Degradation of high affinity HuD targets releases Kv1.1 mRNA from miR-129 repression by mTORC1.
Degradation of high affinity HuD targets releases Kv1.1 mRNA from miR-129 repression by mTORC1.
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DOI：
10.1083/jcb.201212089
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发表时间：
2013-07-08
期刊：
影响因子：
--
通讯作者：
Raab-Graham KF
中科院分区：
文献类型：
--
作者：
Sosanya NM;Huang PP;Cacheaux LP;Chen CJ;Nguyen K;Perrone-Bizzozero NI;Raab-Graham KF
抑制mTORC1导致高亲和力HUD靶mRNAs的降解，释放HUD与Kv1.1 mRNA结合，并通过克服miR-129介导的抑制促进其翻译。关于神经元在神经元活动过程中如何经历特定部位的内在兴奋性变化，目前知之甚少。我们为mTORC1依赖的电压门控性钾通道Kv1.1信使RNA(MRNA)的翻译调节提供了新的机制。我们鉴定了一种microRNA，miR-129，当mTORC1激活时，它抑制Kv1.1 mRNA的翻译。当mTORC1失活时，我们发现RNA结合蛋白HUD与Kv1.1 mRNA结合并促进其翻译。出乎意料的是，抑制mTORC1活性并没有改变miR-129和HUD的水平，而有利于与Kv1.1 mRNA结合。然而，mTORC1信号的减少导致高亲和力HUD靶标mRNAs的降解，释放了HUD结合Kv1.1 mRNA。因此，mTORC1对mRNA稳定性的活性调节和高亲和力HUD靶向mRNA的降解介导了树突状Kv1.1离子通道的双向表达。
Inhibition of mTORC1 leads to the degradation of high affinity HuD target mRNAs, freeing HuD to bind Kv1.1 mRNA and promote its translation by overcoming miR-129–mediated repression. Little is known about how a neuron undergoes site-specific changes in intrinsic excitability during neuronal activity. We provide evidence for a novel mechanism for mTORC1 kinase–dependent translational regulation of the voltage-gated potassium channel Kv1.1 messenger RNA (mRNA). We identified a microRNA, miR-129, that repressed Kv1.1 mRNA translation when mTORC1 was active. When mTORC1 was inactive, we found that the RNA-binding protein, HuD, bound to Kv1.1 mRNA and promoted its translation. Unexpectedly, inhibition of mTORC1 activity did not alter levels of miR-129 and HuD to favor binding to Kv1.1 mRNA. However, reduced mTORC1 signaling caused the degradation of high affinity HuD target mRNAs, freeing HuD to bind Kv1.1 mRNA. Hence, mTORC1 activity regulation of mRNA stability and high affinity HuD-target mRNA degradation mediates the bidirectional expression of dendritic Kv1.1 ion channels.
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