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靶向溶酶体的嵌合体可降解细胞外蛋白
2020-07-30 14:29

美国斯坦福大学Carolyn R. Bertozzi课题组发现,靶向溶酶体的嵌合体可降解细胞外蛋白。2020年7月29日出版的《自然》在线发表了这项成果。

使用结合细胞表面溶酶体梭动受体和靶蛋白胞外结构域的嵌合物,研究人员实现了胞外和膜相关蛋白的靶向降解。这些靶向溶酶体的嵌合体(研究人员称为LYTAC)是由与化学合成糖肽配体融合的小分子或抗体组成,这些配体是不依赖于阳离子甘露糖6-磷酸受体(CI-M6PR)的激动剂。使用LYTACs开发CRISPR干扰筛选,研究人员发现了I-M6PR介导的细胞内容物内吞的生化途径,并揭示了囊外复合物是该途径以前未知但必不可少的组成部分。

研究人员通过降解治疗相关的蛋白(包括载脂蛋白E4、表皮生长因子受体、CD71和程序性死亡配体1)证明了该平台的应用范围。该结果建立了指导溶酶体降解分泌和膜蛋白模块化策略,对生化研究具有广泛的应用前景和治疗意义。

据了解,大多数靶向单个蛋白的治疗都依赖于与靶蛋白特定活性有关的相互作用,例如酶抑制或配体阻断。然而,几类治疗相关的蛋白具有未知或难以获得的活性概况,因此不能用于靶向治疗。已经研发的蛋白质降解平台,例如靶向蛋白水解的chimaeras(PROTAC)和其他蛋白质降解平台(例如dTAGs3、Trim-Away4、伴侣蛋白介导的自噬靶向和SNIPERs),用于通常难以靶向的蛋白质。然而,这些方法涉及对细胞内蛋白质降解机制的调控,因此从根本上限于含有胞浆结构域的蛋白质、配体可以结合并招募必需的细胞成分。细胞外和膜相关蛋白(占所有蛋白编码基因40%的产物)是癌症、衰老相关疾病和自身免疫性疾病的关键诱因,因此选择性降解这些蛋白具有改善人类健康的潜能。

附:英文原文

Title: Lysosome-targeting chimaeras for degradation of extracellular proteins

Author: Steven M. Banik, Kayvon Pedram, Simon Wisnovsky, Green Ahn, Nicholas M. Riley, Carolyn R. Bertozzi

Issue&Volume: 2020-07-29

Abstract: The majority of therapies that target individual proteins rely on specific activity-modulating interactions with the target protein—for example, enzyme inhibition or ligand blocking. However, several major classes of therapeutically relevant proteins have unknown or inaccessible activity profiles and so cannot be targeted by such strategies. Protein-degradation platforms such as proteolysis-targeting chimaeras (PROTACs)1,2 and others (for example, dTAGs3, Trim-Away4, chaperone-mediated autophagy targeting5 and SNIPERs6) have been developed for proteins that are typically difficult to target; however, these methods involve the manipulation of intracellular protein degradation machinery and are therefore fundamentally limited to proteins that contain cytosolic domains to which ligands can bind and recruit the requisite cellular components. Extracellular and membrane-associated proteins—the products of 40% of all protein-encoding genes7—are key agents in cancer, ageing-related diseases and autoimmune disorders8, and so a general strategy to selectively degrade these proteins has the potential to improve human health. Here we establish the targeted degradation of extracellular and membrane-associated proteins using conjugates that bind both a cell-surface lysosome-shuttling receptor and the extracellular domain of a target protein. These initial lysosome-targeting chimaeras, which we term LYTACs, consist of a small molecule or antibody fused to chemically synthesized glycopeptide ligands that are agonists of the cation-independent mannose-6-phosphate receptor (CI-M6PR). We use LYTACs to develop a CRISPR interference screen that reveals the biochemical pathway for CI-M6PR-mediated cargo internalization in cell lines, and uncover the exocyst complex as a previously unidentified—but essential—component of this pathway. We demonstrate the scope of this platform through the degradation of therapeutically relevant proteins, including apolipoprotein E4, epidermal growth factor receptor, CD71 and programmed death-ligand 1. Our results establish a modular strategy for directing secreted and membrane proteins for lysosomal degradation, with broad implications for biochemical research and for therapeutics.

DOI: 10.1038/s41586-020-2545-9

Source: https://www.nature.com/articles/s41586-020-2545-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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