Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation

Chengyu Shi, Ying Wang, Minjie Wu, Yu Chen, Fangzhou Liu, Zheyuan Shen, Yiran Wang, Shaofang Xie, Yingying Shen, Lingjie Sang, Zhen Zhang, Zerui Gao, Luojia Yang, Lei Qu, Zuozhen Yang, Xinyu He, Yu Guo, Chenghao Pan, Jinxin Che, Huaiqiang Ju, Jian Liu, Zhijian Cai, Qingfeng Yan, Luyang Yu, Liangjing Wang, Xiaowu Dong, Pinglong Xu, Jianzhong Shao, Yang Liu, Xu Li (), Wenqi Wang (), Ruhong Zhou (), Tianhua Zhou () and Aifu Lin ()
Additional contact information
Chengyu Shi: Zhejiang University
Ying Wang: Zhejiang University
Minjie Wu: Zhejiang University
Yu Chen: Zhejiang University
Fangzhou Liu: Zhejiang University
Zheyuan Shen: Zhejiang University
Yiran Wang: Zhejiang University
Shaofang Xie: Westlake University
Yingying Shen: Zhejiang University School of Medicine
Lingjie Sang: Zhejiang University
Zhen Zhang: Zhejiang University
Zerui Gao: Zhejiang University
Luojia Yang: Zhejiang University
Lei Qu: Zhejiang University
Zuozhen Yang: Zhejiang University
Xinyu He: Zhejiang University
Yu Guo: Zhejiang University
Chenghao Pan: Zhejiang University
Jinxin Che: Zhejiang University
Huaiqiang Ju: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Jian Liu: Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University
Zhijian Cai: Zhejiang University School of Medicine
Qingfeng Yan: Zhejiang University
Luyang Yu: Zhejiang University
Liangjing Wang: Zhejiang University
Xiaowu Dong: Zhejiang University
Pinglong Xu: Zhejiang University
Jianzhong Shao: Zhejiang University
Yang Liu: Zhejiang University School of Medicine
Xu Li: Westlake University
Wenqi Wang: University of California
Ruhong Zhou: Zhejiang University
Tianhua Zhou: Zhejiang University
Aifu Lin: Zhejiang University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target.

Date: 2022
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DOI: 10.1038/s41467-022-34346-x

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