RIG-like receptors (RLRs) are cytosolic sensors of viral RNA that respond to viral nucleic acids by inducing the production of the antiviral type I interferons. RLRs can recognize double-stranded and single-stranded RNA, which includes the genomes of RNA viruses and RNA transcripts of RNA and DNA viruses. The two best characterized RLRs are RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated gene 5). Both of these proteins contain two N-terminal caspase recruitment domains, which interact with other signaling proteins, and an RNA-helicase domain of unknown function. RIG-I and MDA5 display different specificities for viral RNA, partly based on length of double-stranded RNA genome, which may enhance sensitivity in detecting a wide range of viral double-stranded RNAs with heterogeneous lengths. RLRs also can discriminate viral single-stranded RNA from normal cellular single-stranded RNA transcripts. For example, RIG-I will only recognize RNA with a 5' triphosphate moiety, which is not present in mammalian host cell cytoplasmic RNA because of addition of a 7-methylguanosine cap or removal of the 5' triphosphate. RLRs are expressed in a wide variety of cell types, including bone marrow-derived leukocytes and various tissue cells. Therefore, these receptors enable the many cell types susceptible to infection by RNA viruses to participate in innate immune responses to these viruses.
On binding RNA, the RLRs initiate signaling events that lead to IRF3 and IRF7 activation, and these transcription factors induce production of type I interferons. In addition, RLR signaling can also activate NF-kB. Signaling of both RIG-I and MDA5 depends on their binding to adaptor proteins and activation of signaling cascades that lead to either IRF3/7 or NF-kB activation.
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