Publication in Nature Communications by Prof. LIN Aifu’s Laboratory, Institute of Genetics and Regenerative Biology

Title: 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 & Aifu Lin

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.

Link:  https://www.nature.com/articles/s41467-022-34346-x

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