Neuronal adaptor FE65 stimulates Rac1-mediated neurite outgrowth by recruiting and activating ELMO1
Neuronal adaptor FE65 stimulates Rac1-mediated neurite outgrowth by recruiting and activating ELMO1
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DOI：
10.1074/jbc.ra117.000505
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发表时间：
2018-05-18
影响因子：
4.8
通讯作者：
Lau, Kwok-Fai
中科院分区：
文献类型：
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作者：
Li, Wen;Tam, Ka Ming Vincent;Lau, Kwok-Fai
神经突生长是神经元发育形成神经网络的关键过程。了解神经突生长的调控机制对于开发刺激神经损伤后和神经退行性疾病中神经突再生的策略至关重要。FE 65是一种脑富集适配器，可刺激Rac 1介导的神经突延伸。然而，FE 65促进这一过程的确切机制仍然难以捉摸。在这里，我们表明，ELMO 1，ELMO 1-DOCK 180二分Rac 1鸟嘌呤核苷酸交换因子（GEF）的一个亚基，与FE 65 N-末端区域相互作用。FE 65和/或ELMO 1的过表达增强，而FE 65或ELMO 1的敲低抑制，神经突生长和Rac 1激活。FE 65单独或与ELMO 1一起的作用通过破坏FE 65-ELMO 1相互作用的FE 65双突变而减弱。值得注意的是，发现FE 65通过减少ELMO 1分子内自抑制相互作用来激活ELMO 1，并促进ELMO 1靶向质膜，其中Rac 1被激活。我们还表明，FE 65，ELMO 1，和DOCK 180形成一个三方复合物。DOCK 180的敲低降低了FE 65-ELMO 1对Rac 1活化和神经突生长的刺激作用。因此，我们确定了一种新的机制，FE 65刺激Rac 1介导的神经突生长的招募和激活ELMO 1。
Neurite outgrowth is a crucial process in developing neurons for neural network formation. Understanding the regulatory mechanisms of neurite outgrowth is essential for developing strategies to stimulate neurite regeneration after nerve injury and in neurodegenerative disorders. FE65 is a brain-enriched adaptor that stimulates Rac1-mediated neurite elongation. However, the precise mechanism by which FE65 promotes the process remains elusive. Here, we show that ELMO1, a subunit of ELMO1-DOCK180 bipartite Rac1 guanine nucleotide exchange factor (GEF), interacts with the FE65 N-terminal region. Overexpression of FE65 and/or ELMO1 enhances, whereas knockdown of FE65 or ELMO1 inhibits, neurite outgrowth and Rac1 activation. The effect of FE65 alone or together with ELMO1 is attenuated by an FE65 double mutation that disrupts FE65-ELMO1 interaction. Notably, FE65 is found to activate ELMO1 by diminishing ELMO1 intramolecular autoinhibitory interaction and to promote the targeting of ELMO1 to the plasma membrane, where Rac1 is activated. We also show that FE65, ELMO1, and DOCK180 form a tripartite complex. Knockdown of DOCK180 reduces the stimulatory effect of FE65-ELMO1 on Rac1 activation and neurite outgrowth. Thus, we identify a novel mechanism by which FE65 stimulates Rac1-mediated neurite outgrowth by recruiting and activating ELMO1.