The integrated stress response: From mechanism to disease

BACKGROUND: The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that helps the cell, tissue, and organism to adapt to a variable environment and maintain health. In response to different environmental and pathological conditions, including protein homeostasis (proteostasis) defects, nutrient deprivation, viral infection, and oxidative stress, the ISR restores balance by reprogramming gene expression. The various stresses are sensed by four specialized kinases (PERK, GCN2, PKR and HRI) that converge on phosphorylation of a single serine on the eukaryotic translation initiation factor eIF2. eIF2 phosphorylation blocks the action of eIF2’s guanine nucleotide exchange factor termed eIF2B, resulting in a general reduction in protein synthesis. Paradoxically, phosphorylation of eIF2 also triggers the translation of specific mRNAs, including key transcription factors, such as ATF4. These mRNAs contain short inhibitory upstream open reading frames in their 5′-untranslated regions that prevent translation initiation at their canonical AUGs. By tuning down general mRNA translation and up-regulating the synthesis of a few proteins that drive a new transcriptional program, the ISR aims to maintain or reestablish physiological homeostasis. However, if the stress cannot be mitigated, the ISR triggers apoptosis to eliminate the damaged cell. ADVANCES: Our understanding of the central mechanisms that govern the ISR has advanced vastly. The ISR’s central regulatory hub lies in the eIF2-eIF2B complex, which controls the formation of the eIF2•GTP•methionyl-intiator tRNA ternary complex (TC), a prerequisite for initiating new protein synthesis. Assembly of functional TC is inhibited by eIF2-P, which blocks eIF2B noncompetitively. In mammalian cells, the phosphorylation of eIF2 is a tightly regulated process. In addition to the four specialized eIF2 kinases that phosphorylate eIF2, two dedicated phosphatases antagonize this reaction. Both phosphatases contain a common catalytic core subunit, the protein phosphatase 1 (PP1), and a regulatory subunit (GADD34 or CReP), which render the phosphatase specific to eIF2. Structural and biophysical approaches have elucidated the mechanism of action of eIF2B and its modulation by ISR inhibitors and activators. Gene expression analyses have revealed complex ISR-driven reprogramming. Although it has been long recognized that, in the brain, long-term memory formation requires new protein synthesis, recent causal and convergent evidence across different species and model systems has shown that the ISR serves as a universal regulator of this process. Briefly, inhibition of the ISR enhances long-term memory formation, whereas activation of the ISR prevents it. Consistent with this notion, unbiased genome-wide association studies have identified mutations in key components of the ISR in humans with intellectual disability. Furthermore, age-related cognitive disorders are commonly associated with the activation of the ISR. Most notably, oxidative stress, misfolded proteins, and other stressors induce the ISR in several neurodegenerative disorders, including Alzheimer’s disease. Recent genetic and pharmacological evidence suggest that tuning the ISR reverses cognitive dysfunction as well as neurodegeneration in a wide range of memory disorders that result from protein homeostasis defects. Thus, long-term memory deficits may primarily results as a consequence of ISR activation rather than from the particular proteostasis defects that lead to its induction. Finally, the ISR is also implicated in the pathogenesis of a plethora of other complex diseases, including cancer, diabetes, and metabolic disorders. OUTLOOK: The ISR is emerging as a central regulator of protein homeostasis at both the cellular and organismal level. Mechanistically, much remains to be understood regarding additional inputs into the eIF2B-eIF2 regulatory hub controlling TC concentration, as well as the ISR’s connectivity to other intracellular signaling networks. As yet, little is known about the role of the specific proteins whose synthesis is altered during acute and persistent ISR activation and how these effectors collaborate to compute the life or death decisions cells make upon ISR activation. ISR gene expression signatures and functional consequences will need to be mapped across different tissues, cell types, and developmental stages. In addition, it will be invaluable to generate additional genetic and molecular tools that permit the direct temporal and spatial manipulation of ISR pathway in specific cells and circuits to determine their function. From a medical perspective, the ISR is implicated in the etiology of several disorders, and manipulation of the ISR is emerging as a promising therapeutic avenue for the treatment of a variety of diseases. The use of innovative mouse models, patient-derived induced pluripotent stem cells, and human organoids will greatly enhance our ability to explore the ISR’s clinical relevance further and help define therapeutic windows in which ISR modulation may prove beneficial. Identifying additional specific small-molecule inhibitors and activators of the ISR will offer valuable opportunities to dissect the role of the ISR pharmacologically in health and disease. Finally, discovery and mechanistic understanding of additional ISR modulators will increase the repertoire of therapeutic targets and may further enable clinical development in a wide range of age-related human diseases.