Protein kinase R–eukaryotic translation initiation factor 2 alpha–protein phosphatase 1 pathway (PKR–eIF-2α–PP1 pathway)

The PKR–eIF-2α–PP1 pathway is a central regulatory axis of the integrated stress response (ISR) that controls protein synthesis in eukaryotic cells [1, 8]. Protein kinase R (PKR), an interferon-induced enzyme, is activated by double-stranded RNA or other cellular stressors, leading to the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2α) at Ser51 [1, 4, 6]. This phosphorylation event prevents the formation of the eIF2-GTP-Met-tRNAi ternary complex, thereby inhibiting global mRNA translation and promoting the translation of specific stress-responsive mRNAs like ATF4 [8, 9]. To terminate the stress response and restore homeostasis, protein phosphatase 1 (PP1) associates with regulatory subunits such as GADD34 (PPP1R15A) to dephosphorylate eIF-2α [2, 5, 11]. Dysregulation of this pathway is implicated in various diseases, including viral infections, neurodegenerative disorders like Alzheimer's and ALS, and certain cancers [1, 3, 10]. Therapeutic strategies involve either inhibiting PKR to prevent translation arrest in neurodegeneration or inhibiting the PP1-GADD34 complex with drugs like Sephin1 to prolong the protective effects of the stress response [5, 10].

Other names

PKR-eIF2α axisPKR-eIF2α-GADD34 pathwayIntegrated stress response (PKR branch)EIF2AK2-EIF2S1-PPP1R15A axis

Modulation of eIF-2α phosphorylation levels through inhibition of PKR (to prevent translation arrest) or inhibition of the PP1-GADD34 phosphatase complex (to prolong translation arrest and enhance proteostasis).