Shen Haowei, Korutla Laxminarayana, Champtiaux Nicholas, Toda Shigenobu, LaLumiere Ryan, Vallone Joseph, Klugmann Matthias, Blendy Julie A, Mackler Scott A, Kalivas Peter W
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
J Neurosci. 2007 Aug 15;27(33):8903-13. doi: 10.1523/JNEUROSCI.1571-07.2007.
Coordinated proteolysis of synaptic proteins is required for synaptic plasticity, but a mechanism for recruiting the ubiquitin-proteasome system (UPS) into dendritic spines is not known. NAC1 is a cocaine-regulated transcriptional protein that was found to complex with proteins in the UPS, including cullins and Mov34. NAC1 and the proteasome were cotranslocated from the nucleus into dendritic spines in cortical neurons in response to proteasome inhibition or disinhibiting synaptic activity with bicuculline. Bicuculline also produced a progressive accumulation of the proteasome and NAC1 in the postsynaptic density. Recruitment of the proteasome into dendrites and postsynaptic density by bicuculline was prevented in neurons from mice harboring an NAC1 gene deletion or in neurons transfected with mutated NAC1 lacking the proteasome binding domain. These experiments show that NAC1 modulates the translocation of the UPS from the nucleus into dendritic spines, thereby suggesting a potential missing link in the recruitment of necessary proteolysis machinery for synaptic remodeling.
突触可塑性需要突触蛋白的协同蛋白水解作用，但将泛素 - 蛋白酶体系统（UPS）募集到树突棘中的机制尚不清楚。NAC1是一种受可卡因调节的转录蛋白，已发现它与UPS中的蛋白质形成复合物，包括cullin蛋白和Mov34。响应蛋白酶体抑制或用荷包牡丹碱解除突触活动抑制，NAC1和蛋白酶体在皮质神经元中从细胞核共转运到树突棘中。荷包牡丹碱还导致蛋白酶体和NAC1在突触后致密物中逐渐积累。在携带NAC1基因缺失的小鼠的神经元中或在用缺乏蛋白酶体结合结构域的突变NAC1转染的神经元中，荷包牡丹碱阻止蛋白酶体募集到树突和突触后致密物中。这些实验表明，NAC1调节UPS从细胞核到树突棘的转运，从而提示在为突触重塑募集必要的蛋白水解机制方面可能存在缺失环节。
