title: Ubiquitination-dependent quality control of hERG K+ channel with acquired and inherited conformational defect at the plasma membrane.
abstract: Membrane trafficking in concert with the peripheral quality control machinery plays a critical role in preserving plasma membrane (PM) protein homeostasis. Unfortunately, the peripheral quality control may also dispose of partially or transiently unfolded polypeptides and thereby contribute to the loss-of-expression phenotype of conformational diseases. Defective functional PM expression of the human ether-a-go-go-related gene (hERG) K(+) channel leads to the prolongation of the ventricular action potential that causes long QT syndrome 2 (LQT2), with increased propensity for arrhythmia and sudden cardiac arrest. LQT2 syndrome is attributed to channel biosynthetic processing defects due to mutation, drug-induced misfolding, or direct channel blockade. Here we provide evidence that a peripheral quality control mechanism can contribute to development of the LQT2 syndrome. We show that PM hERG structural and metabolic stability is compromised by the reduction of extracellular or intracellular K(+) concentration. Cardiac glycoside-induced intracellular K(+) depletion conformationally impairs the complex-glycosylated channel, which provokes chaperone- and C-terminal Hsp70-interacting protein-dependent polyubiquitination, accelerated internalization, and endosomal sorting complex required for transport-dependent lysosomal degradation. A similar mechanism contributes to the down-regulation of PM hERG harboring LQT2 missense mutations, with incomplete secretion defect. These results suggest that PM quality control plays a determining role in the loss-of-expression phenotype of hERG in certain hereditary and acquired LTQ2 syndromes.
authors.affiliation: Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montréal, QC H3E 1Y6, Canada.
authors.forename: Pirjo M
authors.initials: PM
authors.lastname: Apaja
authors.forename: Brian
authors.initials: B
authors.lastname: Foo
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Okiyoneda
authors.forename: William C
authors.initials: WC
authors.lastname: Valinsky
authors.forename: Herve
authors.initials: H
authors.lastname: Barriere
authors.forename: Roxana
authors.initials: R
authors.lastname: Atanasiu
authors.forename: Eckhard
authors.initials: E
authors.lastname: Ficker
authors.forename: Gergely L
authors.initials: GL
authors.lastname: Lukacs
authors.forename: Alvin
authors.initials: A
authors.lastname: Shrier
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002301:Cardiac Glycosides / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics*; D004077:Digoxin / Q000494:pharmacology; D015536:Down-Regulation; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000096:biosynthesis / Q000235:genetics*; D057809:HEK293 Cells; D006367:HeLa Cells; D006321:Heart / Q000502:physiology; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D010042:Ouabain / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D017510:Protein Folding; D021381:Protein Transport / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D054875:Ubiquitination / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002301:Cardiac Glycosides; D002316:Cardiotonic Agents; D027682:Cation Transport Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C116331:HSPBP1 protein, human; D034741:RNA, Small Interfering; D010042:Ouabain; D004077:Digoxin; D011188:Potassium