RIG-I-Like Receptors Evolved Adaptively in Mammals, with Parallel Evolution at LGP2 and RIG-I

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• 作者：Rachele Cagliani¹ ; ^&dagger ; ; Diego Forni¹ ; ^&dagger ; ; Claudia Tresoldi¹ ; Uberto Pozzoli¹ ; Giulia Filippi² ; Veronica Rainone³ ; Luca De Gioia² ; Mario Clerici⁴ ; ⁵ ; Manuela Sironi¹ ; ^{manuela.sironi@bp.lnf.it" class="auth_mail}
• 关键词：RLR ; RIG-I-like receptor ; PRR ; pattern recognition receptor ; PAML ; phylogenetic analysis by maximum likelihood ; BS-REL ; branch site-random effects likelihood ; MEME ; mixed effects model of evolution ; BEB ; Bayes empirical Bayes ; SLAC ; single-likelihood ancestor counting ; GARD ; genetic algorithm recombination detection ; FDR ; false discovery rate ; CTD ; C-terminal regulatory domain ; CARD ; caspase activation and recruitment domain ; PIV5 ; parainfluenza virus 5 V protein ; dsRNA ; double-stranded RNA ; 3D
• 刊名：Journal of Molecular Biology
• 出版年：20 March, 2014
• 年：2014
• 卷：426
• 期：6
• 页码：1351-1365
• 全文大小：2617 K

文摘

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 伪-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.