The integrated stress response: From mechanism to disease

Abstract

Protein quality control is essential for the proper function of cells and the organisms that they make up. The resulting loss of proteostasis, the processes by which the health of the cell’s proteins is monitored and maintained at homeostasis, is associated with a wide range of age-related human diseases. Here, we highlight how the integrated stress response (ISR), a central signaling network that responds to proteostasis defects by tuning protein synthesis rates, impedes the formation of long-term memory. In addition, we address how dysregulated ISR signaling contributes to the pathogenesis of complex diseases, including cognitive disorders, neurodegeneration, cancer, diabetes, and metabolic disorders. The development of tools through which the ISR can be modulated promises to uncover new avenues to diminish pathologies resulting from it for clinical benefit.

Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity and memory in mouse models of Alzheimer’s disease

“…( 27 ) may be due to the fact that, in their case, a single and higher dose of ISRIB (5 mg/kg) was administered within a critical window for memory consolidation, during which de novo protein synthesis is essential for the persistence of newly formed memories ( 41 ). This is in line with previous reports showing that ISRIB modifies the ISR under conditions of increased eIF2α-P, but not under basal conditions ( 42 ), ( 43 ).…”

Proteostasis in dendritic cells is controlled by the PERK signaling axis independently of ATF4

“…In homeostatic conditions, eIF2 mediates the assembly of the mRNA translation initiation complex and regulates start codon recognition. During stress, phosphorylation of the α subunit of eIF2 (eIF2α) on serine 51 is mediated by a group of four eIF2α kinases (EIF2AK1-4), which specifically senses physiological imbalance (Arguello et al, 2016;Costa-Mattioli & Walter, 2020). Phosphorylation of eIF2α converts eIF2 into an inhibitor of the GDP-GTP guanidine exchange factor eIF2B, impairing the GDP-GTP recycling required to form new translation initiation complexes (Yamasaki & Anderson, 2008).…”

“…Phosphorylation of eIF2α converts eIF2 into an inhibitor of the GDP-GTP guanidine exchange factor eIF2B, impairing the GDP-GTP recycling required to form new translation initiation complexes (Yamasaki & Anderson, 2008). Consequently, increased eIF2α phosphorylation impacts cells in two main ways: (i) By reducing the rate of translation initiation and thus global protein synthesis levels; (ii) By favoring the translation of the activating transcription factor 4 (ATF4) (Han et al, 2013;Fusakio et al, 2016) which in turn activates the transcription of genes involved in the integrated stress response (ISR) (Costa-Mattioli & Walter, 2020).…”

Small molecule strategies to harness the unfolded protein response: where do we go from here?

“…Phosphorylation of eIF2a disrupts protein translation by increasing the affinity of the eIF2 complex for the eIF2B GTP exchange factor. This prevents eIF2B activity, which is required for translation initiation (92,93). As a result, ribosomal protein synthesis is globally reduced.…”

“…Interestingly, ISRIB did not reduce PERKdependent phosphorylation of eIF2a, indicating that this compound worked downstream of PERK kinase activity and likely functions by desensitizing cells to eIF2a phosphorylation. A consequence of this specific mechanism is that ISRIB can block eIF2a phosphorylation-dependent signaling induced by other stress-regulated eIF2a kinases including General Control Nonderepressible 4 (GCN4) activated in response to nutrient deprivation, Heme-Regulated Inhibitor (HRI) activated by oxidative or mitochondrial stress, and Protein Kinase R (PKR) activated by viral infection (92). This means care must be taken when assigning ISRIB-sensitive phenotypes specifically to PERK signaling under conditions where these other kinases may be active.…”