Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5

Brisse, Morgan; Ly, Hinh

RIG-I (357) and MDA5 (357, 358) are known to influence antiviral signaling in zebrafish (Danio rerio) and other fish species (357, (359) (360) (361) through the canonical MAVS signaling pathway. Fish RIG-I like receptors (RLRs) have been shown to be regulated by the expression of alternate splicing isoforms (358, 362) , which have also been found to occur with a dominant-negative splice variant of the human RIG-I (363). RIG-I and MDA5 have also been found to participate in anti-viral signaling in ducks (364) (365) (366) (367) and geese (340, 368, 369) , and MDA5 alone in chickens (370) (371) (372) and other birds (373) . The observation across species of RLR's performing compensatory mechanisms when a function or a pathway protein is absent is reiterated in birds, as MDA5 has been found to sense short and long dsRNA in chickens (372) and in the Chinese shrew (374) , both of which lack RIG-I. Additionally, TRIM25 activates RIG-I in ducks (364) and in the Chinese goose (375) in the absence of the K172 activating ubiquitin binding site that is conserved in primates and some rodents (364) . Finally, the rainbow trout (Oncorhynchus mykiss) has been found to express a LGP2 variant in addition to the canonical LGP2 that contains an incomplete C-terminal domain of RIG-I (376). The differential presence of PRRs may also influence viral evolution. A mutation in the IAV polymerase subunit PB2 found in avian-adapted H1N1 strains decreases the inhibition of human RIG-I function by IAV nucleoproteins, which may indicate a differential selective pressure for viruses that propagate in species that don't contain RIG-I (377) . The evolutionary pattern and compensatory mechanisms of RLRs across species implicate them as critical for anti-viral function, and that evolutionary forces drive the available pathway proteins to meet these functional needs. Future studies need to be done to further differentiate RLR function among the different species, as this will provide critical information concerning the various methods of disease control by targeting the pathogen by these important host proteins.