环状 RNA circZbtb20 通过 Alkbh5 依赖的 Nr4a1 mRNA mA 去甲基化来维持 ILC3 的动态平衡和功能。
Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent mA demethylation of Nr4a1 mRNA.
机构信息
Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Research Center of Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
出版信息
Cell Mol Immunol. 2021 Jun;18(6):1412-1424. doi: 10.1038/s41423-021-00680-1. Epub 2021 Apr 28.
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 mA 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.
摘要
第三组固有淋巴细胞（ILC3）在先天免疫和肠道稳态中发挥着关键作用。然而，ILC3 稳态如何调节仍然难以捉摸。在这里，我们鉴定了一种新型的环状 RNA，circZbtb20，它在 ILC3 中高度表达，是维持其功能所必需的。circZbtb20 的缺失导致 ILC3 数量减少，增加了对 C. rodentium 感染的易感性。在机制上，circZbtb20 增强了 Alkbh5 与 Nr4a1 mRNA 的相互作用，导致 Nr4a1 mRNA 的 mA 修饰被消除，从而促进其稳定性。Nr4a1 启动 Notch2 信号激活，有助于维持 ILC3 稳态。Alkbh5 或 Nr4a1 的缺失也会损害 ILC3 稳态并增加对细菌感染的易感性。因此，我们的研究结果揭示了环状 RNA 在调节固有淋巴细胞稳态中的重要作用。
相似文献
1
Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent mA demethylation of Nr4a1 mRNA.环状 RNA circZbtb20 通过 Alkbh5 依赖的 Nr4a1 mRNA mA 去甲基化来维持 ILC3 的动态平衡和功能。
Cell Mol Immunol. 2021 Jun;18(6):1412-1424. doi: 10.1038/s41423-021-00680-1. Epub 2021 Apr 28.
2
An inducible circular RNA circKcnt2 inhibits ILC3 activation to facilitate colitis resolution.诱导型环状 RNA circKcnt2 抑制 ILC3 激活，促进结肠炎缓解。
Nat Commun. 2020 Aug 14;11(1):4076. doi: 10.1038/s41467-020-17944-5.
3
ALKBH5-mediated mA demethylation of FOXM1 mRNA promotes progression of uveal melanoma.ALKBH5 介导的 FOXM1 mRNA mA 去甲基化促进葡萄膜黑色素瘤的进展。
Aging (Albany NY). 2021 Jan 10;13(3):4045-4062. doi: 10.18632/aging.202371.
4
RNA mA demethylase ALKBH5 regulates the development of γδ T cells.RNA mA 去甲基酶 ALKBH5 调控 γδ T 细胞的发育。
Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2203318119. doi: 10.1073/pnas.2203318119. Epub 2022 Aug 8.
5
m A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis.去甲基酶 ALKBH5 促进食管鳞状细胞癌的增殖，与预后不良相关。
Genes Cells. 2020 Aug;25(8):547-561. doi: 10.1111/gtc.12792. Epub 2020 Jul 1.
6
ALKBH5-mediated m6A-demethylation of USP1 regulated T-cell acute lymphoblastic leukemia cell glucocorticoid resistance by Aurora B.ALKBH5 通过调控 USP1 介导的 m6A 去甲基化促进 Aurora B 促进 T 细胞急性淋巴细胞白血病细胞糖皮质激素耐药
Mol Carcinog. 2021 Sep;60(9):644-657. doi: 10.1002/mc.23330. Epub 2021 Jun 25.
7
A novel lncRNA NR4A1AS up-regulates orphan nuclear receptor NR4A1 expression by blocking UPF1-mediated mRNA destabilization in colorectal cancer.一种新型长链非编码 RNA NR4A1AS 通过阻断 UPF1 介导的 mRNA 不稳定性上调结直肠癌中孤儿核受体 NR4A1 的表达。
Clin Sci (Lond). 2019 Jul 15;133(13):1457-1473. doi: 10.1042/CS20181061.
