The switch-like expression of heme-regulated kinase 1 mediates neuronal proteostasis following proteasome inhibition
The switch-like expression of heme-regulated kinase 1 mediates neuronal proteostasis following proteasome inhibition
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DOI：
10.7554/elife.52714
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发表时间：
2020-04-24
期刊：
影响因子：
7.7
通讯作者：
Schuman, Erin M.
中科院分区：
文献类型：
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作者：
Alvarez-Castelao, Beatriz;Dieck, Susanne Tom;Schuman, Erin M.
我们研究了大鼠和小鼠神经元中主要蛋白质降解途径，泛素-蛋白酶体系统（UPS）和蛋白质合成之间的反馈。当蛋白质降解被抑制时，我们观察到神经元细胞体和树突中新生蛋白质合成的协调显着减少。翻译抑制的机制涉及eIF 2 α的磷酸化，令人惊讶地由eIF 2 α激酶1或血红素调节激酶抑制剂（HRI）介导。在基础条件下，HRI的神经元表达几乎检测不到。在蛋白酶体抑制后，HRI蛋白水平由于HRI的稳定和增强的翻译而增加，可能是通过其稀有密码子的tRNA的可用性增加。一旦表达，HRI在神经元中是组成性活性的，因为内源性血红素水平如此低; HRI活性导致eIF 2 α磷酸化和由此产生的翻译抑制。这些数据证明了神经元HRI的新作用，它可以感知并响应蛋白酶体功能受损以恢复蛋白质稳态。
We examined the feedback between the major protein degradation pathway, the ubiquitin-proteasome system (UPS), and protein synthesis in rat and mouse neurons. When protein degradation was inhibited, we observed a coordinate dramatic reduction in nascent protein synthesis in neuronal cell bodies and dendrites. The mechanism for translation inhibition involved the phosphorylation of eIF2 alpha, surprisingly mediated by eIF2 alpha kinase 1, or heme-regulated kinase inhibitor (HRI). Under basal conditions, neuronal expression of HRI is barely detectable. Following proteasome inhibition, HRI protein levels increase owing to stabilization of HRI and enhanced translation, likely via the increased availability of tRNAs for its rare codons. Once expressed, HRI is constitutively active in neurons because endogenous heme levels are so low; HRI activity results in eIF2 alpha phosphorylation and the resulting inhibition of translation. These data demonstrate a novel role for neuronal HRI that senses and responds to compromised function of the proteasome to restore proteostasis.