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Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent m6A demethylation of Nr4a1 mRNA

Abstract

Group 3 innate lymphoid cells (ILC3s) play critical roles in innate immunity and gut homeostasis. However, how ILC3 homeostasis is regulated remains elusive. Here, we identified a novel circular RNA, circZbtb20, that is highly expressed in ILC3s and required for their maintenance and function. CircZbtb20 deletion causes reduced ILC3 numbers, increasing susceptibility to C. rodentium infection. Mechanistically, circZbtb20 enhances the interaction of Alkbh5 with Nr4a1 mRNA, leading to ablation of the m6A modification of Nr4a1 mRNA to promote its stability. Nr4a1 initiates Notch2 signaling activation, which contributes to the maintenance of ILC3 homeostasis. Deletion of Alkbh5 or Nr4a1 also impairs ILC3 homeostasis and increases susceptibilities to bacterial infection. Thus, our findings reveal an important role of circular RNA in the regulation of innate lymphoid cell homeostasis.

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Acknowledgements

We thank Shu Meng, Dongdong Fan, Yan Teng, Junying Jia, and Xiang Shi for technical support. We also thank Jing Li (Cnkingbio Company, Ltd., Beijing, China) for technical support. This work was supported by the Ministry of Science and Technology of China (2020YFA0803501 and 2019YFA0508501), the National Natural Science Foundation of China (31930036, 81921003, 92042302, 31870883, 91940305, 31728006, 81772646, and 31871494), the Strategic Priority Research Programs of the Chinese Academy of Sciences (XDB19030203), the Beijing Natural Science Foundation (5192018), the Biological Resource Program of the Chinese Academy of Science (KFJ-BRP-017-04), and the Young Elite Scientist Sponsorship Program of CAST (2018QNRC001).

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B.L. and N.L. performed experiments; B.L. designed the project, analyzed the data, and wrote the paper; and X.Z. constructed genetic mouse strains. L.Y., B.Y., H.L., P.Z., and T.L. analyzed data; Y.T. initiated the study and analyzed data; and Z.F. initiated the study and organized, designed, and wrote the paper.

Corresponding authors

Correspondence to Benyu Liu or Yong Tian or Zusen Fan.

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Liu, B., Liu, N., Zhu, X. et al. Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent m6A demethylation of Nr4a1 mRNA. Cell Mol Immunol 18, 1412–1424 (2021). https://doi.org/10.1038/s41423-021-00680-1

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Keywords

  • circZbtb20
  • ILC3
  • Alkbh5
  • Nr4a1
  • Homeostasis

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