RTN3 Is a Novel Cold-Induced Protein and Mediates Neuroprotective Effects of RBM3.
RTN3 Is a Novel Cold-Induced Protein and Mediates Neuroprotective Effects of RBM3.
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DOI：
10.1016/j.cub.2017.01.047
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发表时间：
2017-03-06
期刊：
影响因子：
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通讯作者：
Willis AE
中科院分区：
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作者：
Bastide A;Peretti D;Knight JR;Grosso S;Spriggs RV;Pichon X;Sbarrato T;Roobol A;Roobol J;Vito D;Bushell M;von der Haar T;Smales CM;Mallucci GR;Willis AE
降温和低温对神经具有深远的保护作用，至少部分是由冷休克蛋白RBM3介导的。然而，RBM3诱导的神经保护效应蛋白以及编码冷休克蛋白的mrna逃避冷却诱导的翻译抑制的机制尚不清楚。在这里，我们发现冷却诱导翻译体的重编程，包括一种新的冷休克蛋白RTN3的上调，RTN3是一种参与突触形成的网状蛋白。我们报告说，这有两个机制组成部分。因此，RTN3既避开了冷却诱导的翻译伸长抑制，又与RBM3结合，从而驱动RTN3的表达增加。在小鼠中，敲低RTN3表达可消除冷却诱导的神经保护作用。然而，慢病毒介导的RTN3过表达在神经变性小鼠模型中阻止突触丧失和认知缺陷，这是下游且独立于RBM3的。我们得出结论，RTN3的表达是rbm3诱导的神经保护的一个介质，受逃避冷却时翻译抑制的新机制控制。降温诱导的翻译体重编程增加RTN3的合成神经保护蛋白RBM3结合RTN3 mRNA并驱动其表达RTN3过表达可防止朊病毒病小鼠突触丢失RTN3表达是RBM3诱导的神经保护的中介，治疗性低温具有神经保护作用，冷休克蛋白RMB3在介导降温伴随的突触修复过程中起关键作用。Bastide和Peretti等人的研究表明，冷却可以选择性地重编程翻译体，并鉴定出RTN3是一种冷诱导蛋白，在神经保护途径中作用于RBM3的下游。
Cooling and hypothermia are profoundly neuroprotective, mediated, at least in part, by the cold shock protein, RBM3. However, the neuroprotective effector proteins induced by RBM3 and the mechanisms by which mRNAs encoding cold shock proteins escape cooling-induced translational repression are unknown. Here, we show that cooling induces reprogramming of the translatome, including the upregulation of a new cold shock protein, RTN3, a reticulon protein implicated in synapse formation. We report that this has two mechanistic components. Thus, RTN3 both evades cooling-induced translational elongation repression and is also bound by RBM3, which drives the increased expression of RTN3. In mice, knockdown of RTN3 expression eliminated cooling-induced neuroprotection. However, lentivirally mediated RTN3 overexpression prevented synaptic loss and cognitive deficits in a mouse model of neurodegeneration, downstream and independently of RBM3. We conclude that RTN3 expression is a mediator of RBM3-induced neuroprotection, controlled by novel mechanisms of escape from translational inhibition on cooling. Cooling-induced reprogramming of the translatome increases synthesis of RTN3 The neuroprotective protein RBM3 binds RTN3 mRNA and drives its expression RTN3 overexpression prevents synaptic loss in mice with prion disease RTN3 expression is a mediator of RBM3-induced neuroprotection Therapeutic hypothermia is neuroprotective, and the cold shock protein RMB3 plays a critical role in mediating synaptic repair processes that accompany cooling. Bastide and Peretti et al. show that cooling selectively reprograms the translatome and identify RTN3 as a cold-induced protein that acts downstream of RBM3 in the neuroprotection pathway.