Cited by 538RNA regulation and diseaseinterferon and immune responsesRNA Research and Splicing

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Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown

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Chung, Hachung, Calis, Jorg J.A., Wu, Xianfang, Sun, Tony, Yu, Yingpu, Sarbanes, Stephanie L., Dao Thi, Viet Loan, Shilvock, Abigail R., Hoffmann, H.-Heinrich, Rosenberg, Brad R., Rice, Charles M.·2018·Cell

DOI 10.1016/j.cell.2017.12.038PMC PMC5831367

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Abstract

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.

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Authors: Chung, H., Calis, J. J. A., Wu, X., Sun, T., Yu, Y., Sarbanes, S. L., Dao Thi, V. L., Shilvock, A. R., Hoffmann, H.-H., Rosenberg, B. R., & Rice, C. M.
Affiliations: Rockefeller University (US)
Corresponding author: Rice, Charles M.
ORCID: Chung, Hachung
Calis, Jorg J.A.
Wu, Xianfang
Sun, Tony
Yu, Yingpu
Sarbanes, Stephanie L.
Shilvock, Abigail R.
Hoffmann, H.-Heinrich
Rosenberg, Brad R.
Rice, Charles M.
Venue: Cell
Publisher: Elsevier BV
Published: 2018-02
Volume: 172
Issue: 4
Pages: 811-824.e14
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2017.12.038
PMC: PMC5831367
OpenAlex: W2784970793
Cited by: 538
References: 55
Citations by year: 2026: 53 · 2025: 69 · 2024: 67 · 2023: 71 · 2022: 64 · 2021: 74 · 2020: 60 · 2019: 44 · 2018: 36
FWCI: 19.03
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 372 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: NIAID/NIH (R01-AI091707, F32AI114211)
John C. Whitehead Presidential Fellowship
Netherlands Organization for Scientific Research
Helmsley postdoctoral fellowship
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords: ADAR1, Aicardi-Goutières syndrome, type I interferon, dsRNA sensing, PKR, MDA5, Alu elements, RNA editing, autoinflammation, neural progenitor cells, cell death, RNA polymerase II transcripts
MeSH terms: Interferon-Induced Helicase, IFIH1, Adenosine Deaminase, Humans, Inflammation, Nervous System Malformations, RNA Polymerase II, RNA, Double-Stranded, Protein Biosynthesis, RNA-Binding Proteins, Cell Death, eIF-2 Kinase, Alu Elements, Autoimmune Diseases of the Nervous System, Gene Knockout Techniques, HEK293 Cells, Neural Stem Cells

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Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown

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