Ribonuclease L mediates the cell-lethal phenotype of the double-stranded RNA editing enzyme ADAR1 in a human cell line
- University of Pennsylvania, United States
- Cleveland Clinic, United States
- Princeton University, United States
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.
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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.
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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Ribonuclease L mediates the cell-lethal phenotype of the double-stranded RNA editing enzyme ADAR1 in a human cell line
eLife 6:e25687.
https://doi.org/10.7554/eLife.25687
