title: RIG-I-like receptors evolved adaptively in mammals, with parallel evolution at LGP2 and RIG-I.
abstract: 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.
authors.affiliation: Scientific Institute, IRCCS Eugenio Medea, 23842 Bosisio Parini LC, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.affiliation: Scientific Institute, IRCCS Eugenio Medea, 23842 Bosisio Parini LC, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.affiliation: Scientific Institute, IRCCS Eugenio Medea, 23842 Bosisio Parini LC, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Tresoldi
authors.affiliation: Scientific Institute, IRCCS Eugenio Medea, 23842 Bosisio Parini LC, Italy.
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan Bicocca, 20126 Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Filippi
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, 20100 Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Rainone
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan Bicocca, 20126 Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: De Gioia
authors.affiliation: Department of Physiopathology and Transplantation, University of Milan, 20100 Milan, Italy; Don C. Gnocchi ONLUS Foundation, IRCCS, 20100 Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.affiliation: Scientific Institute, IRCCS Eugenio Medea, 23842 Bosisio Parini LC, Italy. Electronic address: manuela.sironi@bp.lnf.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology*; D019143:Evolution, Molecular; D054884:Host-Pathogen Interactions; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D008322:Mammals; D008969:Molecular Sequence Data; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D020365:RNA Helicases / Q000235:genetics / Q000276:immunology; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000276:immunology*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000276:immunology; D017386:Sequence Homology, Amino Acid
chemical_list: C437968:PLAAT4 protein, human; D051192:Receptors, Pattern Recognition; D018168:Receptors, Retinoic Acid; C520569:DHX58 protein, human; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D020365:RNA Helicases
keywords: LGP2; MDA5; RIG-I; RIG-I-like receptors; positive selection