@article{516c22090e43432aa7d3a5011bf8c9f6,
title = "Introns encode dsRNAs undetected by RIG-I/MDA5/ interferons and sensed via RNase L",
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.",
keywords = "RNase L, dsRNA, interferon, phosphorothioate, retrotransposon",
author = "Alisha Chitrakar and Kristina Solorio-Kirpichyan and Eliza Prangley and Sneha Rath and Jin Du and Alexei Korennykh",
note = "Funding Information: Throughput Sequencing and MicroArray Facility and facility staff and all members of the A.K. laboratory for helpful comments on the manuscript. We would like to also thank Dr. Gary Laevsky at the Confocal Imaging Facility and Nikon Center of Excellence at the Department of Molecular Biology at Princeton University. This study was funded by NIH Grant 1R01GM110161-01 (to A.K.), Sidney Kimmel Foundation Grant AWD1004002 (to A.K.), Burroughs Wellcome Foundation Grant 1013579 (to A.K.), The Vallee Foundation (A.K.), National Institute of General Medical Services (NIGMS) Training Grant 5T32GM007388 (to S.R. and K.S.-K.), and F99 CA212468-01 (to S.R.). Funding Information: We thank Prof. Susan Weiss (University of Pennsylvania School of Medicine) for the gift of KO A549 cells (RNase L, PKR, OAS1/2/3). We thank Dr. Wei Wang at Princeton University High Throughput Sequencing and MicroArray Facility and facility staff and all members of the A.K. laboratory for helpful comments on the manuscript. We would like to also thank Dr. Gary Laevsky at the Confocal Imaging Facility and Nikon Center of Excellence at the Department of Molecular Biology at Princeton University. This study was funded by NIH Grant 1R01GM110161-01 (to A.K.), Sidney Kimmel Foundation Grant AWD1004002 (to A.K.), Burroughs Wellcome Foundation Grant 1013579 (to A.K.), The Vallee Foundation (A.K.), National Institute of General Medical Services (NIGMS) Training Grant 5T32GM007388 (to S.R. and K.S.-K.), and F99 CA212468-01 (to S.R.). Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = nov,
day = "16",
doi = "10.1073/pnas.2102134118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "46",
}