Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown

Cell. 2018 Feb 8;172(4):811-824.e14. doi: 10.1016/j.cell.2017.12.038. Epub 2018 Jan 25.


Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutières syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus. During the IFN response, ADAR1 blocked translational shutdown by inhibiting hyperactivation of PKR, a dsRNA sensor. ADAR1 dsRNA binding and catalytic activities were required to fully prevent endogenous RNA from activating PKR. Remarkably, ADAR1 knockout neuronal progenitor cells exhibited MDA5 (dsRNA sensor)-dependent spontaneous interferon production, PKR activation, and cell death. Thus, human ADAR1 regulates sensing of self versus nonself RNA, allowing pathogen detection while avoiding autoinflammation.

Keywords: ADAR1; AGS; Aicardi-Goutieres syndrome; Alu elements; MDA5; PKR; RNA editing; innate immunity; neuronal progenitor cells; translation; type I interferon.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / immunology
  • Adenosine Deaminase / metabolism*
  • Alu Elements*
  • Autoimmune Diseases of the Nervous System / genetics
  • Autoimmune Diseases of the Nervous System / immunology
  • Autoimmune Diseases of the Nervous System / metabolism*
  • Cell Death / genetics
  • Cell Death / immunology
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interferon-Induced Helicase, IFIH1 / genetics
  • Interferon-Induced Helicase, IFIH1 / immunology
  • Interferon-Induced Helicase, IFIH1 / metabolism
  • Nervous System Malformations / genetics
  • Nervous System Malformations / immunology
  • Nervous System Malformations / metabolism*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / immunology
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Protein Biosynthesis*
  • RNA Polymerase II / genetics
  • RNA Polymerase II / immunology
  • RNA Polymerase II / metabolism
  • RNA, Double-Stranded / genetics
  • RNA, Double-Stranded / immunology
  • RNA, Double-Stranded / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology
  • RNA-Binding Proteins / metabolism*
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / immunology
  • eIF-2 Kinase / metabolism


  • RNA, Double-Stranded
  • RNA-Binding Proteins
  • EIF2AK2 protein, human
  • eIF-2 Kinase
  • RNA Polymerase II
  • ADAR protein, human
  • Adenosine Deaminase
  • IFIH1 protein, human
  • Interferon-Induced Helicase, IFIH1

Supplementary concepts

  • Aicardi-Goutieres syndrome