Retinoic acid-inducible gene I and Melanoma differentiation-associated protein 5 (RIG-I/MDA5)

Retinoic acid-inducible gene I (RIG-I) and Melanoma differentiation-associated protein 5 (MDA5) are essential cytosolic pattern recognition receptors (PRRs) within the RIG-I-like receptor (RLR) family [1, 2]. They function as primary sensors for viral RNA, with RIG-I specializing in short double-stranded RNA (dsRNA) containing 5'-triphosphate or 5'-diphosphate groups, and MDA5 detecting long dsRNA structures [9, 14]. Upon activation by these ligands, the receptors signal through the mitochondrial antiviral-signaling (MAVS) protein to induce the expression of Type I interferons and various pro-inflammatory cytokines [2, 11]. This pathway is a critical component of the innate immune response, providing a first line of defense against viral infections and contributing to the activation of adaptive immunity [10, 13]. In the context of drug development, RIG-I and MDA5 are targeted by synthetic RNA agonists to serve as vaccine adjuvants or to stimulate anti-tumor immunity in oncology [3, 5]. However, inappropriate activation of these receptors is associated with several autoimmune and inflammatory conditions, including Aicardi-Goutières syndrome and Singleton-Merten syndrome, highlighting the need for precise therapeutic modulation [1, 11].

Other names

DDX58IFIH1RIG-I-like receptorsRLRsHelicardCADM-140 autoantigenClinically amyopathic dermatomyositis autoantigen 140 kDa

Agonism of the RIG-I-like receptor pathway to stimulate the production of Type I interferons and pro-inflammatory cytokines, thereby enhancing antiviral and anti-tumor immune responses.