Eukaryotic translation initiation factor 2 subunit alpha (eIF2-alpha) (EIF2S1)

Eukaryotic translation initiation factor 2 subunit alpha (EIF2S1), also known as eIF2-alpha, is a central regulator of protein synthesis initiation in eukaryotic cells (UniProt: P05198). It functions as part of the eIF2 heterotrimeric complex, which is responsible for delivering the initiator methionyl-tRNA to the 40S ribosomal subunit (PubMed: 16289705). The activity of EIF2S1 is primarily controlled by its phosphorylation at Serine 51 by a family of four kinases (PERK, PKR, GCN2, and HRI) in response to various cellular stresses, such as endoplasmic reticulum stress, viral infection, and nutrient deprivation (PubMed: 19131336). This phosphorylation event triggers the integrated stress response (ISR), which globally suppresses protein synthesis to conserve energy while selectively promoting the translation of stress-adaptive genes like ATF4 (PubMed: 33384352). Dysregulation of the EIF2S1-mediated ISR is implicated in a wide range of pathologies, including cancer, where it supports tumor survival under harsh conditions, and neurodegenerative diseases like Alzheimer's and Parkinson's, where chronic activation leads to neuronal dysfunction (PubMed: 36719671). Therapeutic strategies targeting this pathway include small molecules like Salubrinal and Sephin1, which inhibit the dephosphorylation of EIF2S1 to prolong the protective stress response, and ISRIB, which reverses the inhibitory effects of EIF2S1 phosphorylation to restore normal translation (Wikipedia; BioCentury).

Other names

eIF2-alphaeIF-2-alphaEIF2AEukaryotic translation initiation factor 2 subunit 1eIF-2A

Inhibition of eIF2-alpha dephosphorylation and modulation of the integrated stress response