Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent m6A demethylation of Nr4a1 mRNA
Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent m6A demethylation of Nr4a1 mRNA
复制标题
环状RNA circZbtb20通过Nr4a1 mRNA的Alkbh5依赖性m6A去甲基化维持ILC3稳态和功能
DOI：
10.1038/s41423-021-00680-1
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发表时间：
2021-04-28
影响因子：
24.1
通讯作者：
Fan, Zusen
中科院分区：
文献类型：
--
作者：
Liu, Benyu;Liu, Nian;Fan, Zusen
第 3 组先天淋巴细胞 (ILC3) 在先天免疫和肠道稳态中发挥着关键作用。然而，ILC3 稳态是如何调节的仍然难以捉摸。在这里，我们鉴定了一种新型环状 RNA，circZbtb20，它在 ILC3 中高度表达，并且是 ILC3 的维持和功能所必需的。 CircZbtb20 缺失会导致 ILC3 数量减少，从而增加对啮齿类柠檬酸杆菌感染的易感性。从机制上讲，circZbtb20增强了Alkbh5与Nr4a1 mRNA的相互作用，导致Nr4a1 mRNA的m6A修饰被消除，从而提高其稳定性。 Nr4a1 启动 Notch2 信号激活，有助于维持 ILC3 稳态。 Alkbh5 或 Nr4a1 的缺失还会损害 ILC3 稳态并增加对细菌感染的敏感性。因此，我们的研究结果揭示了环状RNA在调节先天淋巴细胞稳态中的重要作用。
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.