发现蛋白水解靶向嵌合体 (PROTAC) 作为 FOXP3 的有效调节剂。
Discovery of a proteolysis targeting chimera (PROTAC) as a potent regulator of FOXP3.
发表日期：2024 Aug 31
作者：
Bowen Yang, Yanhong Cen, Fangfang Li, Yikui Li, Bichun Chen, Jiwei Zheng, Zhongliang Tang, Qiang Gao, Lijing Fang, Fan Pan
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
调节性 T 细胞 (Treg) 在免疫稳态中发挥着核心作用。叉头框 P3 (Foxp3) 是 Tregs 的标志分子，是其发育和功能的重要转录因子，Foxp3 的降解可以为实现有效的抗肿瘤免疫提供治疗益处。在本研究中，我们基于 Foxp3 (P60) 的 15 聚肽抑制剂，设计了三种 PROTAC 分子：P60-L1-VHL、P60-L2-VHL 和 P60-L3-VHL，并探索了它们调节 Foxp3 的潜力。表达和功能。我们的数据表明，在这些分子中，P60-L3-VHL 可以分别抑制 HEK 293T 和 HeLa 细胞中 Foxp3 的表达和核定位。同时，在 P60-L3-VHL 处理的细胞中使用蛋白酶体抑制剂显示 Foxp3 表达增加，表明 P60-L3-VHL 通过蛋白酶体途径中的降解介导 Foxp3 的抑制。我们进一步证实 P60-L3-VHL 减少了体外激活的 Tregs 中的分化和 Foxp3 表达。总体而言，我们的研究结果表明，P60-L3-VHL 通过降解 Foxp3 来抑制 Tregs 分化，并且可能对癌症免疫治疗具有潜在影响。版权所有 © 2024 Elsevier Ltd。保留所有权利。
Regulatory T cells (Tregs) play a central role in immune homeostasis. Forkhead box P3 (Foxp3), a hallmark molecule in Tregs, is a vital transcription factor for their development and function, and degradation of the Foxp3 could provide therapeutic benefits in achieving effective anti-tumor immunity. In this study, we designed three PROTAC molecules, P60-L1-VHL, P60-L2-VHL, and P60-L3-VHL, based on a 15-mer peptide inhibitor of Foxp3 (P60), and explored their potential in regulating Foxp3 expression and function. Our data show that, among these molecules, P60-L3-VHL can inhibit the expression and nuclear localization of Foxp3 in HEK 293 T and HeLa cells, respectively. Meanwhile, use of proteasome inhibitor in P60-L3-VHL treated cells revealed an increased Foxp3 expression, indicating that P60-L3-VHL mediates the inhibition of Foxp3 through its degradation in the proteasome pathway. We further substantiate that P60-L3-VHL reduces the differentiation and Foxp3 expression in the in-vitro activated Tregs. Overall, our findings suggest that P60-L3-VHL inhibits Tregs differentiation by degrading the Foxp3, and it may have potential implications in cancer immunotherapy.Copyright © 2024 Elsevier Ltd. All rights reserved.