title: Ribonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line.
abstract: ADAR1 isoforms are adenosine deaminases that edit and destabilize double-stranded RNA reducing its immunostimulatory activities. Mutation ofADAR1leads to a severe neurodevelopmental and inflammatory disease of children, Aicardi-Goutiéres syndrome. In mice,Adar1mutations are embryonic lethal but are rescued by mutation of theMda5orMavsgenes, which function in IFN induction. However, the specific IFN regulated proteins responsible for the pathogenic effects ofADAR1mutation are unknown. We show that the cell-lethal phenotype ofADAR1deletion in human lung adenocarcinoma A549 cells is rescued by CRISPR/Cas9 mutagenesis of theRNASELgene 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.
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Yize
authors.identifier: 0000-0003-1721-741X
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States.
authors.forename: Shuvojit
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Goldstein
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States.
authors.forename: Beihua
authors.initials: B
authors.lastname: Dong
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States.
authors.forename: Christina
authors.initials: C
authors.lastname: Gaughan
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, United States.
authors.forename: Sneha
authors.initials: S
authors.lastname: Rath
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, United States.
authors.forename: Jesse
authors.initials: J
authors.lastname: Donovan
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, United States.
authors.forename: Alexei
authors.initials: A
authors.lastname: Korennykh
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Susan R
authors.identifier: 0000-0002-8155-4528
authors.initials: SR
authors.lastname: Weiss
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000243:Adenosine Deaminase / Q000172:deficiency*; D016923:Cell Death; D045744:Cell Line, Tumor; D004722:Endoribonucleases / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1 / Q000378:metabolism; D016601:RNA-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D016601:RNA-Binding Proteins; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; C000595356:ADAR protein, human; D000243:Adenosine Deaminase; C452815:IFIH1 protein, human; D000072640:Interferon-Induced Helicase, IFIH1
keywords: adenosine deaminase; cell death; human; immunology; infectious disease; interferonopathay; microbiology; phosphodiesterase; ribonuclease L