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METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells

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  • Hao Song

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Jiaxi Song

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Ming Cheng

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Meijuan Zheng

    (The First Affiliated Hospital of Anhui Medical University)

  • Tian Wang

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Sha Tian

    (Fudan University)

  • Richard A. Flavell

    (Yale University School of Medicine
    Howard Hughes Medical Institute)

  • Shu Zhu

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Hua-Bing Li

    (Shanghai Jiao Tong University School of Medicine)

  • Chen Ding

    (Fudan University)

  • Haiming Wei

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Rui Sun

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Hui Peng

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Zhigang Tian

    (University of Science and Technology of China
    University of Science and Technology of China
    Chinese Academy of Medical Sciences)

Abstract

Natural killer (NK) cells exert critical roles in anti-tumor immunity but how their functions are regulated by epitranscriptional modification (e.g., N6-methyladenosine (m6A) methylation) is unclear. Here we report decreased expression of the m6A “writer” METTL3 in tumor-infiltrating NK cells, and a positive correlation between protein expression levels of METTL3 and effector molecules in NK cells. Deletion of Mettl3 in NK cells alters the homeostasis of NK cells and inhibits NK cell infiltration and function in the tumor microenvironment, leading to accelerated tumor development and shortened survival in mice. The gene encoding SHP-2 is m6A modified, and its protein expression is decreased in METTL3-deficient NK cells. Reduced SHP-2 activity renders NK cells hyporesponsive to IL-15, which is associated with suppressed activation of the AKT and MAPK signaling pathway in METTL3-deficient NK cells. These findings show that m6A methylation safeguards the homeostasis and tumor immunosurveillance function of NK cells.

Suggested Citation

  • Hao Song & Jiaxi Song & Ming Cheng & Meijuan Zheng & Tian Wang & Sha Tian & Richard A. Flavell & Shu Zhu & Hua-Bing Li & Chen Ding & Haiming Wei & Rui Sun & Hui Peng & Zhigang Tian, 2021. "METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25803-0
    DOI: 10.1038/s41467-021-25803-0
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    Cited by:

    1. Yuxiu Xu & Xin Li & Fang Cheng & Bao Zhao & Min Fang & Zihai Li & Songdong Meng, 2024. "Heat shock protein gp96 drives natural killer cell maturation and anti-tumor immunity by counteracting Trim28 to stabilize Eomes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Gaia Timoteo & Andrea Giuliani & Adriano Setti & Martina C. Biagi & Michela Lisi & Tiziana Santini & Alessia Grandioso & Davide Mariani & Francesco Castagnetti & Eleonora Perego & Sabrina Zappone & Se, 2024. "M6A reduction relieves FUS-associated ALS granules," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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