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

Yuxiu Xu, Xin Li (), Fang Cheng, Bao Zhao, Min Fang, Zihai Li and Songdong Meng ()
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Yuxiu Xu: Chinese Academy of Sciences (CAS)
Xin Li: Chinese Academy of Sciences (CAS)
Fang Cheng: Chinese Academy of Sciences (CAS)
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)

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45426-5

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