The CARD-carrying caspase Dronc is essential for most, but not all,developmental cell death in<i>Drosophila</i>

Xu, Dongpo; Liu, Ying; Arcaro, Michael; Lackey, Melinda; Bergmann, Andreas

doi:10.1242/dev.01790

Cited by 169 publications

(271 citation statements)

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“…Genetic inactivation of dronc blocks most developmental cell death during embryogenesis, imaginal disc development and metamorphosis. [8][9][10][11] Dronc is functionally similar to human Caspase-9 because it contains a CARD motif in the prodomain, 12 and interacts with Drosophila Apaf-1-related killer (Ark), also known as Dark, Hac-1 and D-Apaf-1 (reviewed in Ref. 3 ).…”

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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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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“…In response to upstream death stimuli, the initiator caspase Dronc is auto-activated as a component of the apoptosome, and further activates effector caspases, including DrICE and DCP-1. 34 In this experiment, we knocked down ubr3 in a Dronc mutant background and found that the cell death induced by ubr3 RNAi was massively suppressed in the absence of Dronc (Figures 4e and f). This result argues that Ubr3 acts upstream of Dronc in the apoptosis pathway.…”

Section: Ubr3 Regulates Apoptosis Q Huang Et Almentioning

confidence: 89%

“…Dronc I29 is described previously. 34 H99 is a deletion of hid, rpr and grim. A null allele of ubr3 1 was generated by P-element-mediated imprecise excision from p (EP) EP1243, which deletes 1555 bp including the start codon and the first exon.…”

Section: Methodsmentioning

confidence: 99%

Ubr3 E3 ligase regulates apoptosis by controlling the activity of DIAP1 in Drosophila

et al. 2014

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Apoptosis has essential roles in a variety of cellular and developmental processes. Although the pathway is well studied, how the activities of individual components in the pathway are regulated is less understood. In Drosophila, a key component in apoptosis is Drosophila inhibitor of apoptosis protein 1 (DIAP1), which is required to prevent caspase activation. Here, we demonstrate that Drosophila CG42593 (ubr3), encoding the homolog of mammalian UBR3, has an essential role in regulating the apoptosis pathway. We show that loss of ubr3 activity causes caspase-dependent apoptosis in Drosophila eye and wing discs. Our genetic epistasis analyses show that the apoptosis induced by loss of ubr3 can be suppressed by loss of initiator caspase Drosophila Nedd2-like caspase (Dronc), or by ectopic expression of the apoptosis inhibitor p35, but cannot be rescued by overexpression of DIAP1. Importantly, we show that the activity of Ubr3 in the apoptosis pathway is not dependent on its Ring-domain, which is required for its E3 ligase activity. Furthermore, we find that through the UBR-box domain, Ubr3 physically interacts with the neoepitope of DIAP1 that is exposed after caspase-mediated cleavage. This interaction promotes the recruitment and ubiquitination of substrate caspases by DIAP1. Together, our data indicate that Ubr3 interacts with DIAP1 and positively regulates DIAP1 activity, possibly by maintaining its active conformation in the apoptosis pathway. Cell Death and Differentiation (2014) 21, 1961-1970 doi:10.1038/cdd.2014 published online 22 August 2014 Morphogenesis in multicellular organisms is a process with a balanced control of cell proliferation and cell death. To maintain this homeostasis, superfluous or unwanted cells are usually removed promptly via programmed cell death or apoptosis. 1,2 Compelling evidence has shown that dysregulation of apoptosis results in a variety of diseases, such as cancer, neurodegenerative disorders and autoimmune diseases. [3][4][5][6] The apoptotic machinery is conserved from invertebrates to vertebrates. Drosophila has been used as an excellent model to study apoptosis because of its advantages in genetic manipulation. A crucial step in apoptosis is the cascade activation of initiator and effector caspases that eventually causes cell death. Under normal circumstances, the activities of caspases are kept in check by a conserved family of anti-apoptotic proteins termed inhibitor of apoptosis proteins (IAPs). The Drosophila genome encodes four IAPs, including Drosophila inhibitor of apoptosis protein 1 (DIAP1), DIAP2, DBruce and Deterin. 7-10 Among these four proteins, DIAP1 is stringently required to prevent caspase activation. 11,12 Although the requirement of DIAP1 in the apoptosis pathway is well documented, it is unclear how the activity of DIAP1 is regulated during development.The covalent attachment of ubiquitin to proteins is a crucial regulatory mechanism in many developmental and physiological processes. 13 Ubiquitination is a catalytic cascade involving ubiquitin-ac...

