mTOR Signaling Promotes Rapid m<SUP>6</SUP>A mRNA Methylation to Regulate NK-Cell Activation and Effector Functions

作者全名："Meng, Meng; Zhong, Zhaoyang; Song, Liang; Zhang, Zhaohui; Yin, Xiaofeng; Xie, Xiqiang; Tian, Lei; Wu, Wei; Yang, Yao; Deng, Yafei; Peng, Hongyan; Wu, Shuting; Ran, Guanghe; Lin, Yuqing; Lai, Qiangqiang; Bi, Qinghua; Yan, Fulin; Ji, Yan; Wang, Yang; Li, Xiaohui; Yi, Ping; Yu, Jianhua; Deng, Youcai"

作者地址："[Meng, Meng; Zhang, Zhaohui; Yin, Xiaofeng; Xie, Xiqiang; Yang, Yao; Ran, Guanghe; Lin, Yuqing; Lai, Qiangqiang; Bi, Qinghua; Yan, Fulin; Ji, Yan; Li, Xiaohui; Deng, Youcai] Army Med Univ, Coll Pharm & Lab Med Sci, Dept Clin Hematol, Chongqing, Peoples R China; [Meng, Meng] Chongqing Med Univ, Sch Basic Med Sci, Chongqing, Peoples R China; [Zhong, Zhaoyang] Fifth Peoples Hosp Chongqing, Chongqing 400062, Peoples R China; [Song, Liang] Chongqing Med Univ, Coll Tradit Chinese Med, Chongqing, Peoples R China; [Tian, Lei; Yu, Jianhua] City Hope Natl Med Ctr, Dept Hematol & Hematopoiet Cell Transplantat, Los Angeles, CA USA; [Tian, Lei; Yu, Jianhua] City Hope Natl Med Ctr, Hematol Malignancies Res Inst, Los Angeles, CA USA; [Wu, Wei] Army Med Univ, Southwest Hosp, Thorac Surg Dept, Hosp Affiliated 1, Chongqing, Peoples R China; [Deng, Yafei; Peng, Hongyan; Wu, Shuting] Hunan Childrens Hosp, Pediat Res Inst Hunan Prov, Changsha, Peoples R China; [Wang, Yang; Yi, Ping] Chongqing Med Univ, Dept Obstet & Gynecol, Affiliated Hosp 3, Chongqing, Peoples R China"

通信作者："Zhong, ZY (通讯作者)，Fifth Peoples Hosp Chongqing, Chongqing 400062, Peoples R China.; Yi, P (通讯作者)，Chongqing Med Univ, Affiliated Hosp 3, Chongqing 401120, Peoples R China.; Yu, JH (通讯作者)，City Hope Natl Med Ctr, Los Angeles, CA 91010 USA.; Deng, YC (通讯作者)，Army Med Univ, Chongqing 400038, Peoples R China."

来源：CANCER IMMUNOLOGY RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001284902500002

JCR分区：Q1

影响因子：10.1

年份：2024

卷号：12

期号：8

开始页：1039

结束页：1057

文献类型：Article

关键词：　

摘要："NK cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of a large number of genes involved in activating NK cells. In this study, we discovered that NK-cell N-6-methyladenosine (m(6)A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment (TME). Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double-knockout of METTL3/14 more significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing, we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m(6)A methylation. Furthermore, inhibiting mTOR complex 1 activation prevented m(6)A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine supplementation. Collectively, we have unraveled crucial roles for rapid m(6)A mRNA methylation downstream of the mTOR complex 1-S-adenosylmethionine signal axis in regulating NK-cell activation and effector functions."

基金机构："National Natural Science Foundation of China [81922068, 82273938, 81903627]; Chongqing Science and Technology Commission of China [cstc2021jcyj-jqX0006]; National Key Research and Development Project [2020YFA0113500, 2019YFA0111200]; Natural Science Foundation of Hunan Province [2021JJ40274, 2020JJ5279]; Guangdong Association of Clinical Trials (GACT)/Chinese Thoracic Oncology Group (CTONG), Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer [CTONG-YC20210104]"

基金资助正文："We thank the volunteers for donating their cancer tissues. This work was partially supported by the National Natural Science Foundation of China (Nos. 81922068 and 82273938 to Youcai Deng; No. 81903627 to L. Song). This study was supported by grants from the Chongqing Science and Technology Commission of China (cstc2021jcyj-jqX0006 to Youcai Deng). This study was also supported by funding from the National Key Research and Development Project (Nos. 2020YFA0113500 and 2019YFA0111200 to Youcai Deng); the Natural Science Foundation of Hunan Province (No. 2021JJ40274 to H. Peng; No. 2020JJ5279 to Yafei Deng). This study was also supported by funding from the Guangdong Association of Clinical Trials (GACT)/Chinese Thoracic Oncology Group (CTONG), Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (CTONG-YC20210104, YLW to Z. Zhong)."