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

Brisse, Morgan; Ly, Hinh

The presence of certain repetitive RNA elements appears to be another contributing factor in determining interaction of RNA with RIG-I and MDA5, which has recently been described in detail elsewhere (187) . While RIG-I and MDA5 are mostly implicated in the immune response to RNA viruses, it has also been found to be activated by 5 ′ tri-phosphorylated dsRNA intermediates generated by cellular RNA polymerase III from AT-rich DNA sequences (188) and during infection with Epstein-Barr virus (a DNA virus) (189) . RIG-I has additional binding preferences for certain nucleotide motifs, such as uridine-rich 5 ′ tri-phosphorylated hairpin RNA (190) , synthetic AU-rich hairpins (191) and those naturally found in the genomes of Sendai virus defective-interfering (DI) particles (192) , measles (193) , Influenza A virus (IAV) (194) and in KSHV RNA transcripts (195) , and poly (U/UC) regions (196) and poly (A/AG) regions (197) in the antisense Hepatitis C virus (HCV) genome. It is of particular interest that the poly (A/AG) HCV regions are located significantly downstream of the 5 ′ triphosphate group (197) , thus potentially implicating other parts of RIG-I (e.g., helicase domain) as potential RNA interacting domains. Repetitive RNA elements may also be important in allowing for interaction of inhibitory RNAs that do not have 5 ′ or 3 ′ features needed for full activation of RIG-I, as has been shown to be the case with GA-rich regions in circular longnon-coding RNA lnc-Lsm3b (198) . These specific interactions explain their primary role as anti-viral receptors, as these viral motifs are mostly not found in cellular RNAs (199) .