1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
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Ribonuclease L mediates the cell-lethal phenotype of the double-stranded RNA editing enzyme ADAR1 in a human cell line

  1. Yize Li
  2. Shuvojit Banerjee
  3. Stephen A Goldstein
  4. Beihua Dong
  5. Christina Gaughan
  6. Sneha Rath
  7. Jesse Donovan
  8. Alexei V Korennykh
  9. Robert H Silverman  Is a corresponding author
  10. Susan R Weiss  Is a corresponding author
  1. University of Pennsylvania, United States
  2. Cleveland Clinic, United States
  3. Princeton University, United States
Research Article
  • Cited 51
  • Views 4,704
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Cite this article as: eLife 2017;6:e25687 doi: 10.7554/eLife.25687

Abstract

ADAR1 isoforms are adenosine deaminases that edit and destabilize double-stranded RNA reducing its immunostimulatory activities. Mutation of ADAR1 leads to a severe neurodevelopmental and inflammatory disease of children, Aicardi-Goutiéres syndrome. In mice, Adar1 mutations are embryonic lethal but are rescued by mutation of the Mda5 or Mavs genes, which function in IFN induction. However, the specific IFN regulated proteins responsible for the pathogenic effects of ADAR1 mutation are unknown. We show that the cell-lethal phenotype of ADAR1 deletion in human lung adenocarcinoma A549 cells is rescued by CRISPR/Cas9 mutagenesis of the RNASEL 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.

Article and author information

Author details

  1. Yize Li

    Department of Microbiology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Shuvojit Banerjee

    Department of Cancer Biology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Stephen A Goldstein

    Department of Microbiology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Beihua Dong

    Department of Cancer Biology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Christina Gaughan

    Department of Cancer Biology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sneha Rath

    Department of Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jesse Donovan

    Department of Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Alexei V Korennykh

    Department of Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Robert H Silverman

    Department of Cancer Biology, Cleveland Clinic, Cleveland, United States
    For correspondence
    silverr@ccf.org
    Competing interests
    The authors declare that no competing interests exist.
  10. Susan R Weiss

    Department of Microbiology, University of Pennsylvania, Philadelphia, United States
    For correspondence
    weisssr@upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8155-4528

Funding

National Institute of Allergy and Infectious Diseases (R01AI104887 to S.R.W. and R.H.S)

  • Robert H Silverman
  • Susan R Weiss

National Institute of Neurological Disorders and Stroke (R01-NS-080081 to S.R.W.)

  • Susan R Weiss

National Cancer Institute (R01CA044059 to R.H.S)

  • Robert H Silverman

Burroughs Wellcome Fund (Grant 1013579 to A.K.)

  • Alexei V Korennykh

Sidney Kimmel Foundation for Cancer Research (AWD1004002 to A.K.)

  • Alexei V Korennykh

National Institute of General Medical Sciences (R01GM110161 to A.K.)

  • Alexei V Korennykh

Vallee Foundation (23307-G0002-10009-96)

  • Alexei V Korennykh

National Institute of Allergy and Infectious Diseases (T32AI007324)

  • Stephen A Goldstein

National Institute of General Medical Sciences (T32GM007388)

  • Sneha Rath

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Timothy W Nilsen, Case Western Reserve University, United States

Publication history

  1. Received: February 3, 2017
  2. Accepted: March 30, 2017
  3. Accepted Manuscript published: March 31, 2017 (version 1)
  4. Version of Record published: April 25, 2017 (version 2)
  5. Version of Record updated: June 5, 2017 (version 3)

Copyright

© 2017, Li et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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