8
N-methyladenosine ALKBH5 promotes non-small cell lung cancer progress by regulating TIMP3 stability.N6-甲基腺苷 ALKBH5 通过调控 TIMP3 稳定性促进非小细胞肺癌进展。
Gene. 2020 Mar 20;731:144348. doi: 10.1016/j.gene.2020.144348. Epub 2020 Jan 9.
9
The m6A demethylase ALKBH5 controls trophoblast invasion at the maternal-fetal interface by regulating the stability of mRNA.m6A去甲基化酶ALKBH5通过调节mRNA的稳定性来控制母胎界面处的滋养层细胞侵袭。
Theranostics. 2019 May 31;9(13):3853-3865. doi: 10.7150/thno.31868. eCollection 2019.
10
Bioactive peptide inhibits acute myeloid leukemia cell proliferation by downregulating ALKBH5-mediated mA demethylation of EIF4EBP1 and MLST8 mRNA.生物活性肽通过下调 ALKBH5 介导的 EIF4EBP1 和 MLST8 mRNA 的 mA 去甲基化来抑制急性髓系白血病细胞增殖。
Cell Oncol (Dordr). 2022 Jun;45(3):355-365. doi: 10.1007/s13402-022-00666-9. Epub 2022 May 17.
引用本文的文献
1
ALKBH5 exacerbates psoriatic dermatitis in mice by promoting angiogenesis.ALKBH5通过促进血管生成加重小鼠银屑病性皮炎。
Front Med. 2025 Jun 16. doi: 10.1007/s11684-025-1147-1.
2
Enteric GABAergic neuron-derived γ-aminobutyric acid initiates expression of Igfbp7 to sustain ILC3 homeostasis.肠道γ-氨基丁酸能神经元衍生的γ-氨基丁酸启动Igfbp7的表达以维持3型固有淋巴细胞的稳态。
Nat Immunol. 2025 Mar;26(3):404-415. doi: 10.1038/s41590-025-02081-2. Epub 2025 Mar 3.
3
M6A Demethylase ALKBH5 in Human Diseases: From Structure to Mechanisms.人类疾病中的m6A去甲基化酶ALKBH5：从结构到机制
Biomolecules. 2025 Jan 21;15(2):157. doi: 10.3390/biom15020157.
4
Staphylococcus aureus blocks host autophagy through circSyk/miR-5106/Sik3 axis to promote progression of bone infection.金黄色葡萄球菌通过circSyk/miR-5106/Sik3轴阻断宿主自噬，以促进骨感染进展。
PLoS Pathog. 2025 Jan 27;21(1):e1012896. doi: 10.1371/journal.ppat.1012896. eCollection 2025 Jan.
5
Mechanistic and therapeutic insights into the function of N6-methyladenosine in arthritic diseases.对N6-甲基腺苷在关节炎疾病中功能的机制及治疗方面的见解。
Inflamm Res. 2025 Jan 7;74(1):7. doi: 10.1007/s00011-024-01969-3.
6
Gut Microbiota-Derived Hyocholic Acid Enhances Type 3 Immunity and Protects Against Salmonella enterica Serovar Typhimurium in Neonatal Rats.肠道微生物群衍生的猪去氧胆酸增强3型免疫并保护新生大鼠抵抗鼠伤寒沙门氏菌。
Adv Sci (Weinh). 2025 Mar;12(10):e2412071. doi: 10.1002/advs.202412071. Epub 2024 Dec 31.
7
The formidable guardian: Type 3 immunity in the intestine of pigs.强大的守护者：猪肠道中的 3 型免疫。
Virulence. 2024 Dec;15(1):2424325. doi: 10.1080/21505594.2024.2424325. Epub 2024 Nov 8.
8
N-methyladenosine and its epitranscriptomic effects on hematopoietic stem cell regulation and leukemogenesis.N6-甲基腺苷及其对造血干细胞调控和白血病发生的表观转录组学效应。
Mol Med. 2024 Nov 4;30(1):196. doi: 10.1186/s10020-024-00965-x.
