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

Brisse, Morgan; Ly, Hinh

Copy-back RNA motifs specifically seem to be important for RLR activation in that they tend to contain hairpin motifs and 5 ′ tri-phosphate groups, as has been found for Sendai (204) (205) (206) , measles (35, 207), and chikungunya (35) DVG RNAs in activating RIG-I. In the case of IAV, DVG RNAs might even be more potent activators of RIG-I than the full-length viral genome. Cells that were blocked from viral protein synthesis experienced RIG-I mediated IFN1 expression when infected with IAV stocks grown in chicken embryonic eggs (which produced higher relative quantities of DI particles with DVG RNAs) but not with IAV grown in cell culture, indicating that RIG-I activation by the genomes from primarily non-DI IAV particles may require active viral RNA synthesis (208) . A potential explanation to this observation is that RIG-I appears to be activated by the full viral genome via its panhandle structure, the affinity of which is lowered by the presence of mismatched and unpaired nucleotides in this region of the viral genome that is conserved across influenza virus strains (209) . However, the overall panhandle structure is conserved between DVGs (205) and the full length viral genome (209) , and deletions within DVGs are monogenic and internal (210) . The specific molecular mechanisms of enhanced RIG-I signaling by IAV DVGs have yet to be elucidated, although the level of exposure of the panhandle may play a role. While the full extent of MDA5 interacting with DI RNA is currently unknown, MDA5 appears to be more predominantly activated by DVG RNA than RIG-I specifically in dendritic cells early in the viral infection cycle (211) , which may be a contributor toward the phenomenon of DI particles enhancing dendritic cell maturation (212) .