Retinoic acid-inducible gene I-like receptors and Protein kinase R (RLRs and PKR)

RIG-I-like receptors (RLRs) and Protein Kinase R (PKR) are the primary cytosolic sensors of double-stranded RNA (dsRNA), serving as critical components of the innate immune system's defense against viral pathogens. The RLR family, comprising RIG-I (DDX58), MDA5 (IFIH1), and LGP2 (DHX58), functions as RNA helicases that detect non-self RNA signatures, such as 5'-triphosphorylated or long dsRNA, and initiate signaling through the mitochondrial antiviral-signaling protein (MAVS) to produce type I interferons. Concurrently, PKR (EIF2AK2) is a dsRNA-dependent serine/threonine kinase that, upon activation, phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α), leading to a rapid inhibition of protein translation to halt viral replication. These pathways are increasingly targeted in oncology and virology, where agonists like Poly(I:C) or specific RIG-I ligands are used to stimulate immune surveillance against tumors or chronic infections. However, the therapeutic modulation of these sensors carries risks of excessive inflammation or "cytokine storms," requiring precise control over their activation. Collectively, these sensors coordinate the cellular response to nucleic acid threats by integrating transcriptional induction of defenses with the physical shutdown of the protein synthesis machinery.

Other names

Retinoic acid-inducible gene I-like receptors and Eukaryotic translation initiation factor 2-alpha kinase 2RLRs and PKRCytosolic dsRNA sensorsDDX58, IFIH1, and EIF2AK2

Activation of RIG-I-like receptors (RIG-I, MDA5) and Protein kinase R (PKR) by double-stranded RNA (dsRNA) triggers innate immune signaling. RLRs signal through MAVS to induce type I interferons and pro-inflammatory cytokines, while PKR phosphorylates eIF2alpha to inhibit protein synthesis, collectively establishing an antiviral state and promoting anti-tumor immunity.