Retinoic acid-inducible gene I-like receptors (RLRs)

Melanoma differentiation-associated protein 5 (MDA5) and Retinoic acid-inducible gene I (RIG-I) are the primary members of the RIG-I-like receptor (RLR) family, serving as essential cytoplasmic sensors for viral RNA (UniProt O95786, Q9BYX4). RIG-I is characterized by its ability to detect short double-stranded RNA (dsRNA) with 5-triphosphate or diphosphate motifs, while MDA5 recognizes long dsRNA structures (PubMed: 29437594). Upon ligand binding, these receptors interact with the Mitochondrial Antiviral-Signaling protein (MAVS) on the outer mitochondrial membrane, initiating a signaling cascade that activates IRF3, IRF7, and NF-kappaB (PubMed: 31006573). This activation results in the robust induction of Type I interferons and pro-inflammatory cytokines, which are vital for the innate antiviral response and the priming of adaptive immunity. In clinical development, RLR agonists like BO-112 and MK-4621 are being explored as intratumoral therapies to enhance anti-tumor immune responses and overcome resistance to PD-1/PD-L1 inhibitors (PubMed: 32661152). Conversely, dysregulated RLR signaling or gain-of-function mutations in the IFIH1 gene (encoding MDA5) are implicated in the pathogenesis of autoimmune interferonopathies, such as Aicardi-Goutieres syndrome and systemic lupus erythematosus (PubMed: 24562110).

Other names

RIG-I-like receptorsRLRsRIG-I-like helicasesDDX58IFIH1Melanoma differentiation-associated protein 5Retinoic acid-inducible gene IInterferon-induced helicase C domain-containing protein 1Probable ATP-dependent RNA helicase DDX58

Agonism of RIG-I and MDA5 triggers MAVS-dependent signaling, leading to the production of Type I interferons and pro-inflammatory cytokines to stimulate innate and adaptive immunity (PubMed: 31006573).