CSN complex controls the stability of selected synaptic proteins via a torsinA-dependent process
CSN complex controls the stability of selected synaptic proteins via a torsinA-dependent process
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DOI：
10.1038/emboj.2010.285
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发表时间：
2011-01-05
期刊：
影响因子：
11.4
通讯作者：
Warner, Thomas T.
中科院分区：
文献类型：
--
作者：
Granata, Alessandra;Koo, Seong Joo;Warner, Thomas T.
DYT1肌张力障碍是由AAA+ATPase超家族成员TorsinA(TA)的常染色体显性突变导致谷氨酸缺失引起的。在本研究中，我们确定了TA的一个新的结合伙伴，CSN信号体的亚单位4(CSN4)。TA与神经母细胞瘤细胞和脑突触体中的CSN4和突触调节因子Snapin结合。CSN4和TA对于Snapin和突触素特异的内吞接头stin2的稳定性都是必需的，因为CSN4或TA的下调会降低这两种蛋白的水平。Snapin被CSN相关的蛋白激酶D(PKD)磷酸化，抑制PKD后其表达减少。相反，斯图宁2的稳定性受另一种与CSN相关的活动--去甲肾上腺素的调节。病理性TA突变体(SE-TA)的过表达降低了ston2的表达，导致细胞表面钙感受器突触素1的积聚。通过在SE-TA表达细胞中过表达ston2，可以恢复表面链突触素1的恢复，这表明DYT1突变损害了TA在蛋白质稳定和突触小泡循环中的作用。EMBO期刊(2011)30,181-193。DOI：10.1038/Intemj.2010.285；2010年11月19日在线发布
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