METTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells

Zhiqiang Xiao; Shanshan Wang; Yixia Tian; Wenkai Lv; Hao Sheng; Mingjie Zhan; Qiongxiao Huang; Zhanpeng Zhang; Leqing Zhu; Chuyun Zhu; Hui Zhong; Qiong Wen; Zonghua Liu; Jingyi Tan; Yan Xu; Meixiang Yang; Yumei Liu; Richard A Flavell; Quanli Yang; Guangchao Cao; Zhinan Yin

doi:10.1016/j.celrep.2023.112684

METTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells

Cell Rep. 2023 Jul 25;42(7):112684. doi: 10.1016/j.celrep.2023.112684. Epub 2023 Jun 23.

Authors

Zhiqiang Xiao¹, Shanshan Wang¹, Yixia Tian¹, Wenkai Lv¹, Hao Sheng², Mingjie Zhan¹, Qiongxiao Huang³, Zhanpeng Zhang⁴, Leqing Zhu⁵, Chuyun Zhu¹, Hui Zhong¹, Qiong Wen¹, Zonghua Liu¹, Jingyi Tan¹, Yan Xu¹, Meixiang Yang¹, Yumei Liu⁶, Richard A Flavell⁷, Quanli Yang⁸, Guangchao Cao⁹, Zhinan Yin¹⁰

Affiliations

¹ Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China; The Biomedical Translational Research Institute, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China.
² National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518172, China.
³ Institute of Dermatology, Guangzhou Medical University, Guangzhou 510095, China; Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou 510095, China.
⁴ The First Affiliated Hospital, Faculty of Medical Science, Jinan University, Guangzhou 510632, China.
⁵ The Biomedical Translational Research Institute, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; The First Affiliated Hospital, Faculty of Medical Science, Jinan University, Guangzhou 510632, China.
⁶ Institute of Dermatology, Guangzhou Medical University, Guangzhou 510095, China; Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou 510095, China. Electronic address: liuyumei1109@163.com.
⁷ Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. Electronic address: richard.flavell@yale.edu.
⁸ Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China; The Biomedical Translational Research Institute, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China. Electronic address: qlyang@jnu.edu.cn.
⁹ Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China; The Biomedical Translational Research Institute, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China. Electronic address: gccao2016@jnu.edu.cn.
¹⁰ Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China; The Biomedical Translational Research Institute, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China. Electronic address: tzhinan@jnu.edu.cn.

PMID: 37355989
DOI: 10.1016/j.celrep.2023.112684

Abstract

γδ T cells make key contributions to tissue physiology and immunosurveillance through two main functionally distinct subsets, γδ T1 and γδ T17. m6A methylation plays critical roles in controlling numerous aspects of mRNA metabolism that govern mRNA turnover, gene expression, and cellular functional specialization; however, its role in γδ T cells remains less well understood. Here, we find that m6A methylation controls the functional specification of γδ T17 vs. γδ T1 cells. Mechanistically, m6A methylation prevents the formation of endogenous double-stranded RNAs and promotes the degradation of Stat1 transcripts, which converge to prevent over-activation of STAT1 signaling and ensuing inhibition of γδ T17. Deleting Mettl3, the key enzyme in the m6A methyltransferases complex, in γδ T cells reduces interleukin-17 (IL-17) production and ameliorates γδ T17-mediated psoriasis. In summary, our work shows that METTL3-mediated m6A methylation orchestrates mRNA stability and double-stranded RNA (dsRNA) contents to equilibrate γδ T1 and γδ T17 cells.

Keywords: CP: Immunology; CP: Molecular biology; IL-17; m6A methylation; psoriasis; γδ T cells.

Publication types

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

MeSH terms

Methylation
Methyltransferases* / genetics
Methyltransferases* / metabolism
RNA Stability
RNA, Double-Stranded*
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

RNA, Double-Stranded
Methyltransferases
RNA, Messenger