Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs----上海高等研究院

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Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs

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论文题目: Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs
作者: Wang, Qian; Cao, Yunlei; Shen, Lijuan; Xiao, Taoran; Cao, Ruiyu; Wei, Shukun; Tang, Meng; Du, Lingyu; Wu, Hongyi; Wu, Bin; Yu, Yang; Wang, Shuqing; Wen, Maorong; OuYang, Bo
刊名: SCIENCE ADVANCES
出版年: 2022 卷: 8 文献号: 2375-2548
关键词:
Wang, Qian; Cao, Yunlei; Shen, Lijuan; Xiao, Taoran; Cao, Ruiyu; Wei, Shukun; Tang, Meng; Du, Lingyu; Wu, Hongyi; Wu, Bin; Yu, Yang; Wang, Shuqing; Wen, Maorong; OuYang, Bo
摘要:
Cholesterol, an essential molecule for cell structure, function, and viability, plays crucial roles in the development, progression, and survival of cancer cells. Earlier studies have shown that cholesterol-lowering drugs can inhibit the high expression of programmed-death ligand 1 (PD-L1) that contributes to immunoevasion in cancer cells. However, the regulatory mechanism of cell surface PD-L1 abundance by cholesterol is still controversial. Here, using nuclear magnetic resonance and biochemical techniques, we demonstrated that cholesterol can directly bind to the transmembrane domain of PD-L1 through two cholesterol-recognition amino acid consensus (CRAC) motifs, forming a sandwich-like architecture and stabilizing PD-L1 to prevent downstream degradation. Mutations at key binding residues prohibit PD-L1-cholesterol interactions, decreasing the cellular abundance of PD-L1. Our results reveal a unique regulatory mechanism that controls the stability of PD-L1 in cancer cells, providing an alternative method to overcome PD-L1-mediated immunoevasion in cancers.

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中国科学院上海高等研究院