CSN complex controls the stability of selected synaptic proteins via a torsinA-dependent process
Open Access
- 19 November 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 30 (1), 181-193
- https://doi.org/10.1038/emboj.2010.285
Abstract
DYT1 dystonia is caused by an autosomal dominant mutation that leads to a glutamic acid deletion in torsinA (TA), a member of the AAA+ ATPase superfamily. In this study, we identified a novel‐binding partner of TA, the subunit 4 (CSN4) of CSN signalosome. TA binds CSN4 and the synaptic regulator snapin in neuroblastoma cells and in brain synaptosomes. CSN4 and TA are required for the stability of both snapin and the synaptotagmin‐specific endocytic adaptor stonin 2, as downregulation of CSN4 or TA reduces the levels of both proteins. Snapin is phosphorylated by the CSN‐associated kinase protein kinase D (PKD) and its expression is decreased upon PKD inhibition. In contrast, the stability of stonin 2 is regulated by neddylation, another CSN‐associated activity. Overexpression of the pathological TA mutant (ΔE‐TA) reduces stonin 2 expression, causing the accumulation of the calcium sensor synaptotagmin 1 on the cell surface. Retrieval of surface‐stranded synaptotagmin 1 is restored by overexpression of stonin 2 in ΔE‐TA‐expressing cells, suggesting that the DYT1 mutation compromises the role of TA in protein stabilisation and synaptic vesicle recycling.Keywords
This publication has 57 references indexed in Scilit:
- Stonins—Specialized Adaptors for Synaptic Vesicle Recycling and Beyond?Traffic, 2009
- Mammalian COP9 signalosomeGenes to Cells, 2009
- Molecular Circuitry of Endocytosis at Nerve TerminalsAnnual Review of Cell and Developmental Biology, 2009
- Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia PathogenesisJournal of Biological Chemistry, 2009
- Snapin Facilitates the Synchronization of Synaptic Vesicle FusionNeuron, 2009
- Function and regulation of protein neddylationEMBO Reports, 2008
- Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic miceExperimental Neurology, 2008
- Molecular basis of synaptic vesicle cargo recognition by the endocytic sorting adaptor stonin 2The Journal of cell biology, 2007
- Downregulation of COP9 signalosome subunits differentially affects the CSN complex and target protein stabilityBMC Biochemistry, 2007
- The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding proteinNature Genetics, 1997