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

Interferon-induced, double-stranded RNA-activated protein kinase (PKR), encoded by the EIF2AK2 gene, is a key component of the innate immune system that senses viral infection through the detection of double-stranded RNA (dsRNA) (UniProt P19544). Upon activation by dsRNA, PKR undergoes autophosphorylation and subsequently phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2-alpha), leading to a global inhibition of protein synthesis and induction of apoptosis to limit viral spread (PubMed: 19188498). Beyond its antiviral role, PKR is involved in regulating various signaling pathways related to inflammation, such as the NLRP3 inflammasome, and cell survival, making it a significant factor in the pathogenesis of neurodegenerative diseases like Alzheimer's and various cancers (PubMed: 30635117, PubMed: 23233724). In oncology, PKR can act as either a tumor suppressor or a pro-survival factor depending on the context, and therapeutic strategies involve both the activation of PKR to induce tumor cell death and its inhibition to alleviate neuroinflammation or metabolic stress (PubMed: 19188498). Current drug development efforts focus on small-molecule inhibitors to treat neurodegeneration and metabolic disorders, though maintaining the balance of its essential immune functions remains a primary challenge (PubMed: 30635117).

Other names

Eukaryotic translation initiation factor 2-alpha kinase 2EIF2AK2PRKRp68 kinaseProtein kinase RNA-activatedInterferon-inducible RNA-dependent protein kinase

PKR inhibitors typically bind to the ATP-binding pocket of the kinase domain, preventing the phosphorylation of its primary substrate, the alpha subunit of eukaryotic initiation factor 2 (eIF2-alpha), thereby maintaining protein synthesis and preventing apoptosis or inflammatory signaling (PubMed: 30635117, PubChem CID 16722836).