Death Effector Domain as a Transcriptional Regulator

Science's STKE  27 Feb 2007:
Vol. 2007, Issue 375, pp. tw67
DOI: 10.1126/stke.3752007tw67

Apoptotic cell death involves activation of the procaspases, which requires cleavage of those proteins. Thus, replenishment of the procaspase pool requires new protein synthesis. Yao et al. report that a cleaved fragment containing the first death effector domain (DEDa) of procaspase 8 stimulates the transcription of the gene encoding procaspase 8, thereby providing a positive feedback replenishing procaspase 8. Caspase 8 is cleaved and activated in response to ligands such as TRAIL and FasL that stimulate apoptosis. Yao et al. first show that the prodomain of caspase 8 (residues 1 to 233) was cleaved to produce DEDa when transfected into cultured cells or when assayed in vitro with purified caspase 8, indicating self-cleavage by caspase 8. Although in unstressed cells, DEDa is rapidly degraded (even when overexpressed), inhibition of the proteasome or exposure of the cells to TRAIL resulted in the stabilization and accumulation of DEDa in the nucleoli. DEDa interacted with extracellular signal-regulated kinase 1 and 2 (ERK1/2) by coimmunoprecipitation and knockdown of ERK1 and ERK2 with RNAi blocked nuclear translocation of DEDa, suggesting that ERK may shuttle DEDa into the nucleus. HeLa cells that overexpressed DEDa and in which the proteasome was inhibited showed increased transcription of caspase 8. A reporter gene construct containing or lacking the p53 responsive element in the caspase 8 promoter was used to show that DEDa stimulation of caspase 8 gene expression required p53. Further reporter gene experiments showed that DEDa interacted with TOPORS, a p53 binding protein, and appeared to compete with p53 for binding, thus releasing p53 from TOPORS. Cells overexpressing DEDa were more sensitive to TRAIL-induced apoptosis than were nontransfected cells, and apoptosis was inhibited if ERK1 and ERK2 were knocked down by RNAi. Thus, even the cleaved prodomain of caspase 8 appears to contribute to apoptosis by stimulating procaspase 8 biosynthesis.

Z. Yao, S. Duan, D. Hou, K. Heese, M. Wu, 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. EMBO J. 26, 1068-1080 (2007). [PubMed]