The role of ADAR1 in innate immune regulation and cell biology

Thesis (Ph.D.)--University of Washington, 2016-12University of Washington Abstract The Role of ADAR1 in Innate Immune Regulation and Cell Biology Kathleen M. Pestal Chair of Supervisory Committee: Associate Professor Daniel B. Stetson Department of Immunology Mutations in ADAR, which encodes the ADAR1 RNA editing enzyme, cause Aicardi–Goutières syndrome (AGS), a severe inflammatory disease associated with an aberrant type I interferon response. Aicardi–Goutières syndrome has previously been shown to result from ineffectual negative regulation of the cytosolic DNA sensing pathway. Here, we demonstrate that ADAR1 is a specific and essential negative regulator of the MDA5-MAVS RNA sensing pathway. Moreover, we uncovered an MDA5-MAVS-independent function for ADAR1 in the development of multiple organs, including the kidney and intestines. We also discovered a cell-intrinsic role for ADAR1 in B cell development. We showed that the p150 isoform of ADAR1 exclusively 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 define genetically distinct roles for both ADAR1 isoforms in vivo, with implications for the human diseases caused by ADAR mutations