Eukaryotic translation initiation factor 2 subunit alpha (eIF2α) phosphorylation pathway (ISR)

The host eIF2α phosphorylation pathway is a central arm of the Integrated Stress Response (ISR), a signaling network that allows eukaryotic cells to adapt to various environmental and physiological stresses (Costa-Mattioli & Walter, 2020). The pathway is activated when one of four specialized kinases—PERK (ER stress), PKR (viral double-stranded RNA), GCN2 (amino acid starvation), or HRI (heme deficiency)—phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) at Serine 51 (Pakos-Zebrucka et al., 2016). This phosphorylation event transforms eIF2 into a competitive inhibitor of its dedicated guanine nucleotide exchange factor, eIF2B, leading to a global reduction in protein synthesis while paradoxically enhancing the translation of specific stress-responsive mRNAs like ATF4. In the context of infection, many viruses have evolved mechanisms to either trigger or evade this pathway to facilitate their own replication, making the host ISR a critical interface for antiviral defense (Walsh et al., 2013). Chronic activation of this pathway is also a major driver of neuronal loss in neurodegenerative diseases, where sustained translational repression leads to synaptic failure (Moreno et al., 2012). Consequently, small molecules like ISRIB, which stabilizes eIF2B, or Sephin1, which inhibits the eIF2α phosphatase complex, are being investigated for their ability to restore proteostasis and provide neuroprotection or antiviral effects.

Other names

Integrated Stress ResponseeIF2α-P pathwayeIF2 signaling pathwayeIF2α-ATF4 signaling axis

Modulation of the Integrated Stress Response (ISR) through either the inhibition of eIF2α kinases (e.g., PERK, GCN2), the inhibition of the eIF2α-specific phosphatase complex (GADD34-PP1), or the stabilization of the eIF2B decamer to bypass the inhibitory effects of phosphorylated eIF2α (Costa-Mattioli & Walter, 2020).