A peptidic inhibitor for PD-1 palmitoylation targets its expression and functions,RSC Chemical Biology

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A peptidic inhibitor for PD-1 palmitoylation targets its expression and functions
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2020-11-3 , DOI: 10.1039/d0cb00157k
Han Yao ₁ , Chushu Li ₁ , Fang He ₂ , Teng Song ₂ , Jean-Philippe Brosseau ₃ , Huanbin Wang ₁ , Haojie Lu ₄ , Caiyun Fang ₄ , Hubing Shi ₅ , Jiang Lan ₅ , Jing-Yuan Fang ₁ , Jie Xu ₂

Affiliation

Programmed cell death protein 1 (PD-1) is a crucial anticancer target, but the relatively low response rate and acquired resistance to existing antibody drugs highlight an urgent need to develop alternative targeting strategies. Here, we report the palmitoylation of PD-1, discover the main DHHC enzyme for this modification, reveal the mechanism of its effect on PD-1 protein stability, and rationally develop a peptide for targeting PD-1 expression. Palmitoylation promoted the trafficking of PD-1 to the recycling endosome, thus preventing its lysosome-dependent degradation. Palmitoylation of PD-1, but not of PD-L1, promoted mTOR signaling and tumor cell proliferation, and targeting palmitoylation displayed significant anti-tumor effects in a three-dimensional culture system. A peptide was designed to competitively inhibit PD-1 palmitoylation and expression, opening a new route for developing PD-1 inhibitors and combinatorial cancer immunotherapy.

中文翻译：

PD-1 棕榈酰化的肽抑制剂靶向其表达和功能

程序性细胞死亡蛋白 1 (PD-1) 是一个关键的抗癌靶点，但相对较低的反应率和对现有抗体药物的获得性耐药突出了开发替代靶向策略的迫切需要。在这里，我们报告了 PD-1 的棕榈酰化，发现了这种修饰的主要 DHHC 酶，揭示了其影响 PD-1 蛋白稳定性的机制，并合理开发了一种靶向 PD-1 表达的肽。棕榈酰化促进了 PD-1 向循环内体的运输，从而防止了其依赖溶酶体的降解。PD-1 的棕榈酰化而不是 PD-L1 的棕榈酰化促进了 mTOR 信号传导和肿瘤细胞增殖，并且靶向棕榈酰化在三维培养系统中显示出显着的抗肿瘤作用。

更新日期：2020-12-10

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