Drosophila IAP1-Mediated Ubiquitylation Controls Activation of the Initiator Caspase DRONC Independent of Protein Degradation

Department of Biochemistry and Molecular Biology, Genes and Development Graduate Program, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS Genetics (Impact Factor: 7.53). 09/2011; 7(9):e1002261. DOI: 10.1371/journal.pgen.1002261
Source: PubMed


Ubiquitylation targets proteins for proteasome-mediated degradation and plays important roles in many biological processes including apoptosis. However, non-proteolytic functions of ubiquitylation are also known. In Drosophila, the inhibitor of apoptosis protein 1 (DIAP1) is known to ubiquitylate the initiator caspase DRONC in vitro. Because DRONC protein accumulates in diap1 mutant cells that are kept alive by caspase inhibition ("undead" cells), it is thought that DIAP1-mediated ubiquitylation causes proteasomal degradation of DRONC, protecting cells from apoptosis. However, contrary to this model, we show here that DIAP1-mediated ubiquitylation does not trigger proteasomal degradation of full-length DRONC, but serves a non-proteolytic function. Our data suggest that DIAP1-mediated ubiquitylation blocks processing and activation of DRONC. Interestingly, while full-length DRONC is not subject to DIAP1-induced degradation, once it is processed and activated it has reduced protein stability. Finally, we show that DRONC protein accumulates in "undead" cells due to increased transcription of dronc in these cells. These data refine current models of caspase regulation by IAPs.

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Article: Drosophila IAP1-Mediated Ubiquitylation Controls Activation of the Initiator Caspase DRONC Independent of Protein Degradation

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    • "There are two tandem repeats known as the Baculovirus IAP Repeats (BIR) and the RING domain at the carboxyl terminus of DIAP1 [9]. The BIR domains are necessary for binding with caspases [10], [11], [12]; however, binding of DIAP1 with DRONC is not sufficient for inhibition of DRONC as ubiquitination of DRONC is required to regulate its apoptotic activity [13]. The RING domain of DIAP1 provides the E3-ubiquitin ligase activity that is required for ubiquitination of the target proteins [6], [14]. "
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    • "As with Cdc20, Dronc ubiquitination by DIAP1 does not appear to result in degradation, as local overexpression or loss of DIAP1 does not affect Dronc abundance [87]. Instead, ubiquitination modulates the incomplete cleavage and activation of Dronc [87], demonstrating yet another nondestructive role for the UPS in modulating neural morphogenesis. "
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