Coordination of synaptic vesicle trafficking and turnover by the Rab35 signaling network.
Coordination of synaptic vesicle trafficking and turnover by the Rab35 signaling network.
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DOI：
10.1080/21541248.2016.1270392
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发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Waites CL
中科院分区：
文献类型：
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作者：
Sheehan P;Waites CL
Rab35和Rab35由GAP、GEF和效应器组成的网络是从胞质分裂和吞噬到轴突生长的各种细胞过程的膜运输的重要调节因子。在过去的五年中，这个信号网络的组成部分也被认为是突触小泡(SV)循环和蛋白质动态平衡的关键介质。包括我们自己在内的几个小组最近的研究表明，Rab35介导的内体分选是通过ESCRT途径降解SV蛋白所必需的，从而从SV池中消除陈旧或受损的蛋白。这种分选过程受Rab35激活响应神经元活动的调节，并可能受到Rab35和小GTPase Arf6之间的拮抗信号关系的调节，该关系根据神经元活动水平将SVS引导到不同的循环途径。此外，编码Rab35调节蛋白的基因突变正在成为人类神经系统和神经退行性疾病的致病因素，这与它们在突触和神经元健康中的重要作用是一致的。在这里，我们回顾了这些最新的发现，并就Rab35信号网络如何发挥功能以维持神经传递和突触健康提供了我们的观点。
Rab35 and the Rab35 network of GAPs, GEFs, and effectors are important regulators of membrane trafficking for a variety of cellular processes, from cytokinesis and phagocytosis to neurite outgrowth. In the past five years, components of this signaling network have also been implicated as critical mediators of synaptic vesicle (SV) recycling and protein homeostasis. Recent studies by several groups, including our own, have demonstrated that Rab35-mediated endosomal sorting is required for the degradation of SV proteins via the ESCRT pathway, thereby eliminating old or damaged proteins from the SV pool. This sorting process is regulated by Rab35 activation in response to neuronal activity, and potentially by an antagonistic signaling relationship between Rab35 and the small GTPase Arf6 that directs SVs into distinct recycling pathways depending on neuronal activity levels. Furthermore, mutations in genes encoding Rab35 regulatory proteins are emerging as causative factors in human neurologic and neurodegenerative diseases, consistent with their important roles in synaptic and neuronal health. Here, we review these recent findings and offer our perspective on how the Rab35 signaling network functions to maintain neurotransmission and synaptic fitness.