Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling.
Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling.
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DOI：
10.1016/j.devcel.2015.04.009
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发表时间：
2015-06-22
影响因子：
11.8
通讯作者：
Lee FS
中科院分区：
文献类型：
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作者：
Song M;Giza J;Proenca CC;Jing D;Elliott M;Dincheva I;Shmelkov SV;Kim J;Schreiner R;Huang SH;Castrén E;Prekeris R;Hempstead BL;Chao MV;Dictenberg JB;Rafii S;Chen ZY;Rodriguez-Boulan E;Lee FS
最近在人类和遗传小鼠模型中的研究已经将Slitrks确定为神经精神疾病的候选基因。所有Slitrk同种型都在CNS中高度表达，在CNS中它们介导神经突生长、突触发生和神经元存活。然而，这些功能背后的分子机制尚不清楚。在这里，我们报告Slitrk5通过与TrkB受体直接相互作用来调节BDNF依赖的生物反应。在基础条件下，Slitrk5主要与跨突触结合伴侣PTP δ相互作用;然而，在BDNF刺激后，Slitrk5转变为与TrkB顺式相互作用。在缺乏Slitrk5的情况下，TrkB具有降低的配体依赖性再循环速率和改变的对BDNF处理的响应性。结构照明显微镜显示，Slitrk5介导的最佳靶向TrkB受体Rab11阳性再循环内体通过招募Rab11效应蛋白，Rab11-FIP3。因此，Slitrk5作为TrkB辅助受体，介导其BDNF依赖性运输和信号传导。Slitrk家族蛋白质正在成为参与神经精神疾病的候选基因。Song等人表明，Slitrk5通过募集Rab11-FIP3直接调节TrkB受体再循环来调节BDNF依赖性生物反应。
Recent studies in humans and in genetic mouse models have identified Slitrks as candidate genes for neuropsychiatric disorders. All Slitrk isotypes are highly expressed in the CNS, where they mediate neurite outgrowth, synaptogenesis and neuronal survival. However, the molecular mechanisms underlying these functions are not known. Here, we report that Slitrk5 modulates BDNF-dependent biological responses through direct interaction with TrkB receptors. Under basal conditions, Slitrk5 interacts primarily with a trans-synaptic binding partner, PTPδ; however, upon BDNF stimulation, Slitrk5 shifts to cis-interactions with TrkB. In the absence of Slitrk5, TrkB has a reduced rate of ligand-dependent recycling and altered responsiveness to BDNF treatment. Structured illumination microscopy revealed that Slitrk5 mediates optimal targeting of TrkB receptors to Rab11-positive recycling endosomes through the recruitment of a Rab11 effector protein, Rab11-FIP3. Thus, Slitrk5 acts as a TrkB co-receptor that mediates its BDNF-dependent trafficking and signaling. Slitrk family proteins are emerging as candidate genes involved in neuropsychiatric disorders. Song et al. show that Slitrk5 modulates BDNF-dependent biological responses by directly regulating TrkB receptor recycling via recruitment of Rab11-FIP3.