Interactions of DNR1 with the apoptotic machinery of<i>Drosophila</i>melanogaster

Primrose, David A.; Chaudhry, Sidharth; Johnson, A. George D.; Hrdlicka, Adam; Schindler, Anja; Tran, Dave; Foley, Edan

doi:10.1242/jcs.03417

Cited by 13 publications

(9 citation statements)

References 68 publications

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“…In support of this conclusion, we observe elevated expression of AMP genes in dnr1 mutants. We also examined the possibility that loss of Dnr1 might lead to neurodegeneration because of inappropriate activation of apoptosis because Dnr1 appears to negatively regulate apoptosis in S2 cells (6). However, we found little evidence for caspase 3-positive cells in brains of 20-to 25-d-old dnr1 mutants, suggesting that Dnr1 does not have a critical role in regulating apoptosis in the CNS.…”

Section: Discussionmentioning

confidence: 93%

“…Dnr1 was originally identified as a negative regulator of the Dredd caspase in the Imd pathway (6,18). Dredd is required for activation of Relish by associating with Fadd (Fas-associated death domain protein) to cleave off the autoinhibitory domain from Relish, an NF-κB family transcription factor to generate its active form (4,19,20).…”

Section: Resultsmentioning

confidence: 99%

“…One recently identified regulator for the Imd pathway is Dnr1 (defense repressor 1) (Fig. S1), a protein that contains a RING (Really Interesting New Gene) domain (an E3 ubiquitin ligase domain) that shares strong similarity with the RING domain found in inhibitor of apoptosis proteins that inhibit caspase activity by promoting their proteolytic degradation (6,7). Dnr1 acts in a similar manner to down-regulate Dredd.…”

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confidence: 99%

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Dnr1 mutations cause neurodegeneration in Drosophila by activating the innate immune response in the brain

Cao

Chtarbanova

Petersen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

191

230

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A growing body of evidence in humans implicates chronic activation of the innate immune response in the brain as a major cause of neuropathology in various neurodegenerative conditions, although the mechanisms remain unclear. In an unbiased genetic screen for mutants exhibiting neurodegeneration in Drosophila, we have recovered a mutation of dnr1 (defense repressor 1), a negative regulator of the Imd (immune deficiency) innate immuneresponse pathway. dnr1 mutants exhibit shortened lifespan and progressive, age-dependent neuropathology associated with activation of the Imd pathway and elevated expression of AMP (antimicrobial peptide) genes. To test the hypothesis that overactivation of innate immune-response pathways in the brain is responsible for neurodegeneration, we demonstrated that direct bacterial infection in the brain of wild-type flies also triggers neurodegeneration. In both cases, neurodegeneration is dependent on the NF-κB transcription factor, Relish. Moreover, we found that neural overexpression of individual AMP genes is sufficient to cause neurodegeneration. These results provide a mechanistic link between innate immune responses and neurodegeneration and may have important implications for the role of neuroinflammation in human neurodegenerative diseases as well.neuroprotection | neuronal cell death | neurotoxic mechanism

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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Dnr1 mutations cause neurodegeneration in Drosophila by activating the innate immune response in the brain

Cao

Chtarbanova

Petersen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

191

230

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“…The RING finger domain of DNR1 is required for the suppression of the IMD pathway signaling (Guntermann et al, 2009), suggesting that DNR1 functions through a ubiquitin-dependent mechanism. Besides DREDD, DNR1 has been reported to affect DRONC-dependent regulation of apoptosis (Primrose et al, 2007), suggesting a more general function of DNR1 as a repressor of initiator caspases. Interestingly, a recent report also associates DNR1 with neurodegeneration by demonstrating that loss-of-function mutations in dnr1 lead to IMD pathway activation, and increased, Relish-dependent, expression of AMPs in the fly brain, which eventually results in neuropathology.…”

Section: Negative Regulatorsmentioning

confidence: 99%

The Drosophila IMD pathway in the activation of the humoral immune response

Kleino

Silverman

2014

Developmental & Comparative Immunology

311

276

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The IMD pathway signaling plays a pivotal role in the Drosophila defense against bacteria. During the last two decades, significant progress has been made in identifying the components and deciphering the molecular mechanisms underlying this pathway, including the means of bacterial sensing and signal transduction. While these findings have contributed to the understanding of the immune signaling in insects, they have also provided new insights in studying the mammalian NF-κB signaling pathways. Here, we summarize the current view of the IMD pathway focusing on how it regulates the humoral immune response of Drosophila.

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“…The Dnr1 (defense repressor 1) protein was first identified in a cell-based screen for innate immunity, and was found to inhibit Dredd activity (Foley and O'Farrell, 2004). More recently, Dnr1 has been shown to inhibit apoptosis by causing a reduction in the level of Nc protein (Primrose et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Annotation and expression profiling of apoptosis-related genes in the yellow fever mosquito, Aedes aegypti

Bryant¹,

Blair²,

Olson³

et al. 2007

Insect Biochemistry and Molecular Biology

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Apoptosis has been extensively studied in Drosophila by both biochemical and genetic approaches, but there is a lack of knowledge about the mechanisms of apoptosis regulation in other insects. In mosquitoes, apoptosis occurs during Plasmodium and arbovirus infection in the midgut, suggesting that apoptosis plays a role in mosquito innate immunity. We searched the Aedes aegypti genome for apoptosis-related genes using Drosophila and Anopheles gambiae protein sequences as queries. In this study we have identified eleven caspases, three inhibitor of apoptosis (IAP) proteins, a previously unreported IAP antagonist, and orthologs of Drosophila Ark, Dnr1, and BG4 (also called dFadd). While most of these genes have been previously annotated, we have improved the annotation of several of them, and we also report the discovery of four previously unannotated apoptosis-related genes. We examined the developmental expression profile of these genes in Ae. aegypti larvae, pupae and adults, and we also studied the function of a novel IAP antagonist, IMP. Expression of IMP in mosquito cells caused apoptosis, indicating that it is a functional pro-death protein. Further characterization of these genes will help elucidate the molecular mechanisms of apoptosis regulation in Ae. aegypti.

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Interactions of DNR1 with the apoptotic machinery ofDrosophilamelanogaster

Cited by 13 publications

References 68 publications

Dnr1 mutations cause neurodegeneration in Drosophila by activating the innate immune response in the brain

Dnr1 mutations cause neurodegeneration in Drosophila by activating the innate immune response in the brain

The Drosophila IMD pathway in the activation of the humoral immune response

Annotation and expression profiling of apoptosis-related genes in the yellow fever mosquito, Aedes aegypti

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