Integrated Stress Response (ISR)
DEIntegrierte Stressantwort (ISR)
The integrated stress response (ISR) is a built-in alarm system your cells use to cope with trouble. No matter the threat, it funnels down to one move: switching off a key protein (eIF2α) by tagging it with a phosphate. Four different sensor enzymes can pull this trigger, each watching for a different problem. HRI watches for low heme, PKR for viral double-stranded RNA, PERK for misfolded proteins in the ER, and GCN2 for amino-acid shortage. Once eIF2α is tagged, the cell broadly halts normal protein-making to save resources, but it actually boosts a few stress-response proteins, especially ATF4, which directs the cleanup. Short-term, the ISR is protective. But when it stays on too long (as in neurodegeneration, obesity, and aging), it hurts memory, synapse flexibility, and the cell's ability to make proteins. Experimental drugs like ISRIB can switch the brake back off (by restoring a downstream factor called eIF2B) and improve memory and decline in animal models.
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Sources
- Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. (2016). The integrated stress response. *EMBO Reports*doi:10.15252/embr.201642195
- Novoa I, Zhang Y, Zeng H, Jungreis R, Harding HP, Ron D. (2003). Stress-induced gene expression requires programmed recovery from translational repression. *EMBO Journal*doi:10.1093/emboj/cdg112