Neuronal remodeling and apoptosis require VCP-dependent degradation of the apoptosis inhibitor DIAP1

Rumpf, Sebastian; Lee, Sung Bae; Jan, Yuh Nung

doi:10.1242/dev.062703

Cited by 70 publications

(73 citation statements)

References 41 publications

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“…Interestingly, DIAP1 can be ubiquitylated for degradation itself (44,45). The proteolytic process of ubiquitylated DIAP1 remained unclear until a recent report suggesting that TER94-mediated UPS pathway is involved in this process (46). We have further shown in the present work that it is the dephosphorylated form of TER94 that is responsible for rapid DIAP1 degradation.…”

Section: Discussionsupporting

confidence: 47%

Ecdysone-Induced Receptor Tyrosine Phosphatase PTP52F Regulates Drosophila Midgut Histolysis by Enhancement of Autophagy and Apoptosis

Santhanam

Peng

et al. 2014

Molecular and Cellular Biology

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The rapid removal of larval midgut is a critical developmental process directed by molting hormone ecdysone during Drosophila metamorphosis. To date, it remains unclear how the stepwise events can link the onset of ecdysone signaling to the destruction of larval midgut. This study investigated whether ecdysone-induced expression of receptor protein tyrosine phosphatase PTP52F regulates this process. The mutation of the Ptp52F gene caused significant delay in larval midgut degradation. Transitional endoplasmic reticulum ATPase (TER94), a regulator of ubiquitin proteasome system, was identified as a substrate and downstream effector of PTP52F in the ecdysone signaling. The inducible expression of PTP52F at the puparium formation stage resulted in dephosphorylation of TER94 on its Y800 residue, ensuring the rapid degradation of ubiquitylated proteins. One of the proteins targeted by dephosphorylated TER94 was found to be Drosophila inhibitor of apoptosis 1 (DIAP1), which was rapidly proteolyzed in cells with significant expression of PTP52F. Importantly, the reduced level of DIAP1 in response to inducible PTP52F was essential not only for the onset of apoptosis but also for the initiation of autophagy. This study demonstrates a novel function of PTP52F in regulating ecdysone-directed metamorphosis via enhancement of autophagic and apoptotic cell death in doomed Drosophila midguts.

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Section: Discussionsupporting

confidence: 47%

Ecdysone-Induced Receptor Tyrosine Phosphatase PTP52F Regulates Drosophila Midgut Histolysis by Enhancement of Autophagy and Apoptosis

Santhanam

Peng

et al. 2014

Molecular and Cellular Biology

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“…It has been reported that Drosophila inhibitor of apoptosis protein 1 (DIAP1; Thread -FlyBase) inhibits caspases through direct binding or degradation . Moreover, DIAP1 degradation leads to caspase activation and pruning, and DIAP1 stabilization interferes with this process (Rumpf et al, 2011). We therefore examined whether DIAP1 expression affected shaft extension absorbance in a manner similar to its affect on dendrite pruning.…”

Section: Diap1 Overexpression Delays Ectopic Shaft Extension Pruningmentioning

confidence: 99%

Stable and dynamic microtubules coordinately determine and maintain Drosophila bristle shape

Bitan

Rosenbaum

2012

Development

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Live imagingAfter removing the pupal case, pupae were glued using heptane glue thorax side down in a glass-bottom culture dish (MatTek). A press-to-seal silicone isolator (Invitrogen) was placed on the dish to allow water addition to the SUMMARYWithin interphase cells, microtubules (MTs) are organized in a cell-specific manner to support cell shape and function. Here, we report that coordination between stable and dynamic MTs determines and maintains the highly elongated bristle cell shape. By following MT-decorating hooks and by tracking EB1 we identified two MT populations within bristles: a stable MT population polarized with their minus ends distal to the cell body, and a dynamic MT population that exhibits mixed polarity. Manipulating MT dynamics by Klp10A downregulation demonstrates that MTs can initiate new shaft extensions and thus possess the ability to determine growth direction. Actin filament bundling subsequently supports the newly formed shaft extensions. Analysis of ik2 mutant bristles, established by elongation defects in the Drosophila ikk homolog, led to the observation that stable and dynamic MT orientation and polarized organization are important for proper bristle elongation. Thus, we demonstrate for the first time that coordination between stable and dynamic MT sets that are axially organized yet differently polarized drives cell elongation.

