Drosophila Valosin-Containing Protein is required for dendrite pruning through a regulatory role in mRNA metabolism

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-05, Vol.111 (20), p.7331-7336
• Main Authors: Rumpf, Sebastian, Bagley, Joshua A., Thompson-Peer, Katherine L., Zhu, Sijun, Gorczyca, David, Beckstead, Robert B., Jan, Lily Yeh, Jan, Yuh Nung
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - metabolism; Adenosine Triphosphatases - physiology; adenosinetriphosphatase; Animals; Biological Sciences; Dendrites; Dendrites - metabolism; DNA-Binding Proteins - metabolism; Drosophila; Drosophila melanogaster - metabolism; Drosophila Proteins - metabolism; Drosophila Proteins - physiology; Ecdysone - metabolism; Enzymes; Exons; Gene Expression Regulation; genes; humans; larvae; Messenger RNA; Metabolism; Metamorphism; metamorphosis; Molecules; mutants; Mutation; Nervous system diseases; neurodegenerative diseases; Neurons; Neurons - metabolism; Phenotype; proteasome endopeptidase complex; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Proteins; Pruning; Ribonucleic acid; RNA; RNA binding proteins; RNA, Messenger - metabolism; RNA-Binding Proteins - metabolism; Signal Transduction; Ubiquitin - metabolism; ubiquitin-protein ligase; Valosin Containing Protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1406898111

The dendritic arbors of the larval Drosophila peripheral class IV dendritic arborization neurons degenerate during metamorphosis in an ecdysone-dependent manner. This process—also known as dendrite pruning—depends on the ubiquitin–proteasome system (UPS), but the specific processes regulated by the UPS during pruning have been largely elusive. Here, we show that mutation or inhibition of Valosin-Containing Protein (VCP), a ubiquitin-dependent ATPase whose human homolog is linked to neurodegenerative disease, leads to specific defects in mRNA metabolism and that this role of VCP is linked to dendrite pruning. Specifically, we find that VCP inhibition causes an altered splicing pattern of the large pruning gene molecule interacting with CasL and mislocalization of the Drosophila homolog of the human RNA-binding protein TAR–DNA-binding protein of 43 kilo-Dalton (TDP-43). Our data suggest that VCP inactivation might lead to specific gain-of-function of TDP-43 and other RNA-binding proteins. A similar combination of defects is also seen in a mutant in the ubiquitin-conjugating enzyme ubcD1 and a mutant in the 19S regulatory particle of the proteasome, but not in a 20S proteasome mutant. Thus, our results highlight a proteolysis-independent function of the UPS during class IV dendritic arborization neuron dendrite pruning and link the UPS to the control of mRNA metabolism.