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COP1 囊泡形成和 N-豆蔻酰化是衰老细胞的靶向弱点。

COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells.

机构信息

MRC Laboratory of Medical Sciences (LMS), London, UK.

Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.

出版信息

Nat Cell Biol. 2023 Dec;25(12):1804-1820. doi: 10.1038/s41556-023-01287-6. Epub 2023 Nov 27.

DOI:10.1038/s41556-023-01287-6
PMID:38012402
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10709147/
Abstract

Drugs that selectively kill senescent cells (senolytics) improve the outcomes of cancer, fibrosis and age-related diseases. Despite their potential, our knowledge of the molecular pathways that affect the survival of senescent cells is limited. To discover senolytic targets, we performed RNAi screens and identified coatomer complex I (COPI) vesicle formation as a liability of senescent cells. Genetic or pharmacological inhibition of COPI results in Golgi dispersal, dysfunctional autophagy, and unfolded protein response-dependent apoptosis of senescent cells, and knockdown of COPI subunits improves the outcomes of cancer and fibrosis in mouse models. Drugs targeting COPI have poor pharmacological properties, but we find that N-myristoyltransferase inhibitors (NMTi) phenocopy COPI inhibition and are potent senolytics. NMTi selectively eliminated senescent cells and improved outcomes in models of cancer and non-alcoholic steatohepatitis. Our results suggest that senescent cells rely on a hyperactive secretory apparatus and that inhibiting trafficking kills senescent cells with the potential to treat various senescence-associated diseases.

摘要

选择性杀死衰老细胞的药物（衰老细胞清除剂）能改善癌症、纤维化和与年龄相关的疾病的预后。尽管它们有很大的潜力，但我们对影响衰老细胞存活的分子途径的了解是有限的。为了发现衰老细胞清除剂的靶点，我们进行了 RNAi 筛选，发现衣被蛋白复合物 I（COP I）囊泡形成是衰老细胞的一个缺陷。COP I 的遗传或药理学抑制导致高尔基分散、功能失调的自噬和未折叠蛋白反应依赖性衰老细胞凋亡，并且 COPI 亚基的敲低可改善小鼠模型中癌症和纤维化的预后。靶向 COPI 的药物具有较差的药理特性，但我们发现 N-豆蔻酰转移酶抑制剂（NMTi）能模拟 COPI 抑制作用，是有效的衰老细胞清除剂。NMTi 选择性地消除衰老细胞，并改善癌症和非酒精性脂肪性肝炎模型的预后。我们的研究结果表明，衰老细胞依赖于一个过度活跃的分泌装置，并且抑制运输可以杀死衰老细胞，具有治疗各种与衰老相关疾病的潜力。

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