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Heat shock protein gp96 drives natural killer cell maturation and anti-tumor immunity by counteracting Trim28 to stabilize Eomes

Author

Listed:
  • Yuxiu Xu

    (Chinese Academy of Sciences (CAS))

  • Xin Li

    (Chinese Academy of Sciences (CAS))

  • Fang Cheng

    (Chinese Academy of Sciences (CAS)
    University of Chinese Academy of Sciences)

  • Bao Zhao

    (The First Affiliated Hospital of Bengbu Medical College)

  • Min Fang

    (Chinese Academy of Sciences (CAS))

  • Zihai Li

    (The Ohio State University Comprehensive Cancer Center)

  • Songdong Meng

    (Chinese Academy of Sciences (CAS)
    University of Chinese Academy of Sciences)

Abstract

The maturation process of natural killer (NK) cells, which is regulated by multiple transcription factors, determines their functionality, but few checkpoints specifically targeting this process have been thoroughly studied. Here we show that NK-specific deficiency of glucose-regulated protein 94 (gp96) leads to decreased maturation of NK cells in mice. These gp96-deficient NK cells exhibit undermined activation, cytotoxicity and IFN-γ production upon stimulation, as well as weakened responses to IL-15 for NK cell maturation, in vitro. In vivo, NK-specific gp96-deficient mice show increased tumor growth. Mechanistically, we identify Eomes as the downstream transcription factor, with gp96 binding to Trim28 to prevent Trim28-mediated ubiquitination and degradation of Eomes. Our study thus suggests the gp96-Trim28-Eomes axis to be an important regulator for NK cell maturation and cancer surveillance in mice.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45426-5
    DOI: 10.1038/s41467-024-45426-5
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    References listed on IDEAS

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    1. Jiang Zhang & Stéphanie Le Gras & Kevin Pouxvielh & Fabrice Faure & Lucie Fallone & Nicolas Kern & Marion Moreews & Anne-Laure Mathieu & Raphaël Schneider & Quentin Marliac & Mathieu Jung & Aurore Ber, 2021. "Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    2. 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.
    3. Mengmeng Niu & Jing Xu & Yang Liu & Yuhuang Li & Tao He & Liangping Ding & Yajun He & Yong Yi & Fengtian Li & Rongtian Guo & Ya Gao & Rui Li & Luping Li & Mengyuan Fu & Qingyong Hu & Yangkun Luo & Chu, 2021. "FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Srividya Swaminathan & Aida S. Hansen & Line D. Heftdal & Renumathy Dhanasekaran & Anja Deutzmann & Wadie D. M. Fernandez & Daniel F. Liefwalker & Crista Horton & Adriane Mosley & Mariola Liebersbach , 2020. "MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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