Activity-Dependent Palmitoylation Controls SynDIG1 Stability, Localization, and Function
Activity-Dependent Palmitoylation Controls SynDIG1 Stability, Localization, and Function
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DOI：
10.1523/jneurosci.4859-14.2016
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发表时间：
2016-07-20
影响因子：
5.3
通讯作者：
Diaz, Elva
中科院分区：
文献类型：
--
作者：
Kaur, Inderpreet;Yarov-Yarovoy, Vladimir;Diaz, Elva
突触是神经元之间的特殊接触。突触分化诱导基因 I (SynDIG1) 在突触发育过程中发挥着关键作用，可调节兴奋性突触的 AMPA 受体 (AMPAR) 和 PSD-95 含量。棕榈酰化调节许多突触蛋白的定位和功能，包括 AMPAR 和 PSD-95。在这里，我们展示了 SynDIG1 被棕榈酰化，并研究了棕榈酰化对 SynDIG1 稳定性和定位的影响。 SynDIG1 的结构模型表明，膜相关区域形成一个三螺旋束，其中两个半胱氨酸残基位于暴露于细胞质的近跨膜区域的位置 191 和 192。定点诱变表明，C191 和 C192 在异源细胞中被棕榈酰化，并正向调节神经元中的树突靶向。与 PSD-95 一样，大鼠海马切片培养物中的活动阻断会增加 SynDIG1 棕榈酰化，这与我们之前的证明一致，即活动阻断后 SynDIG1 在突触的定位会增加。这些数据表明 SynDIG1 的棕榈酰化受到神经元活动的调节，并在调节其稳定性和亚细胞定位及其功能方面发挥着关键作用。
Synapses are specialized contacts between neurons. Synapse differentiation-induced gene I (SynDIG1) plays a critical role during synapse development to regulate AMPA receptor (AMPAR) and PSD-95 content at excitatory synapses. Palmitoylation regulates the localization and function of many synaptic proteins, including AMPARs and PSD-95. Here we show that SynDIG1 is palmitoylated, and investigate the effects of palmitoylation on SynDIG1 stability and localization. Structural modeling of SynDIG1 suggests that the membrane-associated region forms a three-helical bundle with two cysteine residues located at positions 191 and 192 in the juxta-transmembrane region exposed to the cytoplasm. Site-directed mutagenesis reveals that C191 and C192 are palmitoylated in heterologous cells and positively regulates dendritic targeting in neurons. Like PSD-95, activity blockade in a rat hippocampal slice culture increases SynDIG1 palmitoylation, which is consistent with our prior demonstration that SynDIG1 localization at synapses increases upon activity blockade. These data demonstrate that palmitoylation of SynDIG1 is regulated by neuronal activity, and plays a critical role in regulating its stability and subcellular localization, and thereby its function.