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“…[12][13][14] In fact, mutants of diap1, dronc and drICE genes were isolated in genetic screens searching for modifiers of the eye ablation phenotypes caused by reaper or hid overexpression. [21][22][23][24][25][26][27] Mammalian IAP antagonists are Smac/Diablo and HtrA2/Omi, which function similarly to the RHG proteins. 28 Abbreviations: ALPS, autoimmune lymphoproliferative syndrome; APF, after puparium formation; Ced-3, cell death defective 3; CyO, curly of Oster; Dcp-1, death caspase 1; DIAP1, death-associated inhibitor of apoptosis 1; DNA, desoxyribonucleic acid; drICE, death-related ICE (interleukin converting enzyme); dronc, death regulator Nedd2-like caspase; EMS, ethyl methanesulfonate; Ey, eyeless; Flp, flippase; FRT82B, flippase recombination target at 82B; GFP, green fluorescent protein; Gh, GMR-hid; Hid, head involution defective; GMR, glass multimer reporter; HtrA2, high-temperature-required protein A2; IAP, inhibitor of apoptosis protein; PCR, polymerase chain reaction; R8, photoreceptor 8; RHG, reaper, hid, grim; Smac/Diablo, second mitochondria-derived activator of caspases/direct IAP binding protein with low pI; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; Ubi, ubiquitous; wt, wild-type; XIAP, X-linked inhibitor of apoptosis…”

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confidence: 99%

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confidence: 99%

Genetic characterization of two gain-of-function alleles of the effector caspase DrICE in Drosophila

Lindblad

Garnett

et al. 2015

Cell Death Differ

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Caspases are the executioners of apoptosis. Although much is known about their physiological roles and structures, detailed analyses of missense mutations of caspases are lacking. As mutations within caspases are identified in various human diseases, the study of caspase mutants will help to elucidate how caspases interact with other components of the apoptosis pathway and how they may contribute to disease. DrICE is the major effector caspase in Drosophila required for developmental and stressinduced cell death. Here, we report the isolation and characterization of six de novo drICE mutants, all of which carry point mutations affecting amino acids conserved among caspases in various species. These six mutants behave as recessive loss-offunction mutants in a homozygous condition. Surprisingly, however, two of the newly isolated drICE alleles are gain-of-function mutants in a heterozygous condition, although they are loss-of-function mutants homozygously. Interestingly, they only behave as gain-of-function mutants in the presence of an apoptotic signal. These two alleles carry missense mutations affecting conserved amino acids in close proximity to the catalytic cysteine residue. This is the first time that viable gain-of-function alleles of caspases are described in any intact organism and provides a significant exception to the expectation that mutations of conserved amino acids always abolish the pro-apoptotic activity of caspases. We discuss models about how these mutations cause the gain-offunction character of these alleles. Cell Death and Differentiation (2016) 23, 723-732; doi:10.1038/cdd.2015.144; published online 6 November 2015Apoptosis is a major form of programmed cell death. 1 The core apoptotic machinery is evolutionary conserved with caspases as the fundamental components. [1][2][3] Caspases are specific cysteine proteases that are produced as inactive zymogens composed of an N-terminal pro-domain, a large subunit region with the catalytic cysteine residue, and a small subunit region at the carboxyl end. 2,4 Depending on their structures and functions, caspases are grouped into initiator and effector caspases. 2,3 Initiator caspases possess long pro-domains, which facilitate the recruitment of initiator caspases into cell death signaling complexes for activation. 2,3,5 Effector caspases are activated by initiator caspase complexes through proteolytic processing, cleaving off the pro-domain and separating the large and small subunits. The active effector caspase is a tetramer composed of two large and two small subunits and contains two catalytic sites. 2,3 Activated effector caspases cleave many protein targets to trigger the physiological and morphological changes characteristic of apoptosis. In mammals, apoptotic initiator caspases are Caspase-8, -9, -2 and -10, and effector caspases involved in apoptosis are 3 Of the seven Drosophila caspases, only the initiator caspase Dronc (Caspase-9-like) and the effector caspases DrICE and Dcp-1 (Caspase-3-like) have been implicated in apoptosis in imagina...

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The CARD-carrying caspase Dronc is essential for most, but not all,developmental cell death inDrosophila

Cited by 169 publications

References 74 publications

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

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

Ubr3 E3 ligase regulates apoptosis by controlling the activity of DIAP1 in Drosophila

Genetic characterization of two gain-of-function alleles of the effector caspase DrICE in Drosophila

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