Interferon-induced, double-stranded RNA-activated protein kinase and other innate RNA sensors (PKR/RNA sensors)

Protein kinase R (PKR), formally known as Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2), is a key enzyme in the innate immune system that detects 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), which inhibits global protein synthesis and can induce apoptosis to prevent viral replication (PMID: 31515468). This target category also encompasses other innate RNA sensors, including RIG-I-like receptors (RIG-I, MDA5) and endosomal Toll-like receptors (TLR3, TLR7, TLR8), which recognize various RNA structures to trigger the production of type I interferons and pro-inflammatory cytokines (PMID: 28165509). These sensors are vital for antiviral defense, but their chronic activation is linked to autoimmune diseases, such as Aicardi-Goutières syndrome, and neurodegenerative conditions like Alzheimer's disease (PMID: 30212444). In oncology, agonists of these sensors are being developed to stimulate the immune system against tumors, while inhibitors are explored for treating inflammatory disorders (DrugBank DB06410). The complexity of these pathways presents challenges in achieving specificity and avoiding systemic toxicity, such as cytokine storms (PubMed: 31515468).

Other names

EIF2AK2Double-stranded RNA-activated protein kinaseRIG-I-like receptorsRLRsToll-like receptorsPattern recognition receptorsPRKR

Modulation of innate immune signaling through the detection of viral or endogenous RNA, leading to the production of Type I interferons and pro-inflammatory cytokines, or the regulation of protein translation via eIF2-alpha phosphorylation (PMID: 31515468).