CSN complex controls the stability of selected synaptic proteins via a torsinA-dependent process.

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.

• Authors: Alessandra Granata, Seong Joo Koo, Volker Haucke, Giampietro Schiavo, Thomas T Warner
• Journal: The EMBO journal (EMBO J) Vol. 30 Issue 1 Pg. 181-93 (Jan 05 2011) ISSN: 1460-2075 [Electronic] England
• PMID: 21102408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Adaptor Proteins, Vesicular Transport
• COPS4 protein, human
• Carrier Proteins
• Molecular Chaperones
• SNAPIN protein, human
• STON2 protein, human
• SYT1 protein, human
• Synaptotagmin I
• TOR1A protein, human
• Vesicular Transport Proteins
• COP9 Signalosome Complex

Topics

• Adaptor Proteins, Signal Transducing
• Adaptor Proteins, Vesicular Transport
• Brain (metabolism)
• COP9 Signalosome Complex
• Carrier Proteins (genetics, metabolism)
• Cell Line, Tumor
• Dystonia (genetics, metabolism)
• Gene Expression Regulation
• Gene Knockdown Techniques
• Humans
• Molecular Chaperones (genetics, metabolism)
• Mutation
• Protein Binding
• Protein Processing, Post-Translational
• Synaptic Vesicles (metabolism)
• Synaptotagmin I (metabolism)
• Vesicular Transport Proteins (genetics, metabolism)