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

Retinoic acid-inducible gene I (RIG-I) and Melanoma differentiation-associated protein 5 (MDA5) are essential cytosolic pattern recognition receptors (PRRs) that belong to the RIG-I-like receptor (RLR) family (UniProt O95786, Q9BYX4). These proteins function as sensors for viral double-stranded RNA (dsRNA), with RIG-I primarily detecting shorter 5-triphosphorylated or diphosphorylated dsRNA and MDA5 recognizing long dsRNA structures (Rehwinkel & Gack, 2020). Upon activation, they undergo a conformational change that allows them to interact with the mitochondrial antiviral-signaling protein (MAVS), initiating a signaling cascade that induces the expression of Type I interferons (IFNs) and pro-inflammatory cytokines. This pathway is critical for the innate immune response against a wide range of RNA viruses, including influenza, hepatitis C, and SARS-CoV-2. In clinical development, RIG-I and MDA5 are targeted by small molecule and nucleic acid agonists to treat chronic viral infections and to enhance the immunogenicity of the tumor microenvironment in cancer therapy (e.g., Inarigivir, RGT100). However, dysregulation or over-activation of these receptors is linked to autoimmune conditions such as Aicardi-Goutières syndrome and systemic lupus erythematosus (Loo & Gale, 2011). Therapeutic challenges include the risk of systemic cytokine release and the need for precise delivery to avoid off-target inflammatory responses.

Other names

DDX58IFIH1RIG-I-like receptorsRLRsDExD/H-box helicase 58Interferon induced with helicase C domain 1Melanoma differentiation-associated gene 5

Agonism of the RIG-I and MDA5 receptors triggers the MAVS-dependent signaling pathway, leading to the activation of IRF3/7 and NF-kappaB transcription factors, which subsequently induce the production of Type I and III interferons and pro-inflammatory cytokines to stimulate an antiviral or antitumor immune response.