Innate immune sensors for 5′-end RNA recognition. (A) Functional domains of the human RLR-pathway receptors, RIG-I, MDA5, and LGP2 (top), and IFIT members, IFIT1 and IFIT5 (bottom). (CARD) Caspase activation and recruitment domains; (Hel) helicase domain; (CTD) C-terminal domain; (TRP) tetratricopeptide repeat motif. Numbers indicate residue position. (B) The RIG-I-like receptor RIG-I recognizes single-stranded RNA (ssRNA) or dsRNA containing 5′-PPP, or 5′-diphosphate ends (5′-PP). RIG-I can also bind m7G-RNAs that are unmethylated in positions N1 and N2. The other major RLR receptor MDA5 is specialized in recognizing long dsRNAs. Upon binding to viral RNAs, RIG-I and MDA5 signal through the mitochondrial-associated protein, MAVS. Next, the kinases TBK1 and IKKe are activated, promoting the nuclear translocation of the IRF3/7 and NFkB transcription factors, which drive expression of type I IFNs and proinflammatory cytokines.
