研究者在该文中展示了一种非传统类型的肽硫酯,它包括一个氨乙基硫酯,该基团是硫酯酶的底物,可用于迅速靶向到细胞的高尔基体(GA)。这种肽硫酯——在高于或低于其临界胶束浓度下——分别主要通过小窝蛋白介导的内吞作用或巨胞饮作用进入细胞。在被GA相关的硫酯酶水解后,产生的硫肽可形成二聚体并在GA中积累。GA被硫肽饱和后,硫肽便在内质网(ER)中富集。硫肽在ER和GA中的积累会干扰蛋白质的运输,并通过多种途径导致细胞死亡。
研究人员发现,这种硫酯肽可针对多种细胞的GA,包括人类、小鼠和果蝇细胞。将肽中的D-二苯基丙氨酸转化为L-二苯基丙氨酸,也可以保留其对GA的靶向能力。此外,靶向GA还可重新定向一些蛋白质(如NRAS)的分布。这项工作展示了一个对硫酯酶敏感且具氧化还原活性的分子平台,以用于靶向GA和控制细胞命运。
据介绍,高尔基体(GA)是细胞内运输的中心,但选择性靶向高尔基体仍是一个挑战。
附:英文原文
Title: Enzyme-Responsive Peptide Thioesters for Targeting Golgi Apparatus
Author: Weiyi Tan, Qiuxin Zhang, Monica C. Quiones-Frías, Alan Y. Hsu, Yichi Zhang, Avital Rodal, Pengyu Hong, Hongbo R. Luo, Bing Xu
Issue&Volume: April 11, 2022
Abstract: The Golgi apparatus (GA) is the hub of intracellular trafficking, but selectively targeting GA remains a challenge. We show an unconventional types of peptide thioesters, consisting of an aminoethyl thioester and acting as substrates of thioesterases, for instantly targeting the GA of cells. The peptide thioesters, above or below their critical micelle concentrations, enter cells mainly via caveolin-mediated endocytosis or macropinocytosis, respectively. After being hydrolyzed by GA-associated thioesterases, the resulting thiopeptides form dimers and accumulate in the GA. After saturating the GA, the thiopeptides are enriched in the endoplasmic reticulum (ER). Their buildup in ER and GA disrupts protein trafficking, thus leading to cell death via multiple pathways. The peptide thioesters target the GA of a wide variety of cells, including human, murine, and Drosophila cells. Changing d-diphenylalanine to l-diphenylalanine in the peptide maintains the GA-targeting ability. In addition, targeting GA redirects protein (e.g., NRAS) distribution. This work illustrates a thioesterase-responsive and redox-active molecular platform for targeting the GA and controlling cell fates.
DOI: 10.1021/jacs.2c02238
Source: https://pubs.acs.org/doi/10.1021/jacs.2c02238
JACS:《美国化学会志》,创刊于1879年。隶属于美国化学会,最新IF:14.612
官方网址:https://pubs.acs.org/journal/jacsat
投稿链接:https://acsparagonplus.acs.org/psweb/loginForm?code=1000