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The eIF2α kinase HRI in innate immunity, proteostasis, and mitochondrial stress
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-09-05 , DOI: 10.1111/febs.15553 Stephen E Girardin 1 , Camille Cuziol 2, 3 , Dana J Philpott 4 , Damien Arnoult 2, 3
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-09-05 , DOI: 10.1111/febs.15553 Stephen E Girardin 1 , Camille Cuziol 2, 3 , Dana J Philpott 4 , Damien Arnoult 2, 3
Affiliation
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The integrated stress response (ISR) is an evolutionary conserved stress response pathway that leads to a global arrest in translation as well as to the expression of specific genes, such as the transcription factor ATF4, to promote cellular recovery. The central nexus of this pathway is the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) by one of the four eIF2α kinases that sense specific cellular stressors. The heme‐regulated inhibitor (HRI) is one of these kinases, and it was initially reported to be activated in response to heme deprivation. Nevertheless, further studies have established that cytosolic proteotoxicity, resulting from oxidative or osmotic stress, heat shock, and proteasome inhibition, is the predominant trigger for HRI to induce the ISR. In this review, we present newly identified functions of HRI in innate immunity, proteostasis, and mitochondrial stress. Indeed, HRI‐mediated signaling defines a novel cytosolic unfolded protein response (cUPR) required for the proper formation of some innate immune signalosomes and the control of toxic protein aggregates, and this eIF2α kinase also serves as a relay for mitonuclear communication after a mitochondrial stress.
中文翻译：
eIF2α激酶HRI与先天免疫，蛋白稳态和线粒体应激有关
整合应激反应（ISR）是一种进化保守的应激反应途径，可导致翻译中的整体停滞以及特定基因（例如转录因子ATF4）的表达，从而促进细胞恢复。该途径的中心联系是真核翻译起始因子2（eIF2α）的α亚基被感知特定细胞应激因子的四种eIF2α激酶之一磷酸化。血红素调节的抑制剂（HRI）是这些激酶之一，据报道最初是针对血红素缺乏而被激活的。然而，进一步的研究已经确定，由氧化或渗透胁迫，热休克和蛋白酶体抑制引起的胞质蛋白毒性是HRI诱导ISR的主要诱因。在这篇评论中，我们介绍了HRI在先天免疫，蛋白稳态和线粒体应激中的新发现功能。确实，HRI介导的信号传导定义了新的胞质解折叠蛋白反应（cUPR），这是某些先天免疫信号体的正确形成和毒性蛋白聚集体的控制所必需的，并且该eIF2α激酶还充当线粒体应激后微核通讯的中继。
更新日期：2020-09-05
中文翻译：
eIF2α激酶HRI与先天免疫，蛋白稳态和线粒体应激有关
整合应激反应（ISR）是一种进化保守的应激反应途径，可导致翻译中的整体停滞以及特定基因（例如转录因子ATF4）的表达，从而促进细胞恢复。该途径的中心联系是真核翻译起始因子2（eIF2α）的α亚基被感知特定细胞应激因子的四种eIF2α激酶之一磷酸化。血红素调节的抑制剂（HRI）是这些激酶之一，据报道最初是针对血红素缺乏而被激活的。然而，进一步的研究已经确定，由氧化或渗透胁迫，热休克和蛋白酶体抑制引起的胞质蛋白毒性是HRI诱导ISR的主要诱因。在这篇评论中，我们介绍了HRI在先天免疫，蛋白稳态和线粒体应激中的新发现功能。确实，HRI介导的信号传导定义了新的胞质解折叠蛋白反应（cUPR），这是某些先天免疫信号体的正确形成和毒性蛋白聚集体的控制所必需的，并且该eIF2α激酶还充当线粒体应激后微核通讯的中继。
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