A Cullin1-based SCF E3 ubiquitin ligase targets the InR/PI3K/TOR pathway to regulate neuronal pruning.
A Cullin1-based SCF E3 ubiquitin ligase targets the InR/PI3K/TOR pathway to regulate neuronal pruning.
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DOI：
10.1371/journal.pbio.1001657
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发表时间：
2013-09
期刊：
影响因子：
9.8
通讯作者：
Yu F
中科院分区：
文献类型：
--
作者：
Wong JJ;Li S;Lim EK;Wang Y;Wang C;Zhang H;Kirilly D;Wu C;Liou YC;Wang H;Yu F
有选择地消除不必要的轴突/树突的修剪对于在发育过程中塑造神经系统至关重要。在果蝇变态过程中，树突树突神经元（ddaC）响应类固醇激素蜕皮激素选择性地修剪其幼虫树突，而蘑菇体γ神经元则专门消除其背叶和内叶内的轴突分支。然而，尚不清楚哪种 E3 连接酶指导这两种修剪模式。在这里，我们鉴定了一种保守的 SCF E3 泛素连接酶，它在 ddaC 树突和蘑菇体 γ 轴突的修剪中发挥着关键作用。 SCF E3 连接酶由四个核心组件 Cullin1/Roc1a/SkpA/Slimb 组成，促进 EcR-B1 和 Sox14 下游的 ddaC 树突修剪，但独立于 Mical。此外，我们证明基于 Cullin1 的 E3 连接酶主要通过 InR/PI3K/TOR 通路的失活来促进 ddaC 树突修剪。我们发现 F-box 蛋白 Slimb 与 InR/PI3K/TOR 通路激活剂 Akt 形成复合物，并促进 Akt 泛素化。 InR/PI3K/TOR 通路的激活足以抑制 ddaC 树突修剪。因此，我们的研究结果提供了树突修剪过程中 E3 连接酶和 InR/PI3K/TOR 通路之间的新联系。神经元有能力进行选择性修剪，消除不必要的轴突/树突。这个过程对于发育过程中神经系统的塑造至关重要。在果蝇发育过程中，树突分枝感觉神经元（ddaC）响应蜕皮类固醇激素蜕皮激素选择性地修剪其幼虫树突，而蘑菇体γ神经元则消除其轴突分支。然而，这两种修剪模式的潜在分子机制尚不清楚。在这里，我们进行了全基因组筛选，并鉴定了一种保守的 E3 泛素连接酶，该酶对于修剪 ddaC 树突和蘑菇体 γ 轴突至关重要。该连接酶复合物具有四个核心组件：Cullin1、Roc1a、SkpA 和 Slimb，可响应蜕皮激素促进 ddaC 树突修剪。我们发现这种连接酶通过调节 InR/PI3K/TOR 通路促进 ddaC 树突修剪。底物识别蛋白 Slimb 促进 Akt 泛素化，Akt 是 InR/PI3K/TOR 通路的激活剂。 Akt 泛素化导致其降解和 InR/PI3K/TOR 通路失活，这是树突修剪所必需的。与此一致的是，当 InR/PI3K/TOR 通路被激活时，ddaC 树突修剪会受到抑制。因此，我们确定了基于 Cullin1 的 E3 连接酶和 InR/PI3K/TOR 通路在调节树突修剪方面的联系。这项工作代表了神经元修剪和胰岛素信号通路之间的第一个联系，提出了关于代谢状态如何影响此类发育过程的控制的有趣问题。
Pruning that selectively eliminates unnecessary axons/dendrites is crucial for sculpting the nervous system during development. During Drosophila metamorphosis, dendrite arborization neurons, ddaCs, selectively prune their larval dendrites in response to the steroid hormone ecdysone, whereas mushroom body γ neurons specifically eliminate their axon branches within dorsal and medial lobes. However, it is unknown which E3 ligase directs these two modes of pruning. Here, we identified a conserved SCF E3 ubiquitin ligase that plays a critical role in pruning of both ddaC dendrites and mushroom body γ axons. The SCF E3 ligase consists of four core components Cullin1/Roc1a/SkpA/Slimb and promotes ddaC dendrite pruning downstream of EcR-B1 and Sox14, but independently of Mical. Moreover, we demonstrate that the Cullin1-based E3 ligase facilitates ddaC dendrite pruning primarily through inactivation of the InR/PI3K/TOR pathway. We show that the F-box protein Slimb forms a complex with Akt, an activator of the InR/PI3K/TOR pathway, and promotes Akt ubiquitination. Activation of the InR/PI3K/TOR pathway is sufficient to inhibit ddaC dendrite pruning. Thus, our findings provide a novel link between the E3 ligase and the InR/PI3K/TOR pathway during dendrite pruning. Neurons have the ability to engage in selective pruning that eliminates unnecessary axons/dendrites. This process is crucial for sculpting the nervous system during development. During Drosophila development, dendrite arborization sensory neurons (ddaCs) selectively prune their larval dendrites in response to the molting steroid hormone ecdysone, whereas mushroom body γ neurons eliminate their axon branches. However, the underlying molecular mechanisms for both of these modes of pruning were not well understood. Here, we conduct a genome-wide screen and identify a conserved E3 ubiquitin ligase that is critical for pruning both ddaC dendrites and mushroom body γ axons. This ligase complex has four core components—Cullin1, Roc1a, SkpA, and Slimb—that promote ddaC dendrite pruning in response to ecdysone. We show that this ligase facilitates ddaC dendrite pruning through regulation of the InR/PI3K/TOR pathway. The substrate-recognition protein Slimb promotes ubiquitination of Akt, an activator of the InR/PI3K/TOR pathway. Akt ubiquitination leads to its degradation and inactivation of the InR/PI3K/TOR pathway, which is required for dendritic pruning. Consistent with this, ddaC dendrite pruning is inhibited when the InR/PI3K/TOR pathway is activated. Thus, we identify a link between the Cullin1-based E3 ligase and the InR/PI3K/TOR pathway in regulating dendrite pruning. This work represents the first link between neuronal pruning and the insulin signaling pathway, raising interesting questions about how metabolic states may influence the control of such developmental processes.
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