Ribonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line.

TitleRibonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line.
Publication TypeJournal Article
Year of Publication2017
AuthorsLi, Y, Banerjee, S, Goldstein, SA, Dong, B, Gaughan, C, Rath, S, Donovan, J, Korennykh, A, Silverman, RH, Weiss, SR
JournalElife
Volume6
Date Published2017 03 31
ISSN2050-084X
KeywordsAdaptor Proteins, Signal Transducing, Adenosine Deaminase, Cell Death, Cell Line, Tumor, Endoribonucleases, Epithelial Cells, Humans, Interferon-Induced Helicase, IFIH1, RNA-Binding Proteins
Abstract

<p>ADAR1 isoforms are adenosine deaminases that edit and destabilize double-stranded RNA reducing its immunostimulatory activities. Mutation of leads to a severe neurodevelopmental and inflammatory disease of children, Aicardi-Goutiéres syndrome. In mice, mutations are embryonic lethal but are rescued by mutation of the or genes, which function in IFN induction. However, the specific IFN regulated proteins responsible for the pathogenic effects of mutation are unknown. We show that the cell-lethal phenotype of deletion in human lung adenocarcinoma A549 cells is rescued by CRISPR/Cas9 mutagenesis of the gene or by expression of the RNase L antagonist, murine coronavirus NS2 accessory protein. Our result demonstrate that ablation of RNase L activity promotes survival of ADAR1 deficient cells even in the presence of MDA5 and MAVS, suggesting that the RNase L system is the primary sensor pathway for endogenous dsRNA that leads to cell death.</p>

DOI10.7554/eLife.25687
Alternate JournalElife
PubMed ID28362255
PubMed Central IDPMC5404912
Grant ListT32 AI007324 / AI / NIAID NIH HHS / United States
R01 GM110161 / GM / NIGMS NIH HHS / United States
K00 CA212468 / CA / NCI NIH HHS / United States
R01 AI104887 / AI / NIAID NIH HHS / United States
R01 NS081008 / NS / NINDS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
R01 CA044059 / CA / NCI NIH HHS / United States
F99 CA212468 / CA / NCI NIH HHS / United States