IAPs, RINGs and ubiquitylation

The Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 05/2005; 6(4):287-97. DOI: 10.1038/nrm1621
Source: PubMed


The inhibitor of apoptosis (IAP) proteins all contain one or more baculoviral IAP repeat motifs, through which they interact with various other proteins. Many IAPs also have another zinc-binding motif, the RING domain, which can recruit E2 ubiquitin-conjugating enzymes and catalyse the transfer of ubiquitin onto target proteins. The number of targets of IAP-mediated ubiquitylation is increasing and recent results indicate that outcomes following ubiquitylation are tantalizingly complex. As well as regulating other proteins, the IAPs themselves are controlled by ubiquitin-mediated degradation.

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    • "In this context, survivin protein (BIRC5) can be particularly informative because it exhibits high expression levels almost exclusively in hESCs and cancer cells; it is a member of the baculovirus inhibitor of apoptosis containing repeat (BIRC) family of proteins (Ambrosini et al., 1997; Vaux and Silke, 2005). "
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    ABSTRACT: Understanding the mechanisms that sustain pluripotency in human embryonic stem cells (hESCs) is an active area of research that may prove useful in regenerative medicine and will provide fundamental information relevant to development and cancer. hESCs and cancer cells share the unique ability to proliferate indefinitely and rapidly. Because the protein survivin is uniquely overexpressed in virtually all human cancers and in hESCs, we sought to investigate its role in supporting the distinctive capabilities of these cell types. Results presented here suggest that survivin contributes to the maintenance of pluripotency and that post-transcriptional control of survivin isoform expression is selectively regulated by microRNAs. miR-203 has been extensively studied in human tumors, but has not been characterized in hESCs. We show that miR-203 expression and activity is consistent with the expression and subcellular localization of survivin isoforms that in turn modulate expression of the Oct4 and Nanog transcription factors to sustain pluripotency. This study contributes to understanding of the complex regulatory mechanisms that govern whether hESCs proliferate or commit to lineages. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 01/2015; 230(1). DOI:10.1002/jcp.24681 · 3.84 Impact Factor
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    • "IAPs modify substrates via canonical ubiquitination that involves isopeptide linkages via lysine 48 of ubiquitin (Ub), which provides a signal for proteasomal degradation [2]. However, recent reports have shown that some IAPs ubiquitinate target proteins that do not undergo subsequent degradation. "
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    ABSTRACT: Inhibitors of Apoptosis Proteins (IAPs) are evolutionarily well conserved and have been recognized as the key negative regulators of apoptosis. Recently, the role of IAPs as E3 ligases through the Ring domain was revealed. Using proteomic analysis to explore potential target proteins of DIAP1, we identified Drosophila Endonuclease G (dEndoG), which is known as an effector of caspase-independent cell death. In this study, we demonstrate that human EndoG interacts with IAPs, including human cellular Inhibitor of Apoptosis Protein 1 (cIAP1). EndoG was ubiquitinated by IAPs in vitro and in human cell lines. Interestingly, cIAP1 was capable of ubiquitinating EndoG in the presence of wild-type and mutant Ubiquitin, in which all lysines except K63 were mutated to arginine. cIAP1 expression did not change the half-life of EndoG and cIAP1 depletion did not alter its levels. Expression of dEndoG 54310, in which the mitochondrial localization sequence was deleted, led to cell death that could not be suppressed by DIAP1 in S2 cells. Moreover, EndoG-mediated cell death induced by oxidative stress in HeLa cells was not affected by cIAP1. Therefore, these results indicate that IAPs interact and ubiquitinate EndoG via K63-mediated isopeptide linkages without affecting EndoG levels and EndoG-mediated cell death, suggesting that EndoG ubiquitination by IAPs may serve as a regulatory signal independent of proteasomal degradation.
    Biochemical and Biophysical Research Communications 09/2014; 451(4). DOI:10.1016/j.bbrc.2014.08.047 · 2.30 Impact Factor
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    • "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]. DIAP1-mediated ubiquitination of DRONC does not lead to its degradation by proteasomes; rather, ubiquitination directs the activation of DRONC [13]. "
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    ABSTRACT: The Jun N-terminal kinase pathway plays an important role in inducing programmed cell death (apoptosis) and is activated in a variety of contexts. The deubiquitinating enzymes (DUBs) are proteases regulating the protein stability by ubiquitin-proteasome system. Here, for the first time, we report the phenotypes observed during eye development that are induced by deleting Drosophila USP5 gene, which encodes one of the USP subfamily of DUBs. usp5 mutants displayed defects in photoreceptor differentiation. Using genetic epistasis analysis and molecular markers, we show that most of these phenotypes are caused by the activation of apoptosis and JNK pathway. These data may provide a mechanistic model for understanding the mammalian usp5 gene.
    PLoS ONE 03/2014; 9(3):e92250. DOI:10.1371/journal.pone.0092250 · 3.23 Impact Factor
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