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What is the integrated stress response?

The integrated stress response (ISR) is an elaborate signaling pathway present in eukaryotic cells, which is activated in response to a range of physiological changes and different pathological conditions 1, 2, 3, 4, 5.

What is the cellular stress response?

Cellular stress response is a reaction to changes or fluctuations of extracellular conditions that damage the structure and function of macromolecules.

What is the mechanism of Isrib?

To determine ISRIBs mechanism of action, we solved an atomic structure of ISRIB bound to the human eIF2B decamer. We found that ISRIB acts as a molecular staple, pinning together tetrameric subcomplexes of eIF2B along the assembly path to a fully active, decameric enzyme.

What is the integrated response in biology?

The integrated stress response (ISR) is an evolutionarily conserved homeostatic program activated by specific pathological states. These include amino acid deprivation, viral infection, iron deficiency, and the misfolding of proteins within the endoplasmic reticulum (ER), the so-called ER stress.

What is the role of ATF4 in the ISR?

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 eIF2.

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