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.

Fig. 1.. The molecular wiring of ISR control.

Stress sensing: ISR sensor kinases phosphorylate eIF2 in response to a diverse spectrum of cellular stresses. One of these kinases, PERK, overlaps with the UPR. eIF2B sequestration: Phosphorylation of eIF2 leads to sequestration of inactive eIF2B•eIF2-P, limiting available eIF2B activity in the cell, thus reducing TC concentration. TC control: TC concentration is controlled by GDP/GTP exchange on eIF2, which is catalyzed by eIF2B. The active decameric eIF2B complex is assembled from subcomplexes, a reaction that is facilitated by ISRIB. Translational control: The concentration of TC determines the translational status of general protein synthesis (green) and translation of specific mRNAs, such as ATF4 (red). Feedback regulation: Two phosphatase complexes antagonize the ISR. PP1•CReP in a constitutive regime and PP1•GADD34 in a feedback regime in response to ISR activation.

Fig. 2.. The structure and assembly of eIF2B.

(A) Top view of the human eIF2B decamer bound to ISRIB. The cryo-EM density at a resolution of 2.7 Å shows ISRIB bound in a deep central binding pocket. (B) Model of eIF2B decamer assembly mediated by ISRIB. Top and side views of the same assembly path are shown (11). (C) Model of the eIF2B•eIF2αβγ complex. The interaction stabilizes the open conformation of eIF2γ’s GTP binding site, thus catalyzing GTP exchange. (D) Model of eIF2B bound to its inhibitor eIF2-P. eIF2-P binds to a different site on eIF2B, noncompetitively blocking eIF2B’s GEF activity. (E) Bell-shaped response of ISR inhibition by ISRIB. ISRIB blocks the ISR only at intermediate activation levels, as shown in (22).

Fig. 3.. The ISR in brain disorders.

The ISR is a causative mechanism underlying the cognitive deficits and neurodegeneration in a wide broad range of brain disorders.

Fig. 4.. Model for proteostasis control by the ISR.

Different pathologies may have distinct homeostatic set points that relate to phenotypic fitness, such as cognition. As considered here, either reduced or increased ISR activation can be maladaptive. Therefore, depending on the disease or pathology and the optimal homeostatic set point for a particular phenotype, activation of the ISR (e.g., with sephin1) or inhibition of the ISR (e.g., with ISRIB) would restore homeostasis to optimal cell fitness.