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Terminal loop sequences in viral double-stranded RNAs modulate RIG-I signaling.

Matthew Hackbart1, Patrick Wang1, Victoria Gnazzo1

  • 1Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

RNA (New York, N.Y.)
|February 23, 2026
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Summary
This summary is machine-generated.

Foreign RNAs trigger innate immunity via RIG-I. This study reveals that RNA stem loops, not just 5’ ends, enhance RIG-I signaling and interferon expression, showing potential as immunostimulants.

Keywords:
RIG-IRNA motifcopy-back viral genomesinterferon

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Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • Innate immunity relies on detecting foreign RNA to combat viral infections.
  • Retinoic acid-inducible gene I (RIG-I) is a key cytoplasmic sensor for viral RNA, initiating antiviral responses.
  • While 5'-triphosphate dsRNA is a known RIG-I activator, other RNA motifs' roles are less understood.

Purpose of the Study:

  • To investigate the impact of RNA stem loops away from the 5' end on RIG-I activation.
  • To determine how specific RNA motifs within copy-back viral genomes (cbVGs) influence interferon expression.
  • To evaluate the potential of cbVG-derived stem loops as in vivo immunostimulants.

Main Methods:

  • Analysis of immune-activating copy-back viral genomes (cbVGs) for RNA structural motifs.
  • Assessing RIG-I signaling and type I/III interferon (IFN) expression in response to identified RNA structures.
  • Testing synthetic cbVG-derived stem loops for their ability to trigger innate immune responses in mice.

Main Results:

  • Immune-activating cbVGs possess RNA stem loops distant from the 5' end that potentiate RIG-I signaling.
  • The sequence composition of the terminal loops within these stem loops directly correlates with the magnitude of IFN expression.
  • Synthetic cbVG-derived stem loops successfully elicited innate immune responses in vivo.

Conclusions:

  • RNA stem loops away from the 5' terminus are critical enhancers of RIG-I-mediated innate immunity.
  • The specific sequence of these RNA motifs dictates the strength of the interferon response.
  • Synthetic stem loops derived from viral RNA structures represent a promising strategy for developing novel immunostimulants.