Regulation of Postsynaptic Function by the Dementia-Related ESCRT-III Subunit CHMP2B
Regulation of Postsynaptic Function by the Dementia-Related ESCRT-III Subunit CHMP2B
复制标题
DOI：
10.1523/jneurosci.0586-14.2015
复制
发表时间：
2015-02-18
影响因子：
5.3
通讯作者：
Goldberg, Yves
中科院分区：
文献类型：
--
作者：
Chassefeyre, Romain;Martinez-Hernandez, Jose;Goldberg, Yves
带电多泡体蛋白（Chmp 1 -7）是一个进化上保守的胞质蛋白家族，其瞬时组装成改变细胞膜结构域曲率的螺旋聚合物。人类CHMP 2B的突变导致额颞叶痴呆，这表明这种蛋白质可能通常控制一些神经元特异性过程。在这里，我们研究了神经元Chmp 2b的功能，定位和相互作用。该蛋白在小鼠脑中高度表达，并且可以容易地在神经元树突和棘中检测到。内源性Chmp 2b的耗竭减少了培养的海马神经元的树突分支，降低了兴奋性突触密度在体外和体内，并废除活动诱导的棘扩大和突触增强。为了了解Chmp 2b的突触效应，我们通过定量免疫电镜和免疫共沉淀和质谱测定其生化相互作用来确定其超微结构分布。在原位海马中，神经元Chmp 2b的子集被证明集中在树突棘的突触周膜下方。在突触神经体裂解物中，Chmp 2b稳定地结合到含有Chmp家族的其他成员以及突触后支架的大复合物上。这里检测到的超分子Chmp组装对应于转运蛋白-III（ESCRT-III）所需的内体分选复合物的稳定形式，ESCRT-III是一种普遍存在的细胞质蛋白复合物，已知在脂质膜重塑中发挥核心作用。我们的结论是，Chmp 2b含有ESCRT-III复合物也存在于树突棘，在那里他们调节突触可塑性。我们建议，突触ESCRT-III丝可能作为一个新的元素的膜下细胞骨架的刺。
The charged multivesicular body proteins (Chmp1-7) are an evolutionarily conserved family of cytosolic proteins that transiently assembles into helical polymers that change the curvature of cellular membrane domains. Mutations in human CHMP2B cause frontotemporal dementia, suggesting that this protein may normally control some neuron-specific process. Here, we examined the function, localization, and interactions of neuronal Chmp2b. The protein was highly expressed in mouse brain and could be readily detected in neuronal dendrites and spines. Depletion of endogenous Chmp2b reduced dendritic branching of cultured hippocampal neurons, decreased excitatory synapse density in vitro and in vivo, and abolished activity-induced spine enlargement and synaptic potentiation. To understand the synaptic effects of Chmp2b, we determined its ultrastructural distribution by quantitative immuno-electron microscopy and its biochemical interactions by coimmunoprecipitation and mass spectrometry. In the hippocampus in situ, a subset of neuronal Chmp2b was shown to concentrate beneath the perisynaptic membrane of dendritic spines. In synaptoneurosome lysates, Chmp2b was stably bound to a large complex containing other members of the Chmp family, as well as postsynaptic scaffolds. The supramolecular Chmp assembly detected here corresponds to a stable form of the endosomal sorting complex required for transport-III (ESCRT-III), a ubiquitous cytoplasmic protein complex known to play a central role in remodeling of lipid membranes. We conclude that Chmp2b-containing ESCRT-III complexes are also present at dendritic spines, where they regulate synaptic plasticity. We propose that synaptic ESCRT-III filaments may function as a novel element of the submembrane cytoskeleton of spines.