1. ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy
- Author
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Xiao, Xiangling, Shi, Jie, He, Chuan, Bu, Xia, Sun, Yishuang, Gao, Minling, Xiang, Bolin, Xiong, Wenjun, Dai, Panpan, Mao, Qi, Xing, Xixin, Yao, Yingmeng, Yu, Haisheng, Xu, Gaoshan, Li, Siqi, Ren, Yan, Chen, Baoxiang, Jiang, Congqing, Meng, Geng, Lee, Yu Ru, Wei, Wenyi, Freeman, Gordon J., Xie, Conghua, Zhang, Jinfang, Xiao, Xiangling, Shi, Jie, He, Chuan, Bu, Xia, Sun, Yishuang, Gao, Minling, Xiang, Bolin, Xiong, Wenjun, Dai, Panpan, Mao, Qi, Xing, Xixin, Yao, Yingmeng, Yu, Haisheng, Xu, Gaoshan, Li, Siqi, Ren, Yan, Chen, Baoxiang, Jiang, Congqing, Meng, Geng, Lee, Yu Ru, Wei, Wenyi, Freeman, Gordon J., Xie, Conghua, and Zhang, Jinfang
- Abstract
The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy., The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy.
- Published
- 2023