Foo Brian, Williamson Brittany, Young Jason C, Lukacs Gergely, Shrier Alvin
Department of Physiology, McGill University, Montréal, Québec, Canada, H3G 1Y6.
Department of Biochemistry, McGill University, Montréal, Québec, Canada, H3G 1Y6.
J Physiol. 2016 May 1;594(9):2469-81. doi: 10.1113/JP270531. Epub 2016 Feb 9.
Long-QT syndrome type-2 (LQT2) is characterized by reduced functional expression of the human ether-à-go-go related (hERG) gene product, resulting in impaired cardiac repolarization and predisposition to fatal arrhythmia. Previous studies have implicated abnormal trafficking of misfolded hERG as the primary mechanism of LQT2, with misfolding being caused by mutations in the hERG gene (inherited) or drug treatment (acquired). More generally, environmental and metabolic stresses present a constant challenge to the folding of proteins, including hERG, and must be countered by robust protein quality control (QC) systems. Disposal of partially unfolded yet functional plasma membrane (PM) proteins by protein QC contributes to the loss-of-function phenotype in various conformational diseases including cystic fibrosis (CF) and long-QT syndrome type-2 (LQT2). The prevalent view has been that the loss of PM expression of hERG is attributed to biosynthetic block by endoplasmic reticulum (ER) QC pathways. However, there is a growing appreciation for protein QC pathways acting at post-ER cellular compartments, which may contribute to conformational disease pathogenesis. This article will provide a background on the structure and cellular trafficking of hERG as well as inherited and acquired LQT2. We will review previous work on hERG ER QC and introduce the more novel view that there is a significant peripheral QC at the PM and peripheral cellular compartments. Particular attention is drawn to the unique role of the peripheral QC system in acquired LQT2. Understanding the QC process and players may provide targets for therapeutic intervention in dealing with LQT2.
2型长QT综合征（LQT2）的特征是人类去甲肾上腺素能相关基因（hERG）产物的功能表达降低，导致心脏复极化受损并易患致命性心律失常。先前的研究表明，错误折叠的hERG异常转运是LQT2的主要机制，错误折叠是由hERG基因的突变（遗传性）或药物治疗（获得性）引起的。更普遍地说，环境和代谢应激对包括hERG在内的蛋白质折叠构成持续挑战，必须通过强大的蛋白质质量控制（QC）系统来应对。蛋白质QC对部分未折叠但仍具功能的质膜（PM）蛋白的处理，导致了包括囊性纤维化（CF）和2型长QT综合征（LQT2）在内的各种构象疾病中的功能丧失表型。普遍观点认为，hERG质膜表达的丧失归因于内质网（ER）QC途径的生物合成阻滞。然而，人们越来越认识到作用于ER后细胞区室的蛋白质QC途径，这可能有助于构象疾病的发病机制。本文将提供hERG的结构和细胞转运以及遗传性和获得性LQT2的背景知识。我们将回顾先前关于hERG内质网QC的工作，并介绍一种更新颖的观点，即在质膜和外周细胞区室存在显著的外周QC。特别关注外周QC系统在获得性LQT2中的独特作用。了解QC过程和相关因素可能为治疗LQT2提供治疗干预靶点。
