A Unique ISR Program Determines Cellular Responses to Chronic Stress

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2017 Dec 9

PMID 29220654

Citations 103

Authors

Bo-Jhih Guan

Vincent van Hoef

Raul Jobava

Orna Elroy-Stein

Leos S Valasek

Marie Cargnello

Xing-Huang Gao

Dawid Krokowski

William C Merrick

Scot R Kimball

Anton A Komar

Antonis E Koromilas

Anthony Wynshaw-Boris

Ivan Topisirovic

Ola Larsson

Maria Hatzoglou

Affiliations

Soon will be listed here.

Abstract

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.

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