Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila

Kuranaga, Erina; Kanuka, Hirotaka; Igaki, Tatsushi; Sawamoto, Kazunobu; Ichijo, Hidenori; Okano, Hideyuki; Miura, Masayuki

doi:10.1038/ncb842

Cited by 124 publications

(132 citation statements)

References 29 publications

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“…3M-O). As it has been reported that DIAP1 degrades two proteins, Drosophila caspase DRONC [20] and TRAF1 [21] as its E3 substrate, our result suggest that the caspase cascade is implicated in the apoptosis induced by dXNP. Supporting this idea, Drice, a downstream caspase of DRONC [22], was activated in dXNP-overexpressing tissues (Fig.…”

Section: Discussionmentioning

confidence: 52%

dXNP, a Drosophila homolog of XNP/ATRX, induces apoptosis via Jun‐N‐terminal kinase activation

Lee

Hong

et al. 2007

FEBS Letters

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XNP/ATRX, a causative gene of X-linked a-thalassemia/mental retardation syndrome, encodes an SNF2 family ATPase/helicase protein. To better understand the role of XNP/ATRX in development, we isolated and characterized a Drosophila XNP/ATRX homolog, dXNP, which contains highly conserved SNF2 and helicase domains. Ectopically expressed dXNP induced strong apoptosis in the developing eye and wing, but did not affect cell cycle progression or the expression of wingless and engrailed, essential regulators of development. The dXNP-induced apoptosis was strongly suppressed by DJNKK/ hemipterous mutation, and dXNP increased JNK activity. Taken together, these results suggest that dXNP regulates apoptosis via JNK activation.

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Section: Discussionmentioning

confidence: 52%

dXNP, a Drosophila homolog of XNP/ATRX, induces apoptosis via Jun‐N‐terminal kinase activation

Lee

Hong

et al. 2007

FEBS Letters

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“…Heads were cut from freshly eclosed flies of indicated genotypes and homogenized in lysis buffer. 46 Immunoprecipitation, western blot, antibody staining and detection were performed as previously described. 46 …”

Section: Uas-gfp-irmentioning

confidence: 99%

“…46 Immunoprecipitation, western blot, antibody staining and detection were performed as previously described. 46 …”

Section: Uas-gfp-irmentioning

confidence: 99%

Bendless modulates JNK-mediated cell death and migration in Drosophila

et al. 2013

Cell Death Differ

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The TNF-JNK pathway is a highly conserved signaling pathway that regulates a wide spectrum of biological processes including cell death and migration. To further delineate this pathway, we carried out a genetic screen for dominant modifiers of the cell death phenotype triggered by ectopic expression of Eiger (Egr), the Drosophila TNF ortholog. Here we show that Bendless (Ben), an E2 ubiquitin-conjugating enzyme, modulates Egr-induced JNK activation and cell death through dTRAF2. Furthermore, Ben physically interacts with dTRAF2 and regulates Egr-induced dTRAF2 polyubiquitination. Finally, Ben is required for JNKdependent tumor progression, cell migration, oxidative stress resistance and longevity. Our results indicate that Ben constitutes an essential component of the evolutionarily conserved TNF-JNK pathway that modulates cell death and invasion, tumor progression, stress response and lifespan in metazoans.

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“…9 Like some other RING-finger proteins, DIAP1 catalyzes its own ubiquitination, and this activity is stimulated dramatically by the RHG proteins. [9][10][11][12][13][14] The currently known exogenous substrates of DIAP1 include the proapoptotic proteins Rpr and the caspases Dronc and DrICE. 14,15 It has been shown that ubiquitination of Rpr leads to its degradation, which terminates its antiapoptotic function.…”

mentioning

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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Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila

Cited by 124 publications

References 29 publications

dXNP, a Drosophila homolog of XNP/ATRX, induces apoptosis via Jun‐N‐terminal kinase activation

dXNP, a Drosophila homolog of XNP/ATRX, induces apoptosis via Jun‐N‐terminal kinase activation

Bendless modulates JNK-mediated cell death and migration in Drosophila

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

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