RIG-I Selectively Discriminates against 5′-Monophosphate RNA

The innate immune sensor RIG-I must sensitively detect and respond to viral RNAs that enter the cytoplasm, while remaining unresponsive to the abundance of structurally similar RNAs that are the products of host metabolism. In the case of RIG-I, these viral and host targets differ by only a few atoms, and a molecular mechanism for such selective differentiation has remained elusive. Using a combination of quantitative biophysical and immunological studies, we show that RIG-I, which is normally activated by duplex RNAs containing a 5′-tri- or diphosphate (5′-ppp or 5′-pp RNAs), is actively antagonized by RNAs containing 5′-monophosphates (5′-p RNAs). This is accomplished by a gating mechanism in which an alternative RIG-I conformation blocks the C-terminal domain (CTD) upon 5′-p RNA binding, thereby short circuiting the activation of signaling. [Display omitted] •5′-p RNAs, which are common host RNAs, actively antagonize signaling by RIG-I•RIG-I discriminates between RNA ligands that differ by only a single phosphate•RIG-I forms distinct interaction networks with RNAs bearing different 5′ termini•The RIG-I Hel2 loop acts as a gate to prevent 5′-p RNAs (host RNAs) from signaling Ren et al. show that RIG-I blocks activation by abundant self 5′-p dsRNAs by using the Hel2 loop as a steric gate, which enables RIG-I to distinguish between pathogenic and host RNAs that differ by only a few atoms.