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  • The EMBO Journal (2007) 26, 1068 - 1080
  • doi:10.1038/sj.emboj.7601571

Published online: 8 February 2007

Death effector domain DEDa, a self-cleaved product of caspase-8/Mch5, translocates to the nucleus by binding to ERK1/2 and upregulates procaspase-8 expression via a p53-dependent mechanism

Zhan Yao1,a, Shanshan Duan1,a, Dezhi Hou1, Klaus Heese2 and Mian Wu1

  1. Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China
  2. Department of Molecular and Cell Biology, School of Biological Sciences, Nanyang Technological University, Singapore

Correspondence to:

Mian Wu, School of Life Sciences, University of Science and Technology of China, 443 Huang-Shan Road, Hefei, Anhui 230027, People's Republic of China. Tel.: +86 551 3607324; Fax: +86 551 3606264; E-mail: wumian@ustc.edu.cn

aThese authors contributed equally to this work

Received 8 June 2006; Accepted 2 January 2007

Activation of the apical caspase-8 is crucial to the extrinsic apoptotic pathway. Although the death effector domain (DED) of caspase-8 has been reported to be involved in death-inducing signaling complex formation, the detailed mechanism of how DED functions in regulating apoptosis remains largely unknown. Here, we demonstrate that the prodomain of the caspase-8/Mch5 can be further cleaved between two tandemly repeated DEDs (DEDa–DEDb) at the amino-acid residue Asp129 by caspase-8 itself. The DEDa fragment generated from the endogenous caspase-8 was detected in isolated nucleoli upon treatment with TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). Cleaved DEDa appears to translocate into the nucleus by association with extracellular signal-regulated protein kinases-1/2 (ERK1/2). Elimination of ERK1/2 expression by RNA interference resulted in a significant attenuation of nuclear entry of DEDa and reduced caspase-8-dependent apoptosis. In the nucleus, DEDa interacts with TOPORS, a p53 and topoisomerase I binding protein, and possibly displaces p53 from TOPORS, allowing p53 to stimulate caspase-8 gene expression. In summary, we postulate a positive feedback loop involving DEDa, which enables the continual replenishment of procaspase-8 during apoptosis.

  • Keywords:

    • caspase-8/Mch5,
    • death effector domain,
    • ERK1/2,
    • p53,
    • TOPORS