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靶向去泛素化可挽救不同的转运缺陷型离子通道病。

Targeted deubiquitination rescues distinct trafficking-deficient ion channelopathies.

机构信息

Doctoral Program in Neurobiology and Behavior, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

出版信息

Nat Methods. 2020 Dec;17(12):1245-1253. doi: 10.1038/s41592-020-00992-6. Epub 2020 Nov 9.

DOI:10.1038/s41592-020-00992-6
PMID:33169015
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9335257/
Abstract

Impaired protein stability or trafficking underlies diverse ion channelopathies and represents an unexploited unifying principle for developing common treatments for otherwise dissimilar diseases. Ubiquitination limits ion channel surface density, but targeting this pathway for the purposes of basic study or therapy is challenging because of its prevalent role in proteostasis. We developed engineered deubiquitinases (enDUBs) that enable selective ubiquitin chain removal from target proteins to rescue the functional expression of disparate mutant ion channels that underlie long QT syndrome (LQT) and cystic fibrosis (CF). In an LQT type 1 (LQT1) cardiomyocyte model, enDUB treatment restored delayed rectifier potassium currents and normalized action potential duration. CF-targeted enDUBs synergistically rescued common (ΔF508) and pharmacotherapy-resistant (N1303K) CF mutations when combined with the US Food and Drug Administation (FDA)-approved drugs Orkambi (lumacaftor/ivacaftor) and Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor). Altogether, targeted deubiquitination via enDUBs provides a powerful protein stabilization method that not only corrects diverse diseases caused by impaired ion channel trafficking, but also introduces a new tool for deconstructing the ubiquitin code in situ.

摘要

蛋白稳定性或转运障碍是多种离子通道病的基础，代表了一种未被开发的统一原则，可以为原本不同的疾病开发共同的治疗方法。泛素化限制了离子通道的表面密度，但由于其在蛋白稳态中普遍存在的作用，靶向该途径进行基础研究或治疗具有挑战性。我们开发了工程化去泛素化酶（enDUBs），可选择性地从靶蛋白上去除泛素链，从而恢复导致长 QT 综合征（LQT）和囊性纤维化（CF）的不同突变离子通道的功能性表达。在 LQT1 型（LQT1）心肌细胞模型中，enDUB 治疗恢复了延迟整流钾电流，并使动作电位持续时间正常化。CF 靶向的 enDUBs 与美国食品和药物管理局 (FDA) 批准的药物 Orkambi（lumacaftor/ivacaftor）和 Trikafta（elexacaftor/tezacaftor/ivacaftor 和 ivacaftor）联合使用时，可协同挽救常见的（ΔF508）和药物治疗抵抗的（N1303K）CF 突变。总之，通过 enDUBs 进行靶向去泛素化提供了一种强大的蛋白稳定方法，不仅可以纠正由于离子通道转运障碍引起的多种疾病，还为原位解构泛素密码提供了一种新工具。

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