Cell Reports (Jul 2023)
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
Affiliations
- Zhiqiang Xiao
- 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
- Shanshan Wang
- 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
- Yixia Tian
- 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
- Wenkai Lv
- 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
- Hao Sheng
- 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
- Mingjie Zhan
- 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
- Qiongxiao Huang
- Institute of Dermatology, Guangzhou Medical University, Guangzhou 510095, China; Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou 510095, China
- Zhanpeng Zhang
- The First Affiliated Hospital, Faculty of Medical Science, Jinan University, Guangzhou 510632, China
- Leqing Zhu
- 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
- Chuyun Zhu
- 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
- Hui Zhong
- 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
- Qiong Wen
- 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
- Zonghua Liu
- 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
- Jingyi Tan
- 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
- Yan Xu
- 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
- Meixiang Yang
- 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
- Yumei Liu
- Institute of Dermatology, Guangzhou Medical University, Guangzhou 510095, China; Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou 510095, China; Corresponding author
- Richard A. Flavell
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA; Corresponding author
- Quanli Yang
- 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; Corresponding author
- Guangchao Cao
- 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; Corresponding author
- Zhinan Yin
- 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; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 7
p. 112684
Abstract
Summary: 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.
