Deciphering Cholesterol's Role in PD-L2 Stability: A Distinct Regulatory Mechanism From PD-L1

被引:0
|
作者
Zhang, Yu [1 ,2 ]
Xiao, Taoran [1 ,2 ]
Wen, Maorong [1 ]
Shen, Lijuan [1 ]
Du, Lingyu [1 ]
Wei, Shukun [1 ]
Wu, Bin [3 ]
Yu, Yang [3 ]
Wang, Shuqing [1 ,2 ,4 ]
Ouyang, Bo [1 ,2 ]
机构
[1] Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, State Key Lab Mol Biol, 320Yueyang Rd, Shanghai 200031, Peoples R China
[2] Univ Chinese Acad Sci, Beijing 100049, Peoples R China
[3] Chinese Acad Sci, Shanghai Adv Res Inst, ZhangJiang Lab, Natl Facil Prot Sci Shanghai, Shanghai 201203, Peoples R China
[4] Tianjin Med Univ, Sch Pharm, Tianjin Key Lab Technol Enabling Dev Clin Therapeu, Qixiangtai Rd 22, Tianjin 300070, Peoples R China
基金
中国国家自然科学基金; 国家重点研发计划;
关键词
PD-L2; PD-L1; NMR spectroscopy; cholesterol binding motif; protein stability; PROTEIN; EXPRESSION; DYNAMICS; CELLS;
D O I
10.1016/j.jmb.2024.168500
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Programmed cell death 1 ligand 2 (PD-L2), a member of the B7 immune checkpoint protein family, emerges as a crucial player in immune modulation. Despite its functional overlap with programmed cell death 1 ligand 1 (PD-L1) in binding to the programmed cell death protein 1 (PD-1) on T cells, PD-L2 exhibits a divergent expression pattern and a higher affinity for PD-1. However, the regulatory mechanisms of PD-L2 remain under-explored. Here, our investigations illustrate the pivotal role of cholesterol in modulating PD-L2 stability. Using advanced nuclear magnetic resonance (NMR) and biochemical analyses, we demonstrate a direct and specific binding between cholesterol and PD-L2, mediated by an F-xxx-V-xxLR motif in its transmembrane domain, distinct from that in PD-L1. This interaction stabilizes PD-L2 and prevents its downstream degradation. Disruption of this binding motif compromises PD-L20s cellular stability, underscoring its potential significance in cancer biology. These findings not only deepen our understanding of PD-L2 regulation in the context of tumors, but also open avenues for potential therapeutic interventions. (c) 2024 Elsevier Ltd. All rights reserved.
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页数:16
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