Molecular mechanisms of DrICE inhibition by DIAP1 and removal of inhibition by Reaper, Hid and Grim

Yan, Nieng; Wu, Jing; Chai, Jijie; Li, Wenyu; Shi, Yigong

doi:10.1038/nsmb764

Cited by 98 publications

(136 citation statements)

References 40 publications

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“…52 DIAP1 can also bind to processed effector caspases such as DrICE and DCP1 via conserved IAP-binding motifs (IBMs) in the neo-amino-termini of the large caspase subunits. 53 Although some groups report DIAP1 inhibits DrICE, 21 another group suggests that, like cIAP1 and cIAP2, DIAP1 may not inhibit the proteolytic activity of effector caspases even while bound to them. 53 …”

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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“…In apoptotic cells, IAP antagonists such as the Drosophila Reaper, Hid (Head involution defective), and Grim (RHG) proteins (recently reviewed in ref. 3 ) displace IAPs directly from caspases 4,5 which are then released from IAP inhibition, and induce apoptosis. In addition, Reaper, Hid and Grim also promote proteolytic degradation of Drosophila IAP1 (Diap1).…”

Section: Introductionmentioning

confidence: 99%

The effector caspases drICE and dcp-1 have partially overlapping functions in the apoptotic pathway in Drosophila

et al. 2006

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Caspases are essential components of the apoptotic machinery in both vertebrates and invertebrates. Here, we report the isolation of a mutant allele of the Drosophila effector caspase drICE as a strong suppressor of hid-(head involution defective-) induced apoptosis. This mutant was used to determine the apoptotic role of drICE. Our data are consistent with an important function of drICE for developmental and irradiation-induced cell death. Epistatic analysis suggests that drICE acts genetically downstream of Drosophila inhibitor of apoptosis protein 1 (Diap1). However, although cell death is significantly reduced in drICE mutants in all assays, it is not completely blocked. A double-mutant analysis between drICE and death caspase-1 (dcp-1), another effector caspase, reveals that some cells (type I) strictly require drICE for apoptosis, whereas other cells (type II) require either drICE or dcp-1. Thus, these data demonstrate a barely appreciated complexity in the apoptotic pathway, and are consistent with current models about effector caspase regulation in both vertebrates and invertebrates.

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“…However, in contrast to Ditzel et al, 19 they found that the cleavage of DIAP1 promotes its further degradation via autoubiquitination, that requires the RING-finger domain of the protein. 26 In addition, Yan et al 27 proposed that Dronc cleaves DIAP1 after Glu 205 , resulting in the generation of two separate functional units: (i) a BIR1-containing fragment that inhibits DrICE by binding to it and (ii) a BIR2-RING fragment that can bind Dronc and ubiquitinate it. 27 According to these findings, since the initiator caspase Dronc is probably activated before the effector caspase DrICE, the N-end rule pathway will be involved, if at all, in the removal of the N-terminal BIR1 domain-containing fragment (and even that after further removal of its first 20 N-terminal residues by DrICE), but not in removing the BIR2-RING fragment.…”

mentioning

confidence: 99%

“…26 In addition, Yan et al 27 proposed that Dronc cleaves DIAP1 after Glu 205 , resulting in the generation of two separate functional units: (i) a BIR1-containing fragment that inhibits DrICE by binding to it and (ii) a BIR2-RING fragment that can bind Dronc and ubiquitinate it. 27 According to these findings, since the initiator caspase Dronc is probably activated before the effector caspase DrICE, the N-end rule pathway will be involved, if at all, in the removal of the N-terminal BIR1 domain-containing fragment (and even that after further removal of its first 20 N-terminal residues by DrICE), but not in removing the BIR2-RING fragment. Ryoo et al 9 showed that Rpr-induced removal of DIAP1 occurs in the presence of p35, a strong caspase inhibitor, suggesting that caspase cleavage is not essential for removal of DIAP1 under those conditions.…”

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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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Molecular mechanisms of DrICE inhibition by DIAP1 and removal of inhibition by Reaper, Hid and Grim

Cited by 98 publications

References 40 publications

Caspase inhibitors: viral, cellular and chemical

Caspase inhibitors: viral, cellular and chemical

The effector caspases drICE and dcp-1 have partially overlapping functions in the apoptotic pathway in Drosophila

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

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