Inactivation of Effector Caspases through Nondegradative Polyubiquitylation

Ditzel, Mark; Broemer, Meike; Tenev, Tencho; Bolduc, Clare; Lee, Tom V.; Rigbolt, Kristoffer; Elliott, Richard; Zvelebil, Marketa; Blagoev, Blagoy; Bergmann, Andreas; Meier, Pascal

doi:10.1016/j.molcel.2008.09.025

Cited by 111 publications

(148 citation statements)

References 61 publications

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“…49 A similar observation has been reported for DrICE. 48 Furthermore, a mouse mutant deleting the RING domain of XIAP does not significantly affect caspase protein levels. 50 Therefore, it is currently unclear how the protein levels of Dronc are controlled in living cells to avoid deleterious accumulation and autoprocessing of these potentially dangerous proteins.…”

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confidence: 99%

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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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“…43 IAPs carry a RING (really interesting new gene) domain, which has E3 ubiquitin ligase activity. 44 In Drosophila, because the RING domain of Diap1 ubiquitylates Dronc, [45][46][47][48] it is commonly assumed that this ubiquitylation targets the caspase for proteasome-mediated degradation. 45,46 However, in vivo this has not been observed.…”

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

et al. 2016

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“…Ubr3 binds to DIAP1 and promotes DIAP1-dependent caspases ubiquitination. As reported by Ditzel et al, 22 isolated UBR domain can recognize the neo-epitope of DIAP1 exposed after caspase-mediated cleavage. We have found that UBR3 regulates apoptosis in a UBR-boxdependent manner downstream of or in parallel to DIAP1.…”

Section: Ubr3 Regulates Apoptosis Q Huang Et Almentioning

confidence: 58%

“…It has been shown that M-DIAP1 , which cannot be recognized by UBR family proteins, has reduced activities in catalyzing caspase ubiquitination and in inhibiting apoptosis. 22 Here, we further explored how the interaction of DIAP1 with Ubr3 affects DIAP1's activities. As shown in Figure 6c, expression of N-DIAP1 in S2 cells readily ubiquitinated the downstream caspases Dronc and DrICE.…”

Section: Ubr3 Regulates Apoptosis Q Huang Et Almentioning

confidence: 99%

“…Later, Yokokura et al 21 reported that the N-end rule pathway does not have a major role in the turnover of N-terminally truncated DIAP1. More recently, Ditzel et al 22 reported that the UBRbinding motif of DIAP1 is essential for its anti-apoptotic function, indicating UBR family proteins regulate apoptosis via ways other than destroying DIAP1. Although these reports highlight the importance of UBR-box-containing E3 ligases in regulating DIAP1, it is currently unknown which UBR family member is involved in apoptosis.…”

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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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Microbial Inhibitors of Apoptosis

H��cker¹

2009

Encyclopedia of Life Sciences

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Infection with microbial agents (bacteria, fungi, viruses and parasites) is a challenge to a host cell. The host cell's response to infection is complex and entails changes in the activity of a number of intracellular signalling pathways, commonly including the apoptotic machinery. Microbes, if they have evolved the capacity to infect mammals or other complex hosts, have to be able to deal with such defence systems. The lifestyle of microbes varies substantially – viruses, for instance, depend on an intact cell, whereas many bacteria grow on surfaces and are not sensitive to host cell apoptosis. What we know about microbial interference with host cell apoptosis is in accordance with these lifestyles. Viruses often directly target and inhibit the apoptosis machinery with specific proteins whereas other microbes frequently also interfere with host apoptosis but more indirectly. Key concepts: Microbes (bacteria, fungi, viruses and parasites) can vary widely in terms of growth requirements and intimacy of association with host cells. Apoptosis is commonly induced in cells infected with microbes. In infections with obligate intracellular agents, apoptosis can be a defence mechanism of the host cell. A number of viruses carry genes whose products can directly interfere with the host cell's apoptosis apparatus. Many cells become activated when encountering microbial agents, and this activation may entail the triggering of pro‐survival pathways in the host cell. Activation of antiapoptotic pathways in immune cells by microbial components is a regulatory mechanism of the immune response.

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Inactivation of Effector Caspases through Nondegradative Polyubiquitylation

Cited by 111 publications

References 61 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

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

Microbial Inhibitors of Apoptosis

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