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

Kathleen Pestal, Cory C. Funk, Jessica M. Snyder, Nathan D. Price, Piper M. Treuting, Daniel B. Stetson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)933-944
Number of pages12
JournalImmunity
Volume43
Issue number5
DOIs
StatePublished - Nov 17 2015
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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