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Immunity. 2015 Nov 17;43(5):933-44. doi: 10.1016/j.immuni.2015.11.001.

Isoforms of RNA-Editing Enzyme ADAR1 Independently Control Nucleic Acid Sensor MDA5-Driven Autoimmunity and Multi-organ Development.

Author information

1
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
2
Institute for Systems Biology, Seattle, WA 98195, USA.
3
Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
4
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA. Electronic address: stetson@uw.edu.

Abstract

Mutations in ADAR, which encodes the ADAR1 RNA-editing enzyme, cause Aicardi-Goutières syndrome (AGS), a severe autoimmune disease associated with an aberrant type I interferon response. How ADAR1 prevents autoimmunity remains incompletely defined. Here, we demonstrate that ADAR1 is a specific and essential negative regulator of the MDA5-MAVS RNA sensing pathway. Moreover, we uncovered a MDA5-MAVS-independent function for ADAR1 in the development of multiple organs. We showed that the p150 isoform of ADAR1 uniquely regulated the MDA5 pathway, whereas both the p150 and p110 isoforms contributed to development. Abrupt deletion of ADAR1 in adult mice revealed that both of these functions were required throughout life. Our findings delineate genetically separable roles for both ADAR1 isoforms in vivo, with implications for the human diseases caused by ADAR mutations.

PMID:
26588779
PMCID:
PMC4654992
DOI:
10.1016/j.immuni.2015.11.001
[Indexed for MEDLINE]
Free PMC Article

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