Cytosolic RNA:DNA hybrids activate the cGAS-STING axis

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Intracellular nucleic acids trigger immune responses.
• Cyclic GMP-AMP synthase (cGAS) recognizes cytoplasmic dsDNA, activating the STING pathway.
• The sensing of RNA:DNA hybrids by the innate immune system remains largely unexplored.

Purpose of the Study:

• To investigate whether cytosolic RNA:DNA hybrids are sensed by the innate immune system.
• To determine the pathway involved in the recognition of RNA:DNA hybrids.
• To identify RNA:DNA hybrids as potential pathogen-associated molecular patterns (PAMPs).

Main Methods:

• Delivery of synthetic RNA:DNA hybrids into the cytosol.
• Analysis of type I interferon responses.
• Studies in THP-1 knockout cells.
• In vitro assays with recombinant cGAS.

Main Results:

• Cytosolic delivery of RNA:DNA hybrids induced a strong type I interferon response.
• Recognition of RNA:DNA hybrids was dependent on the cGAS-STING pathway.
• Recombinant cGAS synthesized cGAMP in response to RNA:DNA hybrids in vitro.

Conclusions:

• RNA:DNA hybrids represent a novel class of intracellular PAMPs.
• The cGAS-STING pathway recognizes RNA:DNA hybrids.
• RNA:DNA hybrids serve as an alternative ligand for cGAS, alongside dsDNA.