A Unique ISR Program Determines Cellular Responses to Chronic Stress.
A Unique ISR Program Determines Cellular Responses to Chronic Stress.
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DOI：
10.1016/j.molcel.2017.11.007
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发表时间：
2017-12-07
期刊：
影响因子：
16
通讯作者：
Hatzoglou M
中科院分区：
文献类型：
--
作者：
Guan BJ;van Hoef V;Jobava R;Elroy-Stein O;Valasek LS;Cargnello M;Gao XH;Krokowski D;Merrick WC;Kimball SR;Komar AA;Koromilas AE;Wynshaw-Boris A;Topisirovic I;Larsson O;Hatzoglou M
整合应激反应是内质网应激诱导的一种自我平衡机制。在急性/短暂的ER应激中，整体蛋白质合成减少和uORF mRNA翻译增加，随后蛋白质合成正常化。在这里，我们报告了一个显着不同的反应，在慢性内质网应激。这种慢性ISR程序的特征是持续升高的uORF mRNA翻译和同时发生的基因表达重编程，这允许同时进行压力传感和蛋白质稳态。该程序包括PERK依赖性转换为eIF 3依赖性翻译起始机制，导致部分但不完全的翻译恢复，其与转录重编程一起选择性地支持具有ER功能的蛋白质的表达。转录和翻译重编程的协调可防止ER功能障碍并抑制“泡沫细胞”发育，从而为理解与ER功能障碍相关的人类疾病建立分子基础。Guan等人揭示了慢性应激的适应机制，包括以前未被认识到的由PERK引导的翻译起始机制的重塑。翻译机制的这些变化与应激诱导的转录重编程相协调，并且当被破坏时导致泡沫细胞表型和细胞死亡。
Integrated Stress Response is a homeostatic mechanism induced by endoplasmic reticulum (ER) stress. In acute/transient ER stress, decreased global protein synthesis and increased uORF mRNA translation are followed by normalization of protein synthesis. Here, we report a dramatically different response during chronic ER stress. This chronic ISR program is characterized by persistently elevated uORF mRNA translation and concurrent gene expression reprogramming, which permits simultaneous stress sensing and proteostasis. The program includes PERK-dependent switching to an eIF3-dependent translation initiation mechanism resulting in partial but not complete translational recovery, which, together with transcriptional reprogramming, selectively bolsters expression of proteins with ER functions. Coordination of transcriptional and translational reprogramming prevents ER dysfunction and inhibits “foamy cell” development, thus establishing a molecular basis for understanding human diseases associated with ER dysfunction. Guan et al. unravel the mechanism of adaptation to chronic stress which encompasses previously unappreciated remodeling of the translation initiation machinery guided by PERK. These changes in the translation machinery are coordinated with stress-induced transcriptional reprograming and when disrupted result in a foamy cell phenotype and cell death.
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影响因子：
7.7
作者：
Andreev DE;O'Connor PB;Fahey C;Kenny EM;Terenin IM;Dmitriev SE;Cormican P;Morris DW;Shatsky IN;Baranov PV
通讯作者：
Baranov PV
影响因子：
4.7
作者：
Komar AA;Hatzoglou M
通讯作者：
Hatzoglou M
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
4
作者：
Chies, R;Nobbio, L;Brancolini, C
通讯作者：
Brancolini, C