期刊
EMBO JOURNAL
卷 30, 期 1, 页码 181-193出版社
WILEY
DOI: 10.1038/emboj.2010.285
关键词
CSN4; dystonia; DYT1; snapin; stonin 2
资金
- Brain Research Trust
- Dystonia Society
- Cancer Research UK
- Wellcome Trust
- Deutsche Forschungsgemeinschaft [Exc-257, HA2686/6-1]
- Schram Foundation
- Helmholtz International Research School for Molecular Neurobiology
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 (SE-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 SE-TA-expressing cells, suggesting that the DYT1 mutation compromises the role of TA in protein stabilisation and synaptic vesicle recycling. The EMBO Journal (2011) 30, 181-193. doi:10.1038/emboj.2010.285; Published online 19 November 2010
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