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.
Highlights
Adenosine-to-inosine (A-to-I) editing of primary transcripts by ADAR enzymes is the most prevalent RNA-editing mechanism in higher eukaryotes.[5,6] Three mammalian adenosine deaminase acting on RNA (ADAR) genes are found in mammals, which encode two active deaminases (ADAR1 and ADAR2) and one inactive deaminase (ADAR3).[5,6] ADARs act on doublestranded RNA structures in both messenger and noncoding RNAs
The p53/PUMA/p21 axis has a key role in the survival and regeneration of intestinal stem cells (ISCs) following radiation injury, but is largely dispensable for ISC survival and homeostasis.[2,31,32]
We discovered an essential role of the RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) in maintaining intestinal homeostasis and stem cells using whole mouse and isolate crypts
Summary
Adenosine-to-inosine (A-to-I) editing of primary transcripts by ADAR enzymes (adenosine deaminase acting on RNA) is the most prevalent RNA-editing mechanism in higher eukaryotes.[5,6] Three mammalian adenosine deaminase acting on RNA (ADAR) genes are found in mammals, which encode two active deaminases (ADAR1 and ADAR2) and one inactive deaminase (ADAR3).[5,6] ADARs act on doublestranded RNA (dsRNA) structures in both messenger and noncoding RNAs. ADAR1 deletion causes widespread apoptosis, defective hematopoiesis, and embryonic lethality, suggesting an essential role of ADAR1 for embryo development and cell proliferation and differentiation.[11,12] Using conditional knockout models, ADAR1 was PA, USA. ADAR1 was expressed highly in the Lgr[5] þ population, and its deletion in adult mice induced a rapid apoptosis and loss of stem cells in the small intestine and colon. Data from cultured crypts strongly suggest that ADAR1 suppresses epithelial cell death through a cell-autonomous manner. These data reveal a critical role of ADAR1 in maintaining intestinal homeostasis and ISC survival, and a potential involvement of RNA editing in digestive diseases
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