ADAR1 regulates dsRNA formation in nuclear and mitochondrial transcripts through editing-dependent and -independent mechanisms

  • Cell Rep. 2026 Mar 24;45(3):117026. doi: 10.1016/j.celrep.2026.117026.
Heegwon Shin  1 ,  Tyler J Dorrity  1 ,  Justin Aruda  2 ,  Kenenni A Wiegand  1 ,  Jung Seung Nam  3 ,  Jiping Yang  4 ,  Aidan S Jones  1 ,  Jake A Gertie  1 ,  Meera K Singh  1 ,  Yuanjun Yin  1 ,  Keer He  1 ,  Rafan Sarker  1 ,  Rajesh K Soni  5 ,  Yousin Suh  6 ,  Iok In Christine Chio  3 ,  Silvi Rouskin  2 ,  Hachung Chung  7
Affiliations
  • 1. Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • 2. Department of Microbiology, Harvard Medical School, Boston, MA, USA.
  • 3. Department of Genetics and Development, Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, NY, USA.
  • 4. Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, USA.
  • 5. Proteomics and Macromolecular Crystallography Shared Resource, Columbia University Irving Medical Center, New York, NY, USA.
  • 6. Department of Genetics and Development, Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, NY, USA; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, USA.
  • 7. Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: [email protected].
PMID: 41800619 DOI: 10.1016/j.celrep.2026.117026
Abstract

Endogenous (self) double-stranded RNAs (dsRNAs) in human cells can activate innate immune responses. ADAR1, an A-to-I editing enzyme of dsRNAs, suppresses aberrant immune activation by self-dsRNAs. However, how ADAR1 influences the cellular dsRNA landscape remains unclear. We show that human ADAR1 downregulates self-dsRNA abundance through editing-dependent and editing-independent mechanisms. We further conducted quantitative dsRNA Sequencing on wild-type and ADAR1-deficient cells. dsRNAs are enriched in protein-coding mRNAs-especially those with repetitive elements and elongated 3' UTRs-and mitochondrial RNAs. ADAR1-regulated dsRNA transcripts consist of nuclear-encoded mRNAs and, unexpectedly, mitochondria-encoded RNAs rarely edited by ADAR1. Accordingly, dsRNAs accumulate to high levels within the mitochondria of ADAR1-deficient cells. Mass spectrometry and biochemical assays can detect ADAR1p150 in mitochondrial fractions. Notably, ADAR1 loss sensitizes cells to inflammation under mitochondrial stress (e.g., herniation and X-ray irradiation). Hence, we show that dsRNAs regulated by ADAR1 go beyond A-to-I edited transcripts and that ADAR1 can control mitochondrial dsRNAs.

Keywords
A-to-I editing; ADAR1; AGS; Aicardi-Goutieres syndrome; CP: immunology; CP: molecular biology; IFN; PKR; double-stranded RNA; dsRNA; dsRNA-seq; innate immunity; mitochondria; mitochondrial stress; protein kinase R; type 1 interferon.
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