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

Benyu Liu; Nian Liu; Xiaoxiao Zhu; Liuliu Yang; Buqing Ye; Huimu Li; Pingping Zhu; Tiankun Lu; Yong Tian; Zusen Fan

doi:10.1038/s41423-021-00680-1

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

Cell Mol Immunol. 2021 Jun;18(6):1412-1424. doi: 10.1038/s41423-021-00680-1. Epub 2021 Apr 28.

Authors

Benyu Liu^#^{1

2}, Nian Liu^#^{3

4}, Xiaoxiao Zhu^#⁵, Liuliu Yang³, Buqing Ye³, Huimu Li^{3

4}, Pingping Zhu³, Tiankun Lu^{3

4}, Yong Tian^{6

7}, Zusen Fan^{8

9}

Affiliations

¹ Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. benyuliu@zzu.edu.cn.
² Research Center of Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. benyuliu@zzu.edu.cn.
³ Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
⁴ University of Chinese Academy of Sciences, Beijing, China.
⁵ Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
⁶ University of Chinese Academy of Sciences, Beijing, China. ytian@ibp.ac.cn.
⁷ Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. ytian@ibp.ac.cn.
⁸ Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. fanz@moon.ibp.ac.cn.
⁹ University of Chinese Academy of Sciences, Beijing, China. fanz@moon.ibp.ac.cn.

^# Contributed equally.

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.

Keywords: Alkbh5; Homeostasis; ILC3; Nr4a1; circZbtb20.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / metabolism
AlkB Homolog 5, RNA Demethylase / metabolism*
Animals
Cell Proliferation
Cell Survival
Demethylation*
Gastrointestinal Tract / immunology
Homeostasis*
Immunity, Innate / genetics*
Lymphocytes / metabolism*
Mice
Mice, Knockout
Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics*
Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
Protein Binding
RNA Stability
RNA, Circular / genetics
RNA, Circular / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptor, Notch2 / metabolism
Signal Transduction

Substances

Nuclear Receptor Subfamily 4, Group A, Member 1
RNA, Circular
RNA, Messenger
Receptor, Notch2
N-methyladenosine
AlkB Homolog 5, RNA Demethylase
Adenosine