美国哥伦比亚大学Henry M. Colecraft研究组发现，靶向去泛素化可挽救不同运输缺陷的离子通道病。这一研究成果于2020年11月9日在线发表在《自然—方法学》上。

Title: Targeted deubiquitination rescues distinct trafficking-deficient ion channelopathies

Author: Scott A. Kanner, Zunaira Shuja, Papiya Choudhury, Ananya Jain, Henry M. Colecraft

Issue&Volume: 2020-11-09

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. 

DOI: 10.1038/s41592-020-00992-6

Source: https://www.nature.com/articles/s41592-020-00992-6