Protein kinase R–eukaryotic initiation factor 2 alpha (PKR–eIF2α) antiviral pathway (PKR–eIF2α pathway)

The Protein kinase R–eukaryotic initiation factor 2 alpha (PKR–eIF2α) antiviral pathway is a central component of the mammalian innate immune response and the Integrated Stress Response (ISR). This pathway is primarily mediated by PKR (encoded by the EIF2AK2 gene), an interferon-stimulated enzyme that acts as a molecular sensor for double-stranded RNA (dsRNA), a common signature of viral infection (Garcia et al., 2006, Microbiol Mol Biol Rev). Upon binding dsRNA, PKR undergoes activation and phosphorylates the alpha subunit of eIF2 (EIF2S1), which leads to the sequestration of the guanine nucleotide exchange factor eIF2B and a subsequent halt in global protein synthesis, effectively blocking viral replication (Donnelly et al., 2013, J Cell Biol). Beyond its antiviral role, chronic activation of this pathway is implicated in neurodegenerative diseases like Alzheimer's and Parkinson's, where persistent translation inhibition contributes to synaptic loss and neuronal death (Moon et al., 2023, Int J Mol Sci). Conversely, in oncology, the pathway can act as a tumor suppressor by inducing apoptosis in stressed cells, though some cancers exploit it to survive proteotoxic stress. Therapeutic interventions include PKR inhibitors like C16 and small molecules like ISRIB, which can bypass the effects of eIF2α phosphorylation to restore protein synthesis in diseased states (Sidrauski et al., 2013, eLife).

Other names

EIF2AK2-EIF2S1 axisPKR-eIF2-alpha signalingInterferon-induced PKR pathwayIntegrated Stress Response (ISR)Protein kinase RNA-activated pathway

The pathway is activated when PKR binds to viral double-stranded RNA, triggering its dimerization and autophosphorylation. Active PKR then phosphorylates the alpha subunit of eIF2 at Ser51, which converts eIF2 from a substrate to a competitive inhibitor of the guanine nucleotide exchange factor eIF2B, thereby suppressing the initiation of mRNA translation and inhibiting viral replication (Garcia et al., 2006, Microbiol Mol Biol Rev; Donnelly et al., 2013, J Cell Biol).