The integrated stress response (ISR) 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.

整体应激反应（ISR）是由内质网（ER）应激诱导的体内平衡机制。在急性/短暂性内质网应激中，总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，我们报告了在慢性内质网应激期间的显着不同反应。这种长期的ISR程序的特点是uORF mRNA的翻译水平持续升高，同时基因表达重新编程，从而可以同时进行压力感测和蛋白稳态。该程序包括PERK依赖的切换到eIF3依赖的翻译起始机制，从而导致部分但不是完全的翻译恢复，再加上转录重新编程，可以选择性地增强具有ER功能的蛋白质的表达。