作者
Chengyu Shi,Ying Wang,Minjie Wu,Yu Chen,Fangzhou Liu,Zheyuan Shen,Yiran Wang,Shengling Xie,Yingying Shen,Lingjie Sang,Zhen Zhang,Zerui Gao,Luojia Yang,Lei Qu,Zuozhen Yang,Xinyu He,Yu Guo,Chenghao Pan,Jinxin Che,Huai-Qiang Ju,J. Liu,Zhijian Cai,Qingfeng Yan,Luyang Yu,Liang-jing Wang,Xiaowu Dong,Pinglong Xu,Jian-Zhong Shao,Yang Liu,Xu Li,Wenqi Wang,Ruhong Zhou,Tian Zhou,Aifu Lin
摘要
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.