Semaphorin-3A Promotes Degradation of Fragile X Mental Retardation Protein in Growth Cones via the Ubiquitin-Proteasome Pathway
Semaphorin-3A Promotes Degradation of Fragile X Mental Retardation Protein in Growth Cones via the Ubiquitin-Proteasome Pathway
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DOI：
10.3389/fncir.2020.00005
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发表时间：
2020-02
影响因子：
3.5
通讯作者：
Masaru Takabatake;Y. Goshima;Y. Sasaki
中科院分区：
文献类型：
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作者：
Masaru Takabatake;Y. Goshima;Y. Sasaki
脆性X智力低下蛋白（FMRP）是一种RNA结合蛋白，调节树突和棘中的局部翻译以实现突触可塑性。在轴突中，FMRP涉及轴突延伸和轴突引导。我们先前证明了FMRP参与生长锥崩溃通过一个依赖于脑信号蛋白-3A（Sema 3A），排斥性轴突导向因子的反应。在有吸引力的轴突导向因子的情况下，RNA结合蛋白如zipcode binding protein 1（ZBP 1）朝向生长锥的受刺激侧积累以进行局部翻译。然而，目前还不清楚Sema 3A如何影响FMRP在生长锥中的定位。在这里，我们表明，海马神经元生长锥中的FMRP水平下降Sema 3A刺激后。这种FMRP的减少被泛素激活酶E1酶抑制剂PYR-41和蛋白酶体抑制剂MG 132抑制，表明泛素-蛋白酶体途径参与了Sema 3A诱导的生长锥中的FMRP降解。此外，E1酶或蛋白酶体抑制剂抑制Sema 3A诱导的生长锥中微管相关蛋白1B（MAP 1B）的增加，表明泛素-蛋白酶体途径促进MAP 1B的局部翻译，其翻译由FMRP介导。这些抑制剂还阻断了Sema 3A诱导的生长锥塌陷。总的来说，我们的研究结果表明，Sema 3A通过泛素-蛋白酶体途径促进生长锥中FMRP的降解，通过MAP 1B的局部翻译导致生长锥塌陷。这些发现揭示了轴突导向调节的一种新机制：通过泛素-蛋白酶体途径降解翻译抑制因子FMRP。
Fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates local translation in dendrites and spines for synaptic plasticity. In axons, FMRP is implicated in axonal extension and axon guidance. We previously demonstrated the involvement of FMRP in growth cone collapse via a translation-dependent response to Semaphorin-3A (Sema3A), a repulsive axon guidance factor. In the case of attractive axon guidance factors, RNA-binding proteins such as zipcode binding protein 1 (ZBP1) accumulate towards the stimulated side of growth cones for local translation. However, it remains unclear how Sema3A effects FMRP localization in growth cones. Here, we show that levels of FMRP in growth cones of hippocampal neurons decreased after Sema3A stimulation. This decrease in FMRP was suppressed by the ubiquitin-activating enzyme E1 enzyme inhibitor PYR-41 and proteasome inhibitor MG132, suggesting that the ubiquitin-proteasome pathway is involved in Sema3A-induced FMRP degradation in growth cones. Moreover, the E1 enzyme or proteasome inhibitor suppressed Sema3A-induced increases in microtubule-associated protein 1B (MAP1B) in growth cones, suggesting that the ubiquitin-proteasome pathway promotes local translation of MAP1B, whose translation is mediated by FMRP. These inhibitors also blocked the Sema3A-induced growth cone collapse. Collectively, our results suggest that Sema3A promotes degradation of FMRP in growth cones through the ubiquitin-proteasome pathway, leading to growth cone collapse via local translation of MAP1B. These findings reveal a new mechanism of axon guidance regulation: degradation of the translational suppressor FMRP via the ubiquitin-proteasome pathway.