Introns encode dsRNAs undetected by RIG-I/MDA5/interferons and sensed via RNase L

Alisha Chitrakar, Kristina Solorio-Kirpichyan, Eliza Prangley, Sneha Rath, Jin Du, Alexei Korennykh

Research output: Contribution to journalArticlepeer-review

Abstract

Double-stranded RNA (dsRNA), a hallmark viral material that activates antiviral interferon (IFN) responses, can appear in human cells also in the absence of viruses. We identify phosphorothioate DNAs (PS DNAs) as triggers of such endogenous dsRNA (endo-dsRNA). PS DNAs inhibit decay of nuclear RNAs and induce endo-dsRNA via accumulation of high levels of intronic and intergenic inverted retroelements (IIIR). IIIRs activate endo-dsRNA responses distinct from antiviral defense programs. IIIRs do not turn on transcriptional RIG-I/MDA5/IFN signaling, but they trigger the dsRNA-sensing pathways of OAS3/RNase L and PKR. Thus, nuclear RNA decay and nuclear-cytosolic RNA sorting actively protect from these innate immune responses to self. Our data suggest that the OAS3/RNase L and PKR arms of innate immunity diverge from antiviral IFN responses and monitor nuclear RNA decay by sensing cytosolic escape of IIIRs. OAS3 provides a receptor for IIIRs, whereas RNase L cleaves IIIR-carrying introns and intergenic RNAs.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number46
DOIs
StatePublished - Nov 16 2021

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • dsRNA
  • interferon
  • phosphorothioate
  • retrotransposon
  • RNase L

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