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Mammalian integrated stress responses in stressed organelles and their functions

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

The integrated stress response (ISR) triggered in response to various cellular stress enables mammalian cells to effectively cope with diverse stressful conditions while maintaining their normal functions. Four kinases (PERK, PKR, GCN2, and HRI) of ISR regulate ISR signaling and intracellular protein translation via mediating the phosphorylation of eukaryotic translation initiation factor 2 α (eIF2α) at Ser51. Early ISR creates an opportunity for cells to repair themselves and restore homeostasis. This effect, however, is reversed in the late stages of ISR. Currently, some studies have shown the non-negligible impact of ISR on diseases such as ischemic diseases, cognitive impairment, metabolic syndrome, cancer, vanishing white matter, etc. Hence, artificial regulation of ISR and its signaling with ISR modulators becomes a promising therapeutic strategy for relieving disease symptoms and improving clinical outcomes. Here, we provide an overview of the essential mechanisms of ISR and describe the ISR-related pathways in organelles including mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. Meanwhile, the regulatory effects of ISR modulators and their potential application in various diseases are also enumerated.

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Fig. 1: PERK, GCN2, PKR, HRI are the four kinases of ISR.
Fig. 2: The eIF2B-mediated ternary complex (TC) cycle and PP1-mediated negative feedback regulatory pathway.
Fig. 3: Translation translocation of ATF4 under ISR regulation.
Fig. 4: Interaction between ISR and mTORC1.
Fig. 5: Integrated stress responses within various organelles, including the endoplasmic reticulum (ER), mitochondria (MT), Golgi apparatus (GA), and lysosome (LYS).
Fig. 6: ISR modulators in diseases.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 82173811, 81973315), Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003), Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD) and Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases.

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  1. Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences of Soochow University, Suzhou, 215123, China

    Hao-jun Lu, Nirmala Koju & Rui Sheng

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  1. Hao-jun Lu
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  2. Nirmala Koju
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  3. Rui Sheng
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Correspondence to Rui Sheng.

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Lu, Hj., Koju, N. & Sheng, R. Mammalian integrated stress responses in stressed organelles and their functions. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-023-01225-0

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