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Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown
Open accessAbstract
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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“Major sources of dsRNA, inverted Alu repeats, are normally deaminated by ADAR to reduce their double-stranded character; decreased processing can be sensed by MDA5, resulting in IFN-I activation50, 51, 98.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [50]
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Metadata
- 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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 172
- Issue
- 4
- Pages
- 811-824.e14
- ISSN
- 0092-8674 (ISSN-L)
- 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
- 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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