Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Hippocampus-Dependent Memory via Its Deubiquitinating Effect on TrkB
Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Hippocampus-Dependent Memory via Its Deubiquitinating Effect on TrkB
复制标题
泛素 C 端水解酶 L1 (UCH-L1) 通过对 TrkB 的去泛素化作用促进海马依赖性记忆
DOI：
10.1523/jneurosci.3148-16.2017
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发表时间：
2017
影响因子：
5.3
通讯作者：
Su Bo
中科院分区：
文献类型：
--
作者：
Guo Yun-Yun;Lu Yi;Zheng Yuan;Chen Xiao-Rong;Dong Jun-Lu;Yuan Rong-Rong;Huang Shu-Hong;Yu Hui;Wang Yue;Chen Zhe-Yu;Su Bo
多项研究表明，脑源性神经营养因子（BDNF）通过其受体TrkB在调节突触可塑性中起关键作用。除了被磷酸化之外，TrkB还被证明是泛素化的。然而，TrkB泛素化的机制及其生物学功能仍然知之甚少。在这项研究中，我们证明，泛素C-末端水解酶L1（UCH-L1）通过调节TrkB的泛素化促进情境恐惧条件化学习和记忆。我们提供的证据表明，UCH-L1可以直接去泛素化TrkB。K460是TrkB的主要泛素化位点，受UCH-L1调控。通过使用竞争性抑制UCH-L1和TrkB之间的关联的肽，我们表明UCH-L1调节的TrkB去泛素化的阻断导致BDNF诱导的TrkB内化增加，从而将内化的TrkB引导至降解途径，导致表面TrkB的降解增加和TrkB活化及其下游信号通路的衰减。此外，将该肽注射到小鼠的DG区中会损害海马依赖性记忆。总之，我们的研究结果表明，泛素化的TrkB是一种机制，控制其下游信号通路，通过调节其内吞作用和胞后运输和UCH-L1介导的去泛素化的TrkB，并可能是一个潜在的目标调制的海马依赖性记忆。泛素C末端水解酶L1（UCH-L1）已被证明在突触可塑性和学习记忆的调节中发挥重要作用。TrkB是脑源性神经营养因子的受体，也被证明是突触可塑性的有效调节剂。在这项研究中，我们证明了UCH-L1作为TrkB的去泛素化酶发挥作用。阻断UCH-L1调节的TrkB去泛素化最终导致表面TrkB降解增加和TrkB及其下游信号通路活化降低。在体内，UCH-L1调节的TrkB去泛素化对于海马依赖性记忆是必需的。总的来说，我们的研究为UCH-L1介导的神经生物学功能的机制提供了新的见解，并表明泛素化是TrkB功能的重要调节信号。
Multiple studies have established that brain-derived neurotrophic factor (BDNF) plays a critical role in the regulation of synaptic plasticity via its receptor, TrkB. In addition to being phosphorylated, TrkB has also been demonstrated to be ubiquitinated. However, the mechanisms of TrkB ubiquitination and its biological functions remain poorly understood. In this study, we demonstrate that ubiquitin C-terminal hydrolase L1 (UCH-L1) promotes contextual fear conditioning learning and memory via the regulation of ubiquitination of TrkB. We provide evidence that UCH-L1 can deubiquitinate TrkB directly. K460 in the juxtamembane domain of TrkB is the primary ubiquitination site and is regulated by UCH-L1. By using a peptide that competitively inhibits the association between UCH-L1 and TrkB, we show that the blockade of UCH-L1-regulated TrkB deubiquitination leads to increased BDNF-induced TrkB internalization and consequently directs the internalized TrkB to the degradation pathway, resulting in increased degradation of surface TrkB and attenuation of TrkB activation and its downstream signaling pathways. Moreover, injection of the peptide into the DG region of mice impairs hippocampus-dependent memory. Together, our results suggest that the ubiquitination of TrkB is a mechanism that controls its downstream signaling pathways via the regulation of its endocytosis and postendocytic trafficking and that UCH-L1 mediates the deubiquitination of TrkB and could be a potential target for the modulation of hippocampus-dependent memory. SIGNIFICANCE STATEMENT Ubiquitin C-terminal hydrolase L1 (UCH-L1) has been demonstrated to play important roles in the regulation of synaptic plasticity and learning and memory. TrkB, the receptor for brain-derived neurotrophic factor, has also been shown to be a potent regulator of synaptic plasticity. In this study, we demonstrate that UCH-L1 functions as a deubiquitinase for TrkB. The blockage of UCH-L1-regulated deubiquitination of TrkB eventually results in the increased degradation of surface TrkB and decreased activation of TrkB and its downstream signaling pathways. In vivo, UCH-L1-regulated TrkB deubiquitination is necessary for hippocampus-dependent memory. Overall, our study provides novel insights into the mechanisms of UCH-L1-mediated neurobiological functions and suggests that ubiquitination is an important regulatory signal for TrkB functions.