Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium
Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and developmen...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-02-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.153511 |
| _version_ | 1811226962962677760 |
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| author | José B. Sáenz Nancy Vargas Charles J. Cho Jason C. Mills |
| author_facet | José B. Sáenz Nancy Vargas Charles J. Cho Jason C. Mills |
| author_sort | José B. Sáenz |
| collection | DOAJ |
| description | Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of gastric metaplasia. Mouse organoid and in vivo genetic models showed that ADAR1 coordinated a cell-intrinsic, epithelium-autonomous, and interferon signaling–independent dsRNA response. In addition, dsRNA accumulated within a differentiated epithelial population (chief cells) in mouse and human stomachs as these cells reprogrammed to a proliferative, reparative (metaplastic) state. Finally, chief cells required ADAR1 to reenter the cell cycle during metaplasia. Thus, cell-intrinsic ADAR1 signaling is critical for the induction of metaplasia. Because metaplasia increases cancer risk, these findings support roles for ADAR1 and the response to dsRNA in oncogenesis. |
| first_indexed | 2024-04-12T09:33:22Z |
| format | Article |
| id | doaj.art-39e0281ffadf4e029f335b150c622cce |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T09:33:22Z |
| publishDate | 2022-02-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-39e0281ffadf4e029f335b150c622cce2022-12-22T03:38:17ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-02-0173Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epitheliumJosé B. SáenzNancy VargasCharles J. ChoJason C. MillsCells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of gastric metaplasia. Mouse organoid and in vivo genetic models showed that ADAR1 coordinated a cell-intrinsic, epithelium-autonomous, and interferon signaling–independent dsRNA response. In addition, dsRNA accumulated within a differentiated epithelial population (chief cells) in mouse and human stomachs as these cells reprogrammed to a proliferative, reparative (metaplastic) state. Finally, chief cells required ADAR1 to reenter the cell cycle during metaplasia. Thus, cell-intrinsic ADAR1 signaling is critical for the induction of metaplasia. Because metaplasia increases cancer risk, these findings support roles for ADAR1 and the response to dsRNA in oncogenesis.https://doi.org/10.1172/jci.insight.153511Cell biologyGastroenterology |
| spellingShingle | José B. Sáenz Nancy Vargas Charles J. Cho Jason C. Mills Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium JCI Insight Cell biology Gastroenterology |
| title | Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium |
| title_full | Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium |
| title_fullStr | Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium |
| title_full_unstemmed | Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium |
| title_short | Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium |
| title_sort | regulation of the double stranded rna response through adar1 licenses metaplastic reprogramming in gastric epithelium |
| topic | Cell biology Gastroenterology |
| url | https://doi.org/10.1172/jci.insight.153511 |
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