RIG-I Selectively Discriminates against 5'-Monophosphate RNA

Cell Rep. 2019 Feb 19;26(8):2019-2027.e4. doi: 10.1016/j.celrep.2019.01.107.

Abstract

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.

Keywords: PRR; RIG-I receptor; antiviral; autoimmunity; host-pathogen; innate immunity; interferon; pattern recognition receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • DEAD Box Protein 58 / chemistry*
  • DEAD Box Protein 58 / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Molecular Dynamics Simulation
  • Protein Binding
  • RNA, Viral / chemistry*
  • RNA, Viral / metabolism

Substances

  • RNA, Viral
  • Ddx58 protein, mouse
  • DEAD Box Protein 58