RIG-I-like receptors evolved adaptively in mammals, with parallel evolution at LGP2 and RIG-I

Rachele Cagliani, Diego Forni, Claudia Tresoldi, Uberto Pozzoli, Giulia Filippi, Veronica Rainone, Luca De Gioia, Mario Clerici, Manuela Sironi

Research output: Contribution to journalArticlepeer-review


RIG-I-like receptors (RLRs) are nucleic acid sensors that activate antiviral innate immune response. These molecules recognize diverse non-self RNA substrates and are antagonized by several viral inhibitors. We performed an evolutionary analysis of RLR genes (RIG-I, MDA5, and LGP2) in mammals. Results indicated that purifying selection had a dominant role in driving the evolution of RLRs. However, application of maximum-likelihood analyses identified several positions that evolved adaptively. Positively selected sites are located in all domains of MDA5 and RIG-I, whereas in LGP2 they are confined to the helicase domain. In both MDA5 and RIG-I, the linkers separating the caspase activation and recruitment domain and the helicase domain represented preferential targets of positive selection. Independent selective events in RIG-I and LGP2 targeted the corresponding site (Asp421 and Asp179, respectively) within a protruding α-helix that grips the V-shaped structure formed by the pincer. Most of the positively selected sites in MDA5 are in regions unique to this RLR, including a characteristic insertion within the helicase domain. Additional selected sites are located at the contact interface between MDA5 monomers, in spatial proximity to a positively selected human polymorphism (Arg843His) and immediately external to the parainfluenza virus 5 V protein binding region. Structural analyses suggested that the positively selected His834 residue is involved in parainfluenza virus 5 V protein binding. Data herein suggest that RLRs have been engaged in host-virus genetic conflict leading to diversifying selection and indicate parallel evolution at the same site in RIG-I and LGP2, a position likely to be of central importance in antiviral responses.

Original languageEnglish
Pages (from-to)1351-1365
Number of pages15
JournalJournal of Molecular Biology
Issue number6
Publication statusPublished - Mar 20 2014


  • LGP2
  • MDA5
  • positive selection
  • RIG-I
  • RIG-I-like receptors

ASJC Scopus subject areas

  • Molecular Biology

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