title: ADAR1 is essential for intestinal homeostasis and stem cell maintenance.
abstract: Adenosine deaminase acting on RNA 1 (ADAR1) is a double-stranded RNA-editing enzyme that converts adenosine (A) to inosine (I), and essential for normal development. In this study, we reported an essential role of ADAR1 in the survival and maintenance of intestinal stem cells and intestinal homoeostasis by suppressing endoplasmic reticulum (ER) stress and interferon (IFN) signaling. ADAR1 was highly expressed in the Lgr5+ cells, and its deletion in adult mice led to a rapid apoptosis and loss of these actively cycling stem cells in the small intestine and colon. ADAR1 deletion resulted in a drastic expansion of progenitors and Paneth cells but a reduction of three other major epithelial lineages. Moreover, loss of ADAR1 induced ER stress and activation of IFN signaling, and altered expression in WNT targets, followed by intestinal inflammation. An ER stress inhibitor partially suppressed crypt apoptosis. Finally, data from cultured intestinal crypts demonstrated that loss of ADAR1 in the epithelial cells is the primary cause of these effects. These results support an essential role of ADAR1 and RNA editing in tissue homeostasis and stem cells.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Qiu
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Buchanan
authors.forename: K
authors.initials: K
authors.lastname: He
authors.forename: R
authors.initials: R
authors.lastname: Sharma
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Yu
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D007249:Inflammation; D007372:Interferons / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D016601:RNA-Binding Proteins; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D013629:Tamoxifen / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; C493597:Lgr5 protein, mouse; D016601:RNA-Binding Proteins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D013629:Tamoxifen; D007372:Interferons; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase