HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity

作者：Wang, Huanbin; Yao, Han; Li, Chushu; Shi, Hubing; Lan, jiang; Li, Zhaoli; Zhang, Yao; Liang, Lunxi; Fang, Jing-Yuan; Xu, Jie^*

来源：Nature Chemical Biology, 2019, 15(1): 42-+.

DOI：10.1038/s41589-018-0161-x

• SELECTIVE DEGRADATION
• HIV-1 NEF
• PROTEIN
• EXPRESSION
• IDENTIFICATION
• STABILIZATION
• DISRUPTION
• COMPLEXES
• KNOCKDOWN
• APOPTOSIS

Expression of programmed cell death 1 (PD-1) ligand 1 (PD-L1) protects tumor cells from T cell-mediated immune surveillance, and immune checkpoint blockade (ICB) therapies targeting PD-1 and PD-L1 have exhibited significant clinical benefits. However, the relatively low response rate and observed ICB resistance highlight the need to understand the molecular regulation of PD-L1. Here we show that HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity. HIP1R physically interacts with PD-L1 and delivers PD-L1 to the lysosome through a lysosomal targeting signal. Depletion of HIP1R in tumor cells caused PD-L1 accumulation and suppressed T cell-mediated cytotoxicity. A rationally designed peptide (PD-LYSO) incorporating the lysosome-sorting signal and the PD-L1-binding sequence of HIP1R successfully depleted PD-L1 expression in tumor cells. Our results identify the molecular machineries governing the lysosomal degradation of PD-L1 and exemplify the development of a chimeric peptide for targeted degradation of PD-L1 as a crucial anticancer target.

• 出版日期2019-1
• 单位长沙市中心医院; 癌基因与相关基因国家重点实验室; 四川大学; 生物治疗国家重点实验室; 兽医生物技术国家重点实验室; 中国农业科学院哈尔滨兽医研究所; 上海交通大学