程序性细胞死亡 1 配体 2 (PD-L2) 是 B7 免疫检查点蛋白家族的成员，在免疫调节中发挥着至关重要的作用。尽管在与 T 细胞上的程序性细胞死亡蛋白 1 (PD-1) 结合方面与程序性细胞死亡 1 配体 1 (PD-L1) 功能重叠，但 PD-L2 表现出不同的表达模式以及对 PD-1 的更高亲和力。然而，PD-L2 的调控机制仍有待探索。在这里，我们的研究说明了胆固醇在调节 PD-L2 稳定性中的关键作用。使用先进的核磁共振 (NMR) 和生化分析，我们证明了胆固醇和 PD-L2 之间存在直接且特异性的结合，该结合是由其跨膜结构域中的 F-xxx-V-xx-LR 基序介导的，这与 PD-L2 中的结合不同。 L1。这种相互作用可以稳定 PD-L2 并防止其下游降解。这种结合基序的破坏会损害 PD-L2 的细胞稳定性，强调了其在癌症生物学中的潜在重要性。这些发现不仅加深了我们对肿瘤背景下 PD-L2 调控的理解，而且为潜在的治疗干预措施开辟了途径。版权所有 © 2024 Elsevier Ltd. 保留所有权利。

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-xx-LR 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-L2's 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.Copyright © 2024 Elsevier Ltd. All rights reserved.