Retinoic acid-inducible gene I, Melanoma differentiation-associated protein 5, and Protein kinase RNA-activated (RIG-I / MDA5 / PKR)

RIG-I (Retinoic acid-inducible gene I), MDA5 (Melanoma differentiation-associated protein 5), and PKR (Protein kinase RNA-activated) are essential cytosolic pattern recognition receptors that detect double-stranded RNA (dsRNA), a common signature of viral infection [1][2]. RIG-I and MDA5 are DExD/H-box RNA helicases that, upon binding to specific RNA ligands (short 5'-triphosphate dsRNA for RIG-I and long dsRNA for MDA5), undergo conformational changes and aggregate with the mitochondrial antiviral-signaling protein (MAVS) to initiate a signaling cascade resulting in the production of Type I interferons and pro-inflammatory cytokines [2][3]. PKR is a serine/threonine kinase that, when activated by dsRNA, phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2-alpha), leading to a global inhibition of protein synthesis to halt viral replication and potentially induce apoptosis [4]. In therapeutic contexts, these molecules are targeted by agonists to enhance the immunogenicity of the tumor microenvironment in cancer immunotherapy or to provide broad-spectrum antiviral protection [5]. However, dysregulation of these sensors is linked to autoimmune conditions, such as Aicardi-Goutieres syndrome, where the immune system inappropriately reacts to endogenous nucleic acids [1][3].

Other names

DDX58IFIH1EIF2AK2RIG-I-like receptorsRLRsInterferon-induced double-stranded RNA-activated protein kinaseCytosolic RNA sensors

Activation of RIG-I and MDA5 triggers the MAVS signaling adapter to induce Type I interferons and pro-inflammatory cytokines; activation of PKR leads to phosphorylation of eIF2-alpha, inhibiting mRNA translation and viral replication.