Immunobiology of RIG-I

The innate immune system detects viruses based on the recognition of viral nucleic acids. Immunorecognition of viral nucleic acids leads to the initiation of early antiviral immune responses that limit viral replication and are essential for eliciting acquired immune responses to virus specific antigens. Detection of viral nucleic acids in the cytosol is based on the family of the so-called RIG-I-like receptors (RLRs). RNA with a triphosphate group at the 5´end (3pRNA) is the ligand for RIG-I (1). By using a new chemical approach for 5´triphosphate oligoribonucleotide synthesis we found that short double strand conformation with base pairing of the nucleoside carrying the 5´triphosphate is required for RIG-I binding. These results explain how RIG-I detects negative strand RNA viruses which lack long double-stranded RNA but do contain panhandle blunt short double-stranded 5´triphosphate RNA in their single-stranded genome (2). The crystal structure of the RIG-I CTD domain bound to the blunt-end of a 5’-ppp-dsRNA was resolved. The structure, supported by mutation and functional studies, defines how a lysine-rich basic cleft within the RIG-I CTD domain sequesters the 5’-ppp end of the bound RNA (3). We found that a conserved histidine in RIG-I controls immune tolerance of 2′O-methylated cap1 self RNA. Furthermore we demonstrate that RIG-I-RNA ligand interaction not only activates type I IFN, but also induces inflammasome activation (4) and pro-apoptotic signaling (5). Based on these activities, RIG-I ligands are promising candidates for the therapy of viral infection and cancer. We developed short interfering RNA (siRNA) containing triphosphate groups at the 5´ends (3p-siRNA) for the therapy of melanoma (6) and hepatitis B.