9
The landscape of epigenetic regulation and therapeutic application of N-methyladenosine modifications in non-coding RNAs.非编码RNA中N-甲基腺苷修饰的表观遗传调控及治疗应用前景
Genes Dis. 2023 Jul 18;11(5):101045. doi: 10.1016/j.gendis.2023.06.015. eCollection 2024 Sep.
10
Noncoding RNAs in tumorigenesis and tumor therapy.非编码RNA在肿瘤发生与肿瘤治疗中的作用
Fundam Res. 2023 Jun 12;3(5):692-706. doi: 10.1016/j.fmre.2023.05.014. eCollection 2023 Sep.
本文引用的文献
1
An inducible circular RNA circKcnt2 inhibits ILC3 activation to facilitate colitis resolution.诱导型环状 RNA circKcnt2 抑制 ILC3 激活，促进结肠炎缓解。
Nat Commun. 2020 Aug 14;11(1):4076. doi: 10.1038/s41467-020-17944-5.
2
Yeats4 drives ILC lineage commitment via activation of transcription.叶芝 4 通过激活转录来驱动 ILC 谱系的承诺。
J Exp Med. 2019 Nov 4;216(11):2653-2668. doi: 10.1084/jem.20182363. Epub 2019 Aug 21.
3
CircACC1 Regulates Assembly and Activation of AMPK Complex under Metabolic Stress.环状 ACC1 在代谢应激下调节 AMPK 复合物的组装和激活。
Cell Metab. 2019 Jul 2;30(1):157-173.e7. doi: 10.1016/j.cmet.2019.05.009. Epub 2019 May 30.
4
Structure and Degradation of Circular RNAs Regulate PKR Activation in Innate Immunity.环状 RNA 的结构和降解调控先天免疫中 PKR 的激活。
Cell. 2019 May 2;177(4):865-880.e21. doi: 10.1016/j.cell.2019.03.046. Epub 2019 Apr 25.
5
IL-13 secreted by ILC2s promotes the self-renewal of intestinal stem cells through circular RNA circPan3.ILC2 分泌的 IL-13 通过环状 RNA circPan3 促进肠道干细胞的自我更新。
Nat Immunol. 2019 Feb;20(2):183-194. doi: 10.1038/s41590-018-0297-6. Epub 2019 Jan 14.
6
mA modification controls the innate immune response to infection by targeting type I interferons.mA 修饰通过靶向 I 型干扰素来控制感染的固有免疫反应。
Nat Immunol. 2019 Feb;20(2):173-182. doi: 10.1038/s41590-018-0275-z. Epub 2018 Dec 17.
7
Microbiota-Induced TNF-like Ligand 1A Drives Group 3 Innate Lymphoid Cell-Mediated Barrier Protection and Intestinal T Cell Activation during Colitis.微生物群诱导的 TNF 样配体 1A 驱动第 3 组先天淋巴细胞介导的屏障保护和结肠炎期间的肠道 T 细胞激活。
Immunity. 2018 Dec 18;49(6):1077-1089.e5. doi: 10.1016/j.immuni.2018.10.014. Epub 2018 Dec 11.
8
RNA modifications modulate gene expression during development.RNA 修饰在发育过程中调节基因表达。
Science. 2018 Sep 28;361(6409):1346-1349. doi: 10.1126/science.aau1646.
9
Innate Lymphoid Cells: 10 Years On.先天淋巴细胞：十年进展。
Cell. 2018 Aug 23;174(5):1054-1066. doi: 10.1016/j.cell.2018.07.017.
10
LAG3 Regulatory T Cells Restrain Interleukin-23-Producing CX3CR1 Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis.LAG3 调节性 T 细胞在 3 组固有淋巴细胞驱动的结肠炎中抑制产生白细胞介素-23 的 CX3CR1 肠道驻留巨噬细胞。
Immunity. 2018 Aug 21;49(2):342-352.e5. doi: 10.1016/j.immuni.2018.07.007. Epub 2018 Aug 7.
Zotero 插件