Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2
Zhen Wu,
Zhijie Cao,
Han Yao,
Xiaojun Yan,
Wenbin Xu,
Mi Zhang,
Zishan Jiao,
Zijing Zhang,
Jianyuan Chen,
Yajing Liu,
Meng Zhang,
Donglai Wang
Affiliations
Zhen Wu
State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
Zhijie Cao
State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
Han Yao
State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
Xiaojun Yan
State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
Wenbin Xu
State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
Mi Zhang
Department of Anatomy, Histology and Embryology, School of Basic Medicine, China Medical University, Shenyang 110122, China
Zishan Jiao
State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
Zijing Zhang
State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
Jianyuan Chen
State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
Yajing Liu
State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
Meng Zhang
State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
Donglai Wang
State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Corresponding author
Summary: Posttranslational modifications represent a key step in modulating programmed death-1 (PD-1) functions, but the underlying mechanisms remain incompletely defined. Here, we report crosstalk between deglycosylation and ubiquitination in regulating PD-1 stability. We show that the removal of N-linked glycosylation is a prerequisite for efficient PD-1 ubiquitination and degradation. Murine double minute 2 (MDM2) is identified as an E3 ligase of deglycosylated PD-1. In addition, the presence of MDM2 facilitates glycosylated PD-1 interaction with glycosidase NGLY1 and promotes subsequent NGLY1-catalyzed PD-1 deglycosylation. Functionally, we demonstrate that the absence of T cell-specific MDM2 accelerates tumor growth by primarily upregulating PD-1. By stimulating the p53-MDM2 axis, interferon-α (IFN-α) reduces PD-1 levels in T cells, which, in turn, exhibit a synergistic effect on tumor suppression by sensitizing anti-PD-1 immunotherapy. Our study reveals that MDM2 directs PD-1 degradation via a deglycosylation-ubiquitination coupled mechanism and sheds light on a promising strategy to boost cancer immunotherapy by targeting the T cell-specific MDM2-PD-1 regulatory axis.
