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

Brisse, Morgan; Ly, Hinh

Contrary to the traditional paradigm, there is increasing evidence to suggest that RIG-I and MDA5 interact with certain host RNA motifs, resulting in auto-activation or auto-inhibition of the IRF pathway ( Figure 5) . One of the most strongly supported models is activation by host and viral circular RNAs (circRNA). Originally found in a variety of pathogen genomes, circRNAs in eukaryotic cells were first thought to be byproducts of the pre-mRNA splicing process. However, they have later been found to be produced by a non-canonical "backsplicing" process and there is increasing evidence to suggest that they play some important regulatory roles (244) , suggesting that they may have specifically evolved for this purpose. RIG-I was first found to interact with circRNA produced in situ (245) . Interestingly, the minimum component required for RIG-I activation is an intron of pathogenic origin to be spliced out during the circularization process. As human introns have been found to be associated with many RNA binding proteins, it is speculated that these proteins may have prevented circularization of this particular synthetic circRNA used in this study (245) and that host RNA binding proteins normally prevent endogenous circRNAs from being detected by the innate immune system. Nevertheless, some viral infections can potentially expose these endogenous circRNAs for immune detection, as has recently been found to be the case for a novel host-derived circRNA (lnc-Lsm3b) that is IFN-inducible and shows a down-regulation of its binding to host proteins during viral infection and therefore appears to compete with viral dsRNA as an inhibitor of the RIG-I signaling feedback loop (198) . Similar inhibitory mechanisms have also been noted for RNA products of the exonuclease SKIV2L (246) . Finally, recent studies have found that hepatitis C virus (HCV) infection increases the expression of certain cellular RNAs that can inhibit RIG-I function. HCV infection increased the mRNA levels of hepatic selenoprotein, which was able to bind to RIG-I through a hairpin structure and inactivated it during viral infection (247) . Infection by HCV, vesicular stomatitis virus (VSV), or Sendai virus, or direct exposure of cells to type 1 and 3 interferons increases expression of the cellular long non-coding RNA (lncRNA), namely lncATV, which similarly inhibits RIG-I function by directly interacting with it in order to promote virus replication (248) . In addition to the greatly increased implications of RIG-I and MDA5 modulation, these findings also have significant implications in characterizing new biomarkers of disease, as increased serum selenoprotein level has been found to significantly associate with treatment failure of anti-viral drugs in HCV patients, and can possibly explain the increased prevalence of type 2 diabetes in HCV patients (247) . Cellular RNA has also been found to activate RLR signaling during viral infection. Vault RNAs, which are transcribed from four genes and are normally found in large ribonucleoprotein complexes in cytoplasmic "vaults, " are significantly enriched for binding to RIG-I during infection with KSHV (29). This may be due partly to viral infection-induced reduction in the level of cellular triphosphatase DUSP11, which dephosphorylates the 5 ′ ppp group on the vault RNAs, as they could only be immunogenic (in the absence of viral infection) by the addition of the 5 ′ ppp group. RIG-I and MDA5 have also been found to be activated b