Induction of type I interferon by RNA viruses: cellular receptors and their substrates

Baum, Alina; García-Sastre, Adolfo

In addition to 5 0 ppp and dsRNA, a possible novel PAMP was proposed by Saito et al. in a report demonstrating that RNAs with a high U/A composition induced IFN more efficiently than those without (Saito et al. 2008) . In this work, the genomic and replicative intermediate RNAs of HCV were analyzed for their relative IFN inducing ability. The authors found that the 3 0 NTR region of the HCV genome was a much more potent inducer of IFN than other regions of the genome. This region of HCV genome is particularly rich in polyuradine tracks and upon further examination this polyU sequence composition in conjunction with a 5 0 ppp proved to lead to increased RIG-I activation. Addition of a triphosphate to a different region of the genome did not improve induction, showing that sequence components other than the triphosphate group determine the extent of RIG-I activation (Saito et al. 2008) . The conclusions of this work are, however, confounded by another recent study in which the authors demonstrated that the uridine-rich 3 0 UTR of fulminant HCV from strain JFH-1 was a relatively weak inducer of IFN, contrary to the HCV strain used in the previous paper (Uzri and Gehrke 2009) . Although it appears that stretches of U or A residues do stimulate the activity of RIG-I, additional, yet unknown sequence characteristics determine the RNA's immunostimulatory potential. The authors did show that the poly-U region could be separated from the 5 0 ppp by as much as 300 nt and still retain signaling activity, thus possibly explaining how a U-rich 3 0 RNA sequence can contribute to RIG-I activation and again implicating the helicase domain in PAMP recognition.