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

Abstract

Abstract The maturation process of natural killer (NK)cells determines their functionality,during which multiple transcriptional factors play a critical role. However, few checkpoints specifically targeting this process have been discovered. Here, we show that NK-specific deficiency of glucose-regulated protein 94 (gp96) led to decreased maturation of NK cells in mice. These gp96-deficient NK cells exhibited undermined activation, cytotoxicity, and IFN-γ production upon stimulation and weakened response to IL-15 for maturation. NK-specific gp96-deficient mice were prone to tumor growth in vivo. Eomes was identified as a key transcription factor involved in gp96-mediated NK maturation. Interaction between gp96 and E3 ubiquitin ligase Trim28 blocked Trim28 binding to Eomes and protected Eomes from ubiquitination and degradation. Together, our study demonstrates that the gp96-Trim28-Eomes axis plays a critical role in NK cell maturation and anti-tumor immunity in mice, suggesting a novel mechanism for gp96 in regulating NK cell immunity.