Content area
Full Text
Cell Research (2010) 20:211-222. 2010 IBCB, SIBS, CAS All rights reserved 1001-0602/10 $ 32.00
npg
ORIGINAL ARTICLE
www.nature.com/cr
Nuclear entry of active caspase-3 is facilitated by its p3-recognition-based specic cleavage activity
Min Luo1, *, Zhiyong Lu2, *, He Sun1, Kehu Yuan1, Quancang Zhang1, Sha Meng1, Fangxun Wang1, Hongchun Guo1, Xiaofang Ju1, Yuqing Liu3, Tao Ye1, 3, Zhigang Lu1, Zhonghe Zhai4
1Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China; 2Institute of Life Sciences, YunYang Medical College Tai-he Hospital, 32 S Renmin Road, Shiyan, Hubei 442000, China; 3Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong; 4College of Life Science, Peking University, Beijing 100871, China
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 specic 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 specic cleavage activity abrogates the NES function in caspase-3, thus facilitating the nuclear entry of active caspase-3.
Keywords: nuclear entry, caspase-3, apoptosis, nuclear export signalCell Research (2010) 20:211-222. doi: 10.1038/cr.2010.9; published online 26 January 2010
Introduction
Apoptosis is an important physiological event that plays critical roles in the development of multicellular organisms and the maintenance of tissue homeostasis. Apoptosis is also involved in a number of disease processes, such as neuro-degeneration and cancer [1]. Apoptosis-inducing stimuli, such as pro-apoptotic cytokines, UV irradiation and DNA-damaging drugs, induce apoptotic responses characterized by a series of shared morphological changes in the membrane, cytoplasm and nucleus [2].
Many morphological and biochemical apoptotic changes are induced by the activation of the caspase
cascade, in which caspase-3 plays a central role...