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. 2023 Mar 21.
doi: 10.1089/ars.2022.0123. Online ahead of print.

Surviving and adapting to stress: Translational control and the integrated stress response

Affiliations

Surviving and adapting to stress: Translational control and the integrated stress response

Ronald C Wek et al. Antioxid Redox Signal. .

Abstract

εβOrganisms adapt to changing environments by engaging cellular stress response pathways that serve to restore proteostasis and enhance survival. A primary adaptive mechanism is the Integrated stress response (ISR), which features phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2). Four eIF2α kinases respond to different stresses, enabling cells to rapidly control translation to optimize management of resources and reprogram gene expression for stress adaptation. Phosphorylation of eIF2α blocks its guanine nucleotide exchange factor, eIF2B, thus lowering the levels of eIF2•GTP required to deliver initiator tRNA to ribosomes. While bulk mRNA translation can be sharply lowered by heightened phosphorylation of eIF2α, there are other gene transcripts whose translation is unchanged or preferentially translated. Among the preferentially translated genes is ATF4, which directs transcription of adaptive genes in the ISR. This review focuses on how eIF2α kinases function as first responders of stress, the mechanisms by which eIF2α phosphorylation and other stress signals regulate the exchange activity of eIF2B, and the processes by which the ISR triggers differential mRNA translation. The ISR is tunable and integrates with other stress pathways to optimize adaptation. To illustrate the synergy between stress pathways, we describe the mechanisms and functional significance of communication between the ISR and another key regulator of translation, mTORC1, during acute and chronic amino acid insufficiency. Finally, we discuss the pathological conditions that stem from aberrant regulation of the ISR, as well as therapeutic strategies targeting the ISR to alleviate disease.