Eukaryotic translation initiation factor 2-alpha kinase 2 (PKR)–eukaryotic translation initiation factor 2 subunit 1 (eIF2α) signaling pathway (PKR–eIF2α pathway)

The Eukaryotic translation initiation factor 2-alpha kinase 2 (PKR)–eukaryotic translation initiation factor 2 subunit 1 (eIF2α) signaling pathway is a central axis of the mammalian innate immune response and the integrated stress response (ISR). PKR is a serine/threonine kinase that functions as a pattern recognition receptor, activated by double-stranded RNA (dsRNA) produced during viral replication (Gale Jr et al., 2000). Upon activation, PKR phosphorylates eIF2α at the Ser51 residue, which transforms eIF2 into a potent inhibitor of the guanine nucleotide exchange factor eIF2B (Dever, 2002; Sudhakar et al., 2000). This inhibition prevents the regeneration of active eIF2-GTP, leading to a rapid suppression of global protein synthesis and the induction of stress granules to halt viral protein production (Sudhakar et al., 2000). While essential for antiviral defense, chronic activation of this pathway is linked to neurodegenerative conditions, such as Alzheimer's disease, where it drives neuronal apoptosis and cognitive decline (Chang et al., 2002; Hugon et al., 2009). Therapeutic strategies targeting this pathway include small-molecule PKR inhibitors like C16 and ISR modulators like ISRIB, which aim to restore translational homeostasis in disease states (Zhang et al., 2016).

Other names

PKR-eIF2a axisEIF2AK2-EIF2S1 pathwaydsRNA-dependent protein kinase pathwayPKR–eIF2α antiviral stress-response pathwayIntegrated stress response (ISR) pathway

Activation of PKR by double-stranded RNA leads to its autophosphorylation and subsequent phosphorylation of eIF2α at Ser51, which inhibits the eIF2B-mediated exchange of GDP for GTP, thereby suppressing global translation initiation.