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

TitleIntrons encode dsRNAs undetected by RIG-I/MDA5/interferons and sensed via RNase L.
Publication TypeJournal Article
Year of Publication2021
AuthorsChitrakar, A, Solorio-Kirpichyan, K, Prangley, E, Rath, S, Du, J, Korennykh, A
JournalProc Natl Acad Sci U S A
Volume118
Issue46
Date Published2021 11 16
ISSN1091-6490
KeywordsCell Line, Tumor, DEAD Box Protein 58, HeLa Cells, Humans, Immunity, Innate, Interferon-Induced Helicase, IFIH1, Interferons, Introns, Receptors, Immunologic, RNA, Double-Stranded, RNA, Viral, Signal Transduction
Abstract

<p>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.</p>

DOI10.1073/pnas.2102134118
Alternate JournalProc Natl Acad Sci U S A
PubMed ID34772806
PubMed Central IDPMC8609619
Grant ListF99 CA212468 / CA / NCI NIH HHS / United States
R01 GM110161 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States