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Updated: Jun 28, 2026

Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Evolution of MDA-5/RIG-I-dependent innate immunity: independent evolution by domain grafting
Devanand Sarkar1, Rob Desalle, Paul B Fisher
1Department of Human and Molecular Genetics, Institute of Molecular Medicine, Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA. dsarkar@vcu.edu
Abstract:
Type I Interferons (IFNs) are requisite components in antiviral innate immunity. Classically, a Toll-like receptor-dependent pathway induces type I interferons. However, recent recognition of melanoma differentiation associated gene-5 (MDA-5) and retinoic acid inducible gene-I (RIG-I) as primary sensors of RNA viruses for type I interferon induction highlights a potentially unique pathway for innate immunity. Our present investigation tracing the phylogenetic origin of MDA-5 and RIG-I domain arrangement (CARD1-CARD2-helicase-DEAD/DEAH) indicates that these proteins originated specifically in mammals, firmly linking this family of proteins with interferons in a highly derived evolutionary development of innate immunity. MDA-5, but not RIG-I, orthologs are found in fish, indicating that MDA-5 might have evolved before RIG-I. Our analyses also reveal that the MDA-5 and RIG-I domain arrangement evolved independently by domain grafting and not by a simple gene-duplication event of the entire four-domain arrangement, which may have been initiated by differential sensitivity of these proteins to viral infection.
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