗粒酶B可以切割并激活半胱天冬酶以诱导细胞凋亡，但颗粒酶B也可导致非半胱天冬酶依赖性细胞死亡。通过cDNA表达切割筛选鉴定出13种潜在的颗粒酶B底物，包括热休克蛋白70（Hsp70）、Notch1、成纤维细胞生长因子受体1（FGFR1）、聚腺苷酸结合蛋白、cAbl、不均一核核糖核蛋白H'、Br140和相交蛋白-1。验证表明，Notch1是颗粒酶B和半胱天冬酶的底物，而FGFR1是颗粒酶B的非半胱天冬酶依赖性底物。前列腺癌细胞中FGFR1的蛋白水解具有功能相关的后果，表明其切割可能有利于颗粒酶B杀死前列腺癌细胞。因此，颗粒酶B不仅激活靶标内的促死亡功能，而且在使促生长信号失活以导致细胞死亡方面具有先前未被认识的作用。
