Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown

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-Gouti...

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Bibliographic Details
Published in:Cell 2018-02, Vol.172 (4), p.811-824.e14
Main Authors: 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.
Format: Article
Language:English
Subjects:
ADAR1
Adenosine Deaminase - genetics
Adenosine Deaminase - immunology
Adenosine Deaminase - metabolism
AGS
Aicardi-Goutieres syndrome
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
eIF-2 Kinase - genetics
eIF-2 Kinase - immunology
eIF-2 Kinase - metabolism
Gene Knockout Techniques
HEK293 Cells
Humans
Inflammation - genetics
Inflammation - immunology
Inflammation - metabolism
Inflammation - pathology
innate immunity
Interferon-Induced Helicase, IFIH1 - genetics
Interferon-Induced Helicase, IFIH1 - immunology
Interferon-Induced Helicase, IFIH1 - metabolism
MDA5
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
neuronal progenitor cells
PKR
Protein Biosynthesis
RNA editing
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
translation
type I interferon
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Summary: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. [Display omitted] •ADAR1 edits are found in putative RNA polymerase II (but not III)-derived Alu repeats•ADAR1 prevents translational shutdown during the type I IFN response•ADAR1 dsRNA binding and catalytic activities are required to block PKR activation•ADAR1 KO NPCs exhibit MDA5-dependent IFN production, PKR activation, and cell death The human RNA-editing enzyme ADAR1 prevents endogenous RNA from activating innate immune sensors (PKR, MDA5), which allows efficient translation during IFN response.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2017.12.038