Interferon-induced, double-stranded RNA-activated protein kinase (PKR)

Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2), commonly known as Protein Kinase R (PKR), is a critical enzyme that acts as a sensor for viral infection and cellular stress. Upon activation by double-stranded RNA (dsRNA) or other stress signals, EIF2AK2 undergoes autophosphorylation and subsequently phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2-alpha), leading to a global inhibition of protein synthesis. This process is a hallmark of the innate immune response, designed to restrict viral replication and promote apoptosis in infected cells. Beyond its role in immunity, EIF2AK2 is a key regulator of the integrated stress response (ISR) and modulates various signaling pathways, including NF-kappaB and JNK. Dysregulation of EIF2AK2 is associated with a wide range of pathologies, including viral infections, cancers, and neurodegenerative diseases such as Alzheimer's and EIF2AK2-related dystonia (DYT33). While the protein is the primary functional entity, EIF2AK2 mRNA is also a target for therapeutic intervention using RNA interference (RNAi) or antisense oligonucleotides to modulate protein expression levels in specific disease states. Current pharmacological strategies focus on small molecule inhibitors of its kinase activity or dimerization to treat inflammatory and metabolic disorders. Safety concerns regarding PKR inhibition include potential immunosuppression and impaired defense against viruses, as well as possible neurological side effects given its role in synaptic plasticity.

Other names

Protein kinase RPRKREIF2AK2Eukaryotic translation initiation factor 2-alpha kinase 2p68 kinaseDYT33

Inhibition of kinase activity or dimerization to prevent eIF2-alpha phosphorylation and restore protein synthesis or modulate inflammatory signaling.