title: Neuronal remodeling and apoptosis require VCP-dependent degradation of the apoptosis inhibitor DIAP1.
abstract: The regulated degeneration of axons or dendrites (pruning) and neuronal apoptosis are widely used during development to determine the specificity of neuronal connections. Pruning and apoptosis often share similar mechanisms; for example, developmental dendrite pruning of Drosophila class IV dendritic arborization (da) neurons is induced by local caspase activation triggered by ubiquitin-mediated degradation of the caspase inhibitor DIAP1. Here, we examined the function of Valosin-containing protein (VCP), a ubiquitin-selective AAA chaperone involved in endoplasmic reticulum-associated degradation, autophagy and neurodegenerative disease, in Drosophila da neurons. Strong VCP inhibition is cell lethal, but milder inhibition interferes with dendrite pruning and developmental apoptosis. These defects are associated with impaired caspase activation and high DIAP1 levels. In cultured cells, VCP binds to DIAP1 in a ubiquitin- and BIR domain-dependent manner and facilitates its degradation. Our results establish a new link between ubiquitin, dendrite pruning and the apoptosis machinery.
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rumpf
authors.forename: Sung Bae
authors.initials: SB
authors.lastname: Lee
authors.forename: Lily Yeh
authors.initials: LY
authors.lastname: Jan
authors.forename: Yuh Nung
authors.initials: YN
authors.lastname: Jan
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism* / Q000502:physiology; D004330:Drosophila / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D029721:Drosophila Proteins / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics; D000074405:Valosin Containing Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; C111891:DIAP1 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D020169:Caspases; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein