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Integrated Stress Response  Integrated Stress Response

In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis (1).

The ISR can be stimulated by a range of physiological or pathological stimuli including hypoxia, amino acid deprivation, glucose/nutrition deprivation, viral infection and intrinsic endoplasmic reticulum (ER) stress (3).

Integrated stress response signaling (1)

ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2α, the core of ISR. This leads to global attenuation of Cap‐dependent translation while concomitantly initiates the preferential translation of ISR‐specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. It forms homo‐ and heterodimers that bind to DNA targets to control the expression of genes involved in cellular adaptation. Termination of the ISR is regulated by the constitutively expressed CReP and stress‐inducible phosphatase GADD34 that dephosphorylate eIF2α. For more details, see main text and Table 1. Arrows denote activation or induction, while blunt lines indicate inhibition.

Integrated Stress Response  ISR and diseases

The ISR system plays an important part in the pathophysiology of several disorders such as cancer, cardiovascular system, and neurodegeneration (schizophrenia, amyotrophic lateral sclerosis, head or other nerve trauma) (2,4).
Recent studies have shown that ISR activation by salubrinal up-regulates ATF4-modulated gene expression, increases GSH synthesis, and decreases cisplatin-induced oxidative damage, which contribute to cisplatin resistance in gastric cancer cells (5).
The integrated stress response (ISR) is a cytoprotective mechanism induced in CNS injuries. Preliminary results indicate that the enhancement of the ISR pathway is a promising therapeutic target for CNS injuries (6).
(1) Pakos-Zebrucka K & al. The integrated stress response.. EMBO Rep. (2016); 17(10):1374-1395.
(2) Santos-Ribeiro D & al. The integrated stress response system in cardiovascular disease. Drug Discov Today. (2018); 23(4):920-929.
(3) Wang C & al. Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia. Elife. (2018) 19;7.
(4) Pavitt GD. Regulation of translation initiation factor eIF2B at the hub of the integrated stress response. Wiley Interdiscip Rev RNA. (2018);9(6).
(5) Wang SF & al. Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis. Int J Mol Sci. (2018) 29;19(11).
(6)  Romero-Ramírez L& al. Integrated Stress Response as a Therapeutic Target for CNS Injuries. Biomed Res Int. (2017):6953156.
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