Title | Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Chung H, Calis JJA, Wu X, Sun T, Yu Y, Sarbanes SL, Thi VLoan Dao, Shilvock AR, Hoffmann H-H, Rosenberg BR, Rice CM |
Journal | Cell |
Volume | 172 |
Issue | 4 |
Pagination | 811-824.e14 |
Date Published | 2018 02 08 |
ISSN | 1097-4172 |
Keywords | Adenosine Deaminase, Alu Elements, Autoimmune Diseases of the Nervous System, Cell Death, eIF-2 Kinase, Gene Knockout Techniques, HEK293 Cells, Humans, Inflammation, Interferon-Induced Helicase, IFIH1, Nervous System Malformations, Neural Stem Cells, Protein Biosynthesis, RNA Polymerase II, RNA, Double-Stranded, RNA-Binding Proteins |
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. |
DOI | 10.1016/j.cell.2017.12.038 |
Alternate Journal | Cell |
PubMed ID | 29395325 |
PubMed Central ID | PMC5831367 |
Grant List | DP5 OD012142 / OD / NIH HHS / United States F32 AI114211 / AI / NIAID NIH HHS / United States R01 AI091707 / AI / NIAID NIH HHS / United States |
Submitted by api_import on June 6, 2018 - 4:13pm