The Drosophila Caspase Inhibitor DIAP1 Is Essential for Cell Survival and Is Negatively Regulated by HID

Wang, Susan L.; Hawkins, Christine J.; Yoo, Soon Ji; Müller, H.‐Arno J.; Hay, Bruce A.

doi:10.1016/s0092-8674(00)81974-1

Cited by 469 publications

(401 citation statements)

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“…Whereas deletion of genes for XIAP in the mouse has a very minor phenotype, 50 deletion of DIAP1 in the fly results in massive, lethal apoptosis. 51 However, even though they are similar, DIAP1 and XIAP do not act in precisely the same ways. For example, XIAP inhibits caspase 9 activation by binding, via its BIRs, to N terminally processed caspase 9, thereby stopping it from dimerizing.…”

Section: Iapsmentioning

confidence: 99%

Caspase inhibitors: viral, cellular and chemical

2006

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Section: Iapsmentioning

confidence: 99%

Caspase inhibitors: viral, cellular and chemical

2006

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“…2 Loss of DIAP1 function results in early embryonic death as a consequence of massive apoptosis. [3][4][5] The IAP family is characterized structurally by one-three Nterminal copies of Baculovirus IAP Repeat (BIR) domains. DIAP1 contains two copies of BIR that bind effector and initiator caspases.…”

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confidence: 99%

Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways

et al. 2007

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Inhibitors of apoptosis proteins (IAPs) suppress cell death by inactivating proapoptotic regulators, and therefore play important roles in controlling apoptosis in normal and malignant cells. Many IAPs are ubiquitin ligases, and their activity is mediated via ubiquitination and subsequent degradation of their targets. Here we corroborate a previous observation that DIAP1 (Drosophila IAP1) can be degraded via a two-step mechanism: (i) limited caspase-mediated cleavage and (ii) degradation of the released fragment via the ubiquitin N-end rule pathway. Yet, we demonstrate that this pathway is not the only one involved in DIAP1 degradation, and the intact protein can be degraded independent of prior caspase cleavage. Importantly, this mode of degradation does not require the RING-finger-mediated autoubiquitinating activity of DIAP1, believed to target many RING-finger E3s for self-destruction. Our preliminary data suggest that DIAP2 mediates DIAP1 degradation, suggesting a novel regulatory loop within the apoptotic pathway. Studying the role of the autoubiquitinating activity of DIAP1, we demonstrate that it does not involve formation of Lys48-based polyubiquitin chains, but probably chains linked via Lys63. Our preliminary data suggest that the autoubiquitination serves to attenuate the ligase activity of DIAP1 towards its exogenous substrates. Recent studies indicate that ubiquitination plays an important role in regulating apoptosis. This is partially mediated by the inhibitors of apoptosis proteins (IAPs), a centrally important group of cell death regulators, many of them are ubiquitin ligases. IAPs suppress cell death by inactivating different proapoptotic factors, some by targeting them for ubiquitination and subsequent proteasomal degradation. At least eight IAPs have been identified in mammals. In Drosophila melanogaster, expression of DIAP1 and DIAP2 1 can suppress apoptosis that occurs both during normal development as well as following overexpression of proapoptotic factors such as Reaper (Rpr). 2 Loss of DIAP1 function results in early embryonic death as a consequence of massive apoptosis. [3][4][5] The IAP family is characterized structurally by one-three Nterminal copies of Baculovirus IAP Repeat (BIR) domains. DIAP1 contains two copies of BIR that bind effector and initiator caspases. In some cases, this binding leads to ubiquitination and subsequent degradation of the caspase. 2 IAP-mediated inactivation of caspases is effectively inhibited by a family of proapoptotic proteins that share an IAP-binding tetra-peptide motif at their N-termini. Among those proteins are Smac/Diablo in mammals, and Rpr, Hid and Grim (RHG) in Drosophila. It was shown that RHG proteins abrogate effectively DIAP1-mediated inactivation of Dronc and DrICE. 6 DIAP1 contains also a C-terminal RING-finger motif that serves to recruit the E2 component of the ubiquitin conjugation machinery. For RING-finger E3s, their best-characterized activity is self-ubiquitination thought to regulate their cellular level, but it is assumed th...

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“…For example, whereas DIAP1 is essential in fly embryos, mice lacking XIAP show no obvious developmental defects. 2,3 The existence of at least eight mammalian BIR-containing proteins suggests that IAPs may have evolved individually unique antiapoptotic functions. Biochemical analyses have led to the identification of the residues in the BIRs of cIAP-1, cIAP-2, and XIAP responsible for caspase binding.…”

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confidence: 99%

XLX is an IAP family member regulated by phosphorylation during meiosis

Greenwood

Gautier

2006

Cell Death Differ

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The balance between proliferation and cell death is critical for embryonic development and adult tissue homeostasis. Within an individual cell, coordination of these pathways is aided by direct communication between cell cycle factors and molecules that regulate apoptosis. Here, we show that XLX, a Xenopus laevis inhibitor of apoptosis (IAP) family member, exhibits characteristics typical of an IAP, such as caspase inhibition and autoubiquitylation. However, unlike other IAPs described thus far, we found that XLX is phosphorylated during meiosis by protein kinases that belong to the MAPK and MPF pathways. Finally, we show that caspase-dependent cleavage of XLX is altered when XLX is phosphorylated. In addition to furthering our understanding of the post-translational regulation of an IAP, these findings reveal a novel link between cell cycle-regulated protein kinases and a component potentially involved in apoptosis.

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The Drosophila Caspase Inhibitor DIAP1 Is Essential for Cell Survival and Is Negatively Regulated by HID

Cited by 469 publications

References 50 publications

Caspase inhibitors: viral, cellular and chemical

Caspase inhibitors: viral, cellular and chemical

Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways

XLX is an IAP family member regulated by phosphorylation during meiosis

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