Journal Article

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

Qu, Lei, Shen, Zheyuan, Ju, Huaiqiang, Wang, Liangjing, Shi, Chengyu, Wang, Ying, Liu, Fangzhou, Zhou, Ruhong, Wu, Minjie, Gao, Zerui, Shao, Jianzhong, Xie, Shaofang, Yang, Zuozhen, Wang, Wenqi, Liu, Jian, Cai, Zhijian, Yang, Luojia, Li, Xu, Guo, Yu, He, Xinyu, Zhang, Zhen, Wang, Yiran, Liu, Yang, Zhou, Tianhua, Chen, Yu, Pan, Chenghao, Lin, Aifu, Che, Jinxin, Yan, Qingfeng, Yu, Luyang, Sang, Lingjie, Xu, Pinglong, Dong, Xiaowu, Shen, Yingying

2022

Overview

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. Cancer cells exploit immune checkpoint pathways, such as PD-1/PD-L1, to evade elimination by the immune system. Here, the authors demonstrate that TMUB1 regulates post-translational modifications of PD-L1 and that targeting the TMUB1/PD-L1 interaction promotes anti-tumour T cells responses

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/109 / 13/31 / 13/51 / 14 / 14/19 / 14/63 / 38/88 / 631/250/251 / 631/67/580 / 631/80/2023 / 631/80/458 / 64/60 / Animals / B7-H1 Antigen - metabolism / Competition / Endoplasmic reticulum / Glycosylation / Humanities and Social Sciences / Humans / Huwe1 protein / Immune checkpoint / Immune system / Immunity / Immunotherapy / Lymphocytes / Lymphocytes T / Mice / multidisciplinary / Neoplasms - genetics / Neoplasms - therapy / PD-1 protein / PD-L1 protein / Post-translation / Proteins / Regulatory mechanisms (biology) / Science / Science (multidisciplinary) / Survival / Translation / Tumor cells / Tumor Escape / Tumor Suppressor Proteins - metabolism / Tumors / Ubiquitin / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Ubiquitination