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.

Center for Gene Regulation in Health and Disease and Department of Biological Geological and Environmental Sciences Cleveland State University Cleveland OH 44115 USA

Department of Biochemistry Case Western Reserve University Cleveland OH 44106 USA

Department of Cell Research and Immunology George S Wise Faculty of Life Sciences Tel Aviv University Tel Aviv 69978 Israel

Department of Cellular and Molecular Physiology Pennsylvania State University College of Medicine Hershey PA 17033 USA

Department of Genetics and Genome Sciences Case Western Reserve University Cleveland OH 44106 USA

Department of Oncology Pathology Karolinska Institutet SciLifeLab Stockholm 171 76 Sweden

Laboratory of Regulation of Gene Expression Institute of Microbiology AS CR Prague 142 20 Czech Republic

Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology Montreal QC H3T 1E2 Canada

Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology Montreal QC H3T 1E2 Canada; Department of Biochemistry McGill University Montreal QC H3T 1E2 Canada

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