Morgue mediates apoptosis in the Drosophila melanogaster retina by promoting degradation of DIAP1

Hays, Rebecca; Wickline, Laura; Cagan, Ross L.

doi:10.1038/ncb794

Cited by 116 publications

(109 citation statements)

References 37 publications

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“…[59][60][61][62] Consistently, we observe accumulation of Diap1 in prosβ2 and Mov34 mutant cells (Figure 3c-d''). Thus, this assay can detect accumulating proteins in vivo.…”

Section: Resultssupporting

confidence: 82%

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

et al. 2016

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A major function of ubiquitylation is to deliver target proteins to the proteasome for degradation. In the apoptotic pathway in Drosophila, the inhibitor of apoptosis protein 1 (Diap1) regulates the activity of the initiator caspase Dronc (death regulator Nedd2-like caspase; caspase-9 ortholog) by ubiquitylation, supposedly targeting Dronc for degradation by the proteasome. Using a genetic approach, we show that Dronc protein fails to accumulate in epithelial cells with impaired proteasome function suggesting that it is not degraded by the proteasome, contrary to the expectation. Similarly, decreased autophagy, an alternative catabolic pathway, does not result in increased Dronc protein levels. However, combined impairment of the proteasome and autophagy triggers accumulation of Dronc protein levels suggesting that autophagy compensates for the loss of the proteasome with respect to Dronc turnover. Consistently, we show that loss of the proteasome enhances endogenous autophagy in epithelial cells. We propose that enhanced autophagy degrades Dronc if proteasome function is impaired.

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“…[59][60][61][62] Consistently, we observe accumulation of Diap1 in prosβ2 and Mov34 mutant cells (Figure 3c-d''). Thus, this assay can detect accumulating proteins in vivo.…”

Section: Resultssupporting

confidence: 82%

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

et al. 2016

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“…[16][17][18][19][20] In GMR-reaper eye imaginal discs, DIAP1 degradation is very prominent in cells immediately posterior to the column of R8 photoreceptor neurons, which are very resistant to apoptosis 52 and where DIAP1 is not degraded (Figure 7a and b; R8 photoreceptor columns are marked by arrows; the zones of DIAP1 degradation by asterisks (*)). Interestingly, reduced DrICE activity in heterozygous loss-of-function alleles partially protects DIAP1 from reaper-induced degradation (Figure 7c and d), which is consistent with the suppression of GMR-reaper by these alleles (Figure 6a).…”

Section: Resultsmentioning

confidence: 99%

“…47 If reaper is in excess, it triggers degradation of DIAP1 (Figure 7b) and thus apoptosis. [16][17][18][19][20] Therefore, owing to the failure of DIAP1 to bind to the class C subunit, the wt/ class C heterotetramer may shift the equilibrium towards binding of DIAP1 to reaper such that DIAP1 is more efficiently degraded by reaper, resulting in higher enzymatic activity of the wt/class C heterotetramer. Consistent with this notion, reduced DrICE activity in heterozygous loss-of-function alleles partially protects DIAP1 from reaper-induced degradation (Figure 7c and d), whereas the class C alleles of DrICE fail to protect DIAP1 from degradation (Figure 7e and f), suggestive of decreased binding of the wt/class C heterotetramer to DIAP1.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 In cells committed to apoptosis, IAP-mediated inhibition of caspases is counteracted by IAP antagonists. Specifically, the IAP antagonists encoded by reaper, hid and grim (RHG) [12][13][14][15] in Drosophila trigger proteolytic degradation of DIAP1 [16][17][18][19][20] which releases caspases from DIAP1 inhibition and triggers apoptosis. The overexpression of the RHG genes in the fly eye using the eye-specific GMR promoter causes an eye ablation phenotype due to massive apoptosis (see, for example, GMR-hid in Figure 1a).…”

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confidence: 99%

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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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“…Binding of Reaper to DIAP1 leads to auto-ubiquitination and proteasomal degradation of DIAP1 instead, thus facilitating Dronc stabilisation and activation. [10][11][12][13][14][15] Other Drosophila proteins share the ability to neutralise DIAP function. These include Grim and Hid as well as the recently identified DNA damage response protein Sickle, whose gene maps adjacent to the H99 region.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of action of Drosophila Reaper in mammalian cells: Reaper globally inhibits protein synthesis and induces apoptosis independent of mitochondrial permeability

et al. 2004

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Drosophila Reaper can bind inhibitor of apoptosis proteins (IAP) and thereby rescue caspases from proteasomal degradation. In insect cells, this is sufficient to induce apoptosis. Reaper can also induce apoptosis in mammalian cells, in which caspases need to be activated, usually via the mitochondrial pathway. Nevertheless, we find that Reaper efficiently induces apoptosis in mammalian cells in the absence of mitochondrial permeabilisation and cytochrome c release. Moreover, this capacity was only marginally affected by deletion of Reaper's amino-terminal IAP-binding motif. Independent of this motif, Reaper could globally suppress protein synthesis. Deletion of 20 amino acids from the carboxy-terminus of Reaper fully abrogated its potential to inhibit protein synthesis and to induce apoptosis in the absence of IAP-binding. Our findings indicate that the newly identified capacity of Reaper to suppress protein translation can operate in mammalian cells and may be key to its proapoptotic activity.

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Morgue mediates apoptosis in the Drosophila melanogaster retina by promoting degradation of DIAP1

Cited by 116 publications

References 37 publications

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

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

Mechanism of action of Drosophila Reaper in mammalian cells: Reaper globally inhibits protein synthesis and induces apoptosis independent of mitochondrial permeability

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