Signaling plasticity in the integrated stress response

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.

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).