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Signaling plasticity in the integrated stress response - PubMed

  • ️Sun Jan 01 2023

Review

Signaling plasticity in the integrated stress response

Morgane Boone et al. Front Cell Dev Biol. 2023.

Abstract

The Integrated Stress Response (ISR) is an essential homeostatic signaling network that controls the cell's biosynthetic capacity. Four ISR sensor kinases detect multiple stressors and relay this information to downstream effectors by phosphorylating a common node: the alpha subunit of the eukaryotic initiation factor eIF2. As a result, general protein synthesis is repressed while select transcripts are preferentially translated, thus remodeling the proteome and transcriptome. Mounting evidence supports a view of the ISR as a dynamic signaling network with multiple modulators and feedback regulatory features that vary across cell and tissue types. Here, we discuss updated views on ISR sensor kinase mechanisms, how the subcellular localization of ISR components impacts signaling, and highlight ISR signaling differences across cells and tissues. Finally, we consider crosstalk between the ISR and other signaling pathways as a determinant of cell health.

Keywords: homeostasis; integrated stress response; sensor kinase; signal crosstalk; signal heterogeneity; signaling network; subcellular compartmentalization.

Copyright © 2023 Boone and Zappa.

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Conflict of interest statement

Authors MB and FZ were employed by Altos labs.

Figures

FIGURE 1
FIGURE 1

Tissue enrichment of core ISR components. Protein and RNA tissue specificity scores (TS) were extracted from the quantitative proteome map of the human body from the GTEx project, and are calculated as standard deviation from the bulk population average across all tissues for each gene product (Jiang et al., 2020). Grey dots: undetected by mass spectrometry. No data was available for ATF4 or HRI (EIF2AK1).

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The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study received funding from Altos Labs Inc. The funder was not involved in the data collection, interpretation, and writing of this article or the decision to submit it for publication.