title: hERG quality control and the long QT syndrome.
abstract: 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.
authors.affiliation: Department of Physiology, McGill University, Montréal, Québec, Canada, H3G 1Y6.
authors.forename: Brian
authors.initials: B
authors.lastname: Foo
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Québec, Canada, H3G 1Y6.
authors.forename: Brittany
authors.initials: B
authors.lastname: Williamson
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Québec, Canada, H3G 1Y6.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Young
authors.affiliation: Department of Physiology, McGill University, Montréal, Québec, Canada, H3G 1Y6.
authors.forename: Gergely
authors.initials: G
authors.lastname: Lukacs
authors.affiliation: Department of Physiology, McGill University, Montréal, Québec, Canada, H3G 1Y6.
authors.forename: Alvin
authors.initials: A
authors.lastname: Shrier
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins