USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-Dependent Protein Levels
USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-Dependent Protein Levels
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DOI：
10.1523/jneurosci.3305-17.2018
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发表时间：
2018-06-06
影响因子：
5.3
通讯作者：
Sheng, Morgan
中科院分区：
文献类型：
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作者：
Campbell, Meghan Kerrisk;Sheng, Morgan
SHANK 3的突变或改变的蛋白质水平涉及神经发育障碍，例如M-M综合征、自闭症谱系障碍和精神分裂症（Guilmatre et al.，2014年）。小鼠模型中SHANK 3的缺失导致突触密度降低和多种突触蛋白水平降低（Jiang和Ehlers，2013）。SHANK支架分子家族是突触后密度最高的泛素化蛋白。SHANK的泛素依赖性蛋白酶体降解受突触活性调节，并可能有助于活性依赖性突触重塑（Ehlers，2003; Shin et al.，2012年）。然而，在突触上调节SHANK泛素化的特异性去泛素化酶和E3连接酶的身份是未知的。在这里，我们确定USP 8/UBPY作为一种去泛素化酶，调节SHANK 3和SHANK 1泛素化和蛋白质水平。在原代大鼠神经元中，USP 8通过去泛素化增强SHANK 3和SHANK 1蛋白水平，并增加树突棘密度。此外，USP 8对于突触活性调节后SHANK 3蛋白水平的变化至关重要。这些数据将USP 8鉴定为突触活性下游的SHANK 3的关键调节剂。
Mutations or altered protein levels of SHANK3 are implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorders, and schizophrenia (Guilmatre et al., 2014). Loss of SHANK3 in mouse models results in decreased synapse density and reduction in the levels of multiple synaptic proteins (Jiang and Ehlers, 2013). The family of SHANK scaffolding molecules are among the most heavily ubiquitinated proteins at the postsynaptic density. The ubiquitin-dependent proteasome degradation of SHANK is regulated by synaptic activity and may contribute to activity-dependent synaptic remodeling (Ehlers, 2003; Shin et al., 2012). However, the identity of the specific deubiquitinating enzymes and E3 ligases that regulate SHANK ubiquitination at synapses are unknown. Here we identify USP8/UBPY as a deubiquitinating enzyme that regulates SHANK3 and SHANK1 ubiquitination and protein levels. In primary rat neurons, USP8 enhances SHANK3 and SHANK1 protein levels via deubiquitination and increases dendritic spine density. Additionally, USP8 is essential for changes in SHANK3 protein levels following synaptic activity modulation. These data identify USP8 as a key modulator of SHANK3 downstream of synaptic activity.