Sorting nexin 27 rescues neuroligin 2 from lysosomal degradation to control inhibitory synapse number
Sorting nexin 27 rescues neuroligin 2 from lysosomal degradation to control inhibitory synapse number
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DOI：
10.1042/bcj20180504
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发表时间：
2019-03-31
影响因子：
4.1
通讯作者：
Wilkinson, Kevin A.
中科院分区：
文献类型：
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作者：
Binda, Caroline S.;Nakamura, Yasuko;Wilkinson, Kevin A.
逆转录聚体是一种进化上保守的内体运输复合体，它介导从降解途径中恢复货物蛋白，并将其分类回细胞表面。为了促进货物回收，VPS(空泡蛋白分类)26、VPS29和VPS35的核心逆转录三聚体要么直接识别货物，要么通过接头蛋白识别货物，其中最具特征的是PDZ[突触后密度95(PSD95)，盘大，小带闭塞]结构域的分拣Nexin SNX27。神经连接蛋白(NLGS)是突触后跨突触的支架蛋白，在突触后蛋白的聚集中发挥作用，以维持突触的稳定性。在这里，我们证明了每个NLG(NLG1-3)以直接PDZ配体依赖的方式与SNX27结合。神经元中SNX27的缺失导致每个NLG蛋白水平的下降，对于NLG2来说，这是由于溶酶体降解增强的结果。值得注意的是，虽然核心逆转录体组分VPS35的耗尽导致NLG1和NLG3水平的下降，但NLG2没有受到影响，这表明，对于这种货物，SNX27的作用独立于逆转录聚体。与SNX27的缺失导致NLG2的溶酶体降解增强一致，SNX27的敲除导致培养神经元中NLG2簇的减少，而SNX27或VPS35的缺失减少了Gen簇的大小和数量。综上所述，这些数据表明NLGS是SNX27-逆转聚体，并表明SNX27-逆转录聚体至少部分通过运输NLG2来控制抑制突触数量。
Retromer is an evolutionarily conserved endosomal trafficking complex that mediates the retrieval of cargo proteins from a degradative pathway for sorting back to the cell surface. To promote cargo recycling, the core retromer trimer of VPS (vacuolar protein sorting)26, VPS29 and VPS35 recognises cargo either directly, or through an adaptor protein, the most well characterised of which is the PDZ [postsynaptic density 95 (PSD95), disk large, zona occludens] domain-containing sorting nexin SNX27. Neuroligins (NLGs) are postsynaptic trans-synaptic scaffold proteins that function in the clustering of postsynaptic proteins to maintain synaptic stability. Here, we show that each of the NLGs (NLG1-3) bind to SNX27 in a direct PDZ Iigand-dependent manner. Depletion of SNX27 from neurons leads to a decrease in levels of each NLG protein and, for NLG2, this occurs as a result of enhanced lysosomal degradation. Notably, while depletion of the core retromer component VPS35 leads to a decrease in NLG1 and NLG3 levels, NLG2 is unaffected, suggesting that, for this cargo, SNX27 acts independently of retromer. Consistent with loss of SNX27 leading to enhanced lysosomal degradation of NLG2, knockdown of SNX27 results in fewer NLG2 clusters in cultured neurons, and loss of SNX27 or VPS35 reduces the size and number of gephyrin clusters. Together, these data indicate that NLGs are SNX27-retromer cargoes and suggest that SNX27-retromer controls inhibitory synapse number, at least in part through trafficking of NLG2.