Fusing DEDD with ubiquitin changes its intracellular localization and apoptotic potential |
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Authors: | J?C?Lee G?X?Wang O?Schickling Email author" target="_blank">M?E?PeterEmail author |
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Institution: | (1) The Ben May Institute for Cancer Research, University of Chicago, 924 E. 57th Street, Chicago, IL 60637, USA |
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Abstract: | DEDD, a highly conserved and ubiquitous death effector domain containing protein, exists in non, mono, and diubiquitinated
forms. We previously reported that endogenous unmodified DEDD is only found in nucleoli and that mono- and diubiquitinated
DEDD associate with caspase-3 in the cytosol suggesting that ubiquitination may be important to the apoptosis regulating functions
of DEDD in the cytosol. We now demonstrate that many of its 16 lysine residues can serve as alternative acceptors for ubiquitination
to maintain the monoubiquitination status of DEDD. A central region in DEDD (amino acids 109–305) outside the death effector
domain was found to be essential for ubiquitination and/or the docking of the ubiquitination machinery. Fusion of ubiquitin
to the C-terminus of DEDD to mimic monoubiquitinated DEDD relocated DEDD from nucleoli to the cytosol. This fusion protein
also demonstrated a greater apoptosis potential than unmodified DEDD. Finally, we show that both mono- and polyubiquitination
of DEDD can be achieved by the cellular inhibitor of apoptosis proteins 1 and 2 (cIAP-1/2). In addition, the cotransfection
of DEDD with cIAP-1 or cIAP-2 results in the relocalization of the IAPs to the nucleoli. Our data suggest that monoubiquitination
of DEDD regulates both its cytoplasmic localization and its proapoptotic potential and that IAP proteins can regulate DEDD's
ubiquitination status. |
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Keywords: | caspases cytosol DEDD IAPs monoubiquitination nucleolus |
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