Selective RNA Targeting and Regulated Signaling by RIG-I Is Controlled by Coordination of RNA and ATP Binding

Nucleic Acids Res. 2017 Feb 17;45(3):1442-1454. doi: 10.1093/nar/gkw816.

Abstract

RIG-I is an innate immune receptor that detects and responds to infection by deadly RNA viruses such as influenza, and Hepatitis C. In the cytoplasm, RIG-I is faced with a difficult challenge: it must sensitively detect viral RNA while ignoring the abundance of host RNA. It has been suggested that RIG-I has a ‘proof-reading’ mechanism for rejecting host RNA targets, and that disruptions of this selectivity filter give rise to autoimmune diseases. Here, we directly monitor RNA proof-reading by RIG-I and we show that it is controlled by a set of conserved amino acids that couple RNA and ATP binding to the protein (Motif III). Mutations of this motif directly modulate proof-reading by eliminating or enhancing selectivity for viral RNA, with major implications for autoimmune disease and cancer. More broadly, the results provide a physical explanation for the ATP-gated behavior of SF2 RNA helicases and receptor proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Adenosine Triphosphate / metabolism*
  • Amino Acid Substitution
  • Autoimmunity
  • Binding Sites / genetics
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / immunology
  • DEAD Box Protein 58 / metabolism*
  • HEK293 Cells
  • Humans
  • Immunity, Innate
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Protein Interaction Domains and Motifs
  • RNA / chemistry
  • RNA / genetics
  • RNA / metabolism*
  • RNA Viruses / genetics
  • RNA Viruses / immunology
  • RNA Viruses / pathogenicity
  • RNA, Viral / chemistry
  • RNA, Viral / genetics
  • RNA, Viral / metabolism
  • Receptors, Pattern Recognition / chemistry
  • Receptors, Pattern Recognition / genetics
  • Receptors, Pattern Recognition / metabolism
  • Signal Transduction

Substances

  • RNA, Viral
  • Receptors, Pattern Recognition
  • RNA
  • Adenosine Triphosphate
  • Adenosine Triphosphatases
  • DDX58 protein, human
  • DEAD Box Protein 58