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

The Protein kinase R–eukaryotic initiation factor 2 alpha (PKR–eIF2α) pathway is a fundamental signaling axis within the integrated stress response (ISR) that regulates protein synthesis in eukaryotic cells (UniProt P19544, P05198). The pathway is primarily initiated by the activation of PKR, a pro-inflammatory and antiviral kinase that senses double-stranded RNA or cellular stress signals. Once activated, PKR phosphorylates the alpha subunit of eIF2 at Serine 51, which converts eIF2 into a potent inhibitor of its guanine nucleotide exchange factor, eIF2B. This molecular switch results in a rapid decline in global cap-dependent translation, effectively halting the production of most cellular and viral proteins. However, this inhibition selectively allows for the translation of specific stress-response mRNAs, such as ATF4, which mediate cellular adaptation or apoptosis. Chronic or dysregulated activation of the PKR–eIF2α pathway is a hallmark of several neurodegenerative conditions, including Alzheimer’s and Parkinson’s diseases, where it contributes to synaptic dysfunction and neuronal loss (PubMed 23661643). Conversely, the pathway is a critical component of the innate immune response against viral pathogens. Therapeutic modulation of this axis, through PKR inhibitors or ISR modulators like ISRIB, represents a promising strategy for restoring proteostasis in neurodegeneration or enhancing cell survival in various stress-related pathologies (Science 2013).

Other names

PKR-eIF2 signaling axisEIF2AK2-EIF2S1 pathwayIntegrated Stress Response (PKR branch)eIF2α phosphorylation pathway

Inhibition of PKR kinase activity, inhibition of eIF2α dephosphorylation, or activation of eIF2B to bypass the inhibitory effects of eIF2α phosphorylation.