A unique ISR Program Determines Cellular Responses to Chronic Stress

Integrated Stress Response (ISR) is a homeostatic mechanism induced by endoplasmic reticulum (ER) stress. With acute/transient ER stress, decreased global protein synthesis and increased uORF mRNA translation are followed by translation normalization. Here, we report a dramatically different response during more physiologically relevant chronic ER stress. This unique ISR program is characterized by persistently elevated uORF mRNA translation and concurrent gene expression reprogramming, which permits simultaneous stress sensing and proteostasis. PERK-dependent switching from eIF4F/eIF2B- to eIF3D/GADD34-regulated translation initiation results in partial but not complete translation recovery, and together with transcriptional reprogramming, selectively bolsters expression of proteins with ER functions. Coordination of these transcriptional and translational changes prevents ER dysfunction and inhibits “foamy cell” development, thus establishing a molecular basis for understanding human diseases associated with ER dysfunction. Overall design: Four replicates were used for each condition (Control, Tg 1h, Tg 16h and Tg 16h + PERKi). The RNA of every sample was seperated into Input (total RNA) and polysome-associated RNA (resulting in 32 samples) before sequencing.