UNC-16 (JIP3) Acts Through Synapse-Assembly Proteins to Inhibit the Active Transport of Cell Soma Organelles to Caenorhabditis elegans Motor Neuron Axons
UNC-16 (JIP3) Acts Through Synapse-Assembly Proteins to Inhibit the Active Transport of Cell Soma Organelles to Caenorhabditis elegans Motor Neuron Axons
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DOI：
10.1534/genetics.115.177345
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发表时间：
2015-09-01
期刊：
影响因子：
3.3
通讯作者：
Miller, Kenneth G.
中科院分区：
文献类型：
--
作者：
Edwards, Stacey L.;Morrison, Logan M.;Miller, Kenneth G.
保守蛋白JIP 3抑制某些细胞索马细胞器如溶酶体、早期内体和高尔基体主动转运到轴突的突触区。然而，很少有人知道的细胞器运输的调节功能，这是不同于其驱动蛋白-1适配器功能。我们在秀丽隐杆线虫中使用unc-16抑制剂筛选，发现nc-16通过CDK-5（Cdk 5）和两种保守的突触组装蛋白：SAD-1（SAD-A激酶）和SYD-2（Liprin-a）起作用。在unc-16（+）和unc-16（2）背景下对所有双突变体和三突变体组合的遗传分析表明，三种蛋白质（CDK-5、SAD-1和SYD-2）都是同一细胞器运输调节系统的一部分，我们基于其创始蛋白将其命名为CSS系统。进一步的遗传分析揭示了SYD-1（另一种突触组装蛋白）和STRAD α（SAD-1相互作用蛋白）在CSS系统中的作用。在unc-16（2）背景下，CSS系统的缺失改善了unc-16突变体的缓慢运动，抑制了轴突溶酶体的积累，并导致树突中溶酶体的动力蛋白依赖性积累。unc-16（+）和unc-16（2）背景下CSS系统突变体中溶酶体的延时成像显示了与溶酶体稳态分布一致的主动转运缺陷。EST-16还使用CSS系统来调节神经元中早期内体的分布，并且在较小程度上调节高尔基体。这些数据揭示了突触组装蛋白质作为新定义的CSS系统的一部分在介导β-16的细胞器运输调节功能中的一个新的和前所未有的作用。
The conserved protein UNC-16 (JIP3) inhibits the active transport of some cell soma organelles, such as lysosomes, early endosomes, and Golgi, to the synaptic region of axons. However, little is known about UNC-16's organelle transport regulatory function, which is distinct from its Kinesin-1 adaptor function. We used an unc-16 suppressor screen in Caenorhabditis elegans to discover that UNC-16 acts through CDK-5 (Cdk5) and two conserved synapse assembly proteins: SAD-1 (SAD-A Kinase), and SYD-2 (Liprin-a). Genetic analysis of all combinations of double and triple mutants in unc-16(+) and unc-16(2) backgrounds showed that the three proteins (CDK-5, SAD-1, and SYD-2) are all part of the same organelle transport regulatory system, which we named the CSS system based on its founder proteins. Further genetic analysis revealed roles for SYD-1 (another synapse assembly protein) and STRAD alpha (a SAD-1-interacting protein) in the CSS system. In an unc-16(2) background, loss of the CSS system improved the sluggish locomotion of unc-16 mutants, inhibited axonal lysosome accumulation, and led to the dynein-dependent accumulation of lysosomes in dendrites. Time-lapse imaging of lysosomes in CSS system mutants in unc-16(+) and unc-16(2) backgrounds revealed active transport defects consistent with the steady-state distributions of lysosomes. UNC-16 also uses the CSS system to regulate the distribution of early endosomes in neurons and, to a lesser extent, Golgi. The data reveal a new and unprecedented role for synapse assembly proteins, acting as part of the newly defined CSS system, in mediating UNC-16's organelle transport regulatory function.