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“…This process has been broadly termed axon degeneration and is intrinsic to the neuron. Despite their resemblance, axon degeneration and apoptosis are largely mechanistically distinct (1,3); however, axon and dendrite breakdown in the contexts of developmental pruning or trophic withdrawal does involve caspases and other apoptotic machinery (5,6,21). Components of the axon degeneration cascade include calpain proteases and the ubiquitin-proteasome system, and calcium influx is also an important step (7)(8)(9).…”

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confidence: 99%

Image-based Screening Identifies Novel Roles for IκB Kinase and Glycogen Synthase Kinase 3 in Axonal Degeneration

Gerdts

Sasaki

Vohra

et al. 2011

Journal of Biological Chemistry

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Axon degeneration is an active, evolutionarily conserved selfdestruction program by which compromised axons fragment in response to varied insults. Unlike programmed cell death, axon degeneration is poorly understood. We have combined robotic liquid handling with automated microscopy and image analysis to create a robust screening platform to measure axon degeneration in mammalian primary neuronal cultures. Using this assay, we performed an unbiased screen of 480 bioactive compounds, identifying 11 that reproducibly delay fragmentation of severed axons in vitro, including two inhibitors of glycogen synthase kinase 3 and two inhibitors of IB kinase. Knockdown of each of these targets by shRNA lentivirus also delays axon degeneration in vitro, further supporting their role in the axon degeneration program.The axon is a uniquely neuronal structure whose specialized architecture facilitates the rapid transmission of information across long distances. Just as compromised cells undergo programmed cell death, damaged axons undergo an active selfdestruct process that involves cytoskeletal disassembly, swelling, and eventual fragmentation with no concomitant cell death (1, 2). This process has been broadly termed axon degeneration and is intrinsic to the neuron. Despite their resemblance, axon degeneration and apoptosis are largely mechanistically distinct (1, 3); however, axon and dendrite breakdown in the contexts of developmental pruning or trophic withdrawal does involve caspases and other apoptotic machinery (5,6,21). Components of the axon degeneration cascade include calpain proteases and the ubiquitin-proteasome system, and calcium influx is also an important step (7-9). Axon degeneration is thought to be an early, important step in the pathologic progression and morbidity in diseases of the peripheral and central nervous systems including diabetic neuropathy, Parkinson disease, and multiple sclerosis (1, 2). Clearly, understanding the mechanisms that promote axon degeneration could have therapeutic value, yet little is known regarding the mechanisms by which axons commit to and execute this program of self-destruction.Unbiased high-content screening is a powerful approach for uncovering biological signaling cascades. Here, we report an image-based screening assay that combines automated microscopy, liquid handling, and image analysis of primary cultured neurons to screen for experimental conditions that delay or suppress axon degeneration following axotomy. Using this assay, we identified 11 compounds from a library of 480 that delay degeneration of severed axons in vitro in a dose-dependent manner. Among these, several have biologic targets with previously reported involvement in axon degeneration, however, our findings also reveal that inhibitors of IB kinase (IKK) 2 and glycogen synthase kinase 3 (GSK3) suppress axotomy-induced axon degeneration. Finally, we demonstrate through shRNA-mediated knockdown that IKK and GSK3 are required to promote rapid axon degeneration. EXPERIMENTAL PROCEDURESDRG Neuron Culture...

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Neuronal remodeling and apoptosis require VCP-dependent degradation of the apoptosis inhibitor DIAP1

Cited by 70 publications

References 41 publications

Ecdysone-Induced Receptor Tyrosine Phosphatase PTP52F Regulates Drosophila Midgut Histolysis by Enhancement of Autophagy and Apoptosis

Ecdysone-Induced Receptor Tyrosine Phosphatase PTP52F Regulates Drosophila Midgut Histolysis by Enhancement of Autophagy and Apoptosis

Stable and dynamic microtubules coordinately determine and maintain Drosophila bristle shape

Image-based Screening Identifies Novel Roles for IκB Kinase and Glycogen Synthase Kinase 3 in Axonal Degeneration

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