Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown

Hachung Chung, Jorg J.A. Calis, Xianfang Wu, Tony Sun, Yingpu Yu, Stephanie L. Sarbanes, Viet Loan Dao Thi, Abigail R. Shilvock, H. Heinrich Hoffmann, Brad R. Rosenberg, Charles M. Rice

Research output: Contribution to journalArticlepeer-review

305 Scopus citations


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. The human RNA-editing enzyme ADAR1 prevents endogenous RNA from activating innate immune sensors (PKR, MDA5), which allows efficient translation during IFN response.

Original languageEnglish
Pages (from-to)811-824.e14
Issue number4
StatePublished - 8 Feb 2018


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


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