1. Academic Validation
  2. mTOR signaling promotes rapid m6A mRNA methylation to regulate NK-cell activation and effector functions

mTOR signaling promotes rapid m6A mRNA methylation to regulate NK-cell activation and effector functions

  • Cancer Immunol Res. 2024 Apr 19. doi: 10.1158/2326-6066.CIR-23-0339.
Meng Meng 1 Zhaoyang Zhong 2 Liang Song 3 Zhaohui Zhang 1 Xiaofeng Yin 1 Xiqiang Xie 1 Lei Tian 4 Wei Wu 5 Yao Yang 6 Yafei Deng 7 Hongyan Peng 7 Shuting Wu 7 Guanghe Ran 1 Yuqing Lin 1 Qiangqiang Lai 1 Qinghua Bi 1 Fulin Yan 1 Yan Ji 1 Yang Wang 8 Xiaohui Li 9 Ping Yi 8 Jianhua Yu 10 Youcai Deng 9
Affiliations

Affiliations

  • 1 Army Medical University, China.
  • 2 Cancer Center, Chongqing, China.
  • 3 Chongqing Medical University, China.
  • 4 City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
  • 5 Southwest Hospital, Third Military Medical University, CHongqing, China.
  • 6 Third Miltary Medical University, Chongqing, China.
  • 7 Hunan Children's Hospital, Changsha, Hunan, China.
  • 8 The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 9 Army Medical University, Chongqing, China.
  • 10 City Of Hope National Medical Center, Duarte, CA, United States.
Abstract

Natural killer (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 the numerous genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment. Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double knockout of METTL3/14 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 (MeRIP-seq), we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 (mTORC1) activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine (SAM) supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTORC1-SAM signal axis in regulating NK-cell activation and effector functions.

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