Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation
Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation
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DOI：
10.7554/elife.14295
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发表时间：
2016-04-16
期刊：
影响因子：
7.7
通讯作者：
Ackerman, Susan L.
中科院分区：
文献类型：
--
作者：
Ishimura, Ryuta;Nagy, Gabor;Ackerman, Susan L.
核糖体在翻译过程中的停滞最近被证明会导致神经退化，但由停滞的伸长复合体触发的信号通路尚不清楚。为了研究这些途径，我们分析了C57BL/6J-Gtpbp2(nmf205-/-)小鼠的大脑，在C57BL/6J-Gtpbp2(nmf205-/-)小鼠中，由于缺乏tRNA(UCU)(Arg)tRNA和哺乳动物核糖体救援因子GTPBP2，神经元延长复合体在AGA密码子上停滞。在这些小鼠的神经变性之前，检测到eIF2α(Ser51)的磷酸化水平增加，转录组分析表明ATF4激活，ATF4是整合应激反应(ISR)途径中的关键转录因子。遗传学实验表明，这一途径被eIF2α激酶GCN2以一种明显的脱酰化tRNA不依赖的方式激活。此外，我们发现ISR可以减轻C57BL/6J-Gtpbp2(nmf205-/-)小鼠的神经退行性变，强调了细胞和应激背景对这一途径激活结果的重要性。这些结果表明，在细胞应激过程中，翻译延长和启动之间在调节神经元存活方面具有关键的相互作用。
Ribosome stalling during translation has recently been shown to cause neurodegeneration, yet the signaling pathways triggered by stalled elongation complexes are unknown. To investigate these pathways we analyzed the brain of C57BL/6J-Gtpbp2(nmf205-/-) mice in which neuronal elongation complexes are stalled at AGA codons due to deficiencies in a tRNA(UCU)(Arg) tRNA and GTPBP2, a mammalian ribosome rescue factor. Increased levels of phosphorylation of eIF2 alpha (Ser51) were detected prior to neurodegeneration in these mice and transcriptome analysis demonstrated activation of ATF4, a key transcription factor in the integrated stress response (ISR) pathway. Genetic experiments showed that this pathway was activated by the eIF2 alpha kinase, GCN2, in an apparent deacylated tRNA-independent fashion. Further we found that the ISR attenuates neurodegeneration in C57BL/6J-Gtpbp2(nmf205-/-) mice, underscoring the importance of cellular and stress context on the outcome of activation of this pathway. These results demonstrate the critical interplay between translation elongation and initiation in regulating neuron survival during cellular stress.