Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China.
Cell Res. 2010 Feb;20(2):211-22. doi: 10.1038/cr.2010.9. Epub 2010 Jan 26.
As a critical apoptosis executioner, caspase-3 becomes activated and then enters into the nucleus to exert its function. However, the molecular mechanism of this nuclear entry of active caspase-3 is still unknown. In this study, we revealed that caspase-3 harbors a crm-1-independent nuclear export signal (NES) in its small subunit. Using reverse-caspase-3 as the study model, we found that the function of the NES in caspase-3 was not disturbed by the conformational changes during induced caspase-3 activation. Mutations disrupting the cleavage activity or p3-recognition site resulted in a defect in the nuclear entry of active caspase-3. We provide evidence that the p3-mediated specific cleavage activity of active caspase-3 abrogated the function of the NES. In conclusion, our results demonstrate that during caspase-3 activation, NES is constitutively present. p3-mediated specific cleavage activity abrogates the NES function in caspase-3, thus facilitating the nuclear entry of active caspase-3.
作为一个关键的细胞凋亡执行者，半胱天冬酶-3 被激活，然后进入细胞核发挥作用。然而，活性半胱天冬酶-3 进入细胞核的分子机制尚不清楚。在这项研究中，我们揭示了半胱天冬酶-3 的小亚基中存在一个 CRM-1 非依赖性核输出信号（NES）。使用反式半胱天冬酶-3 作为研究模型，我们发现 NES 在半胱天冬酶-3 诱导激活过程中的构象变化不影响其功能。破坏切割活性或 p3 识别位点的突变导致活性半胱天冬酶-3 的核内进入缺陷。我们提供的证据表明，活性半胱天冬酶-3 的 p3 介导的特异性切割活性削弱了 NES 的功能。总之，我们的结果表明，在半胱天冬酶-3 激活过程中，NES 是持续存在的。p3 介导的特异性切割活性削弱了半胱天冬酶-3 中 NES 的功能，从而促进了活性半胱天冬酶-3 的核内进入。
