{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T11:20:32Z","timestamp":1786792832767,"version":"build-2736575974"},"reference-count":65,"publisher":"American Society for Cell Biology (ASCB)","issue":"24","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2013,12,15]]},"abstract":"<jats:p> 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\u2013related gene (hERG) K<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> concentration. Cardiac glycoside\u2013induced intracellular K<jats:sup>+<\/jats:sup> depletion conformationally impairs the complex-glycosylated channel, which provokes chaperone- and C-terminal Hsp70-interacting protein\u2013dependent polyubiquitination, accelerated internalization, and endosomal sorting complex required for transport\u2013dependent 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. <\/jats:p>","DOI":"10.1091\/mbc.e13-07-0417","type":"journal-article","created":{"date-parts":[[2013,10,24]],"date-time":"2013-10-24T02:57:00Z","timestamp":1382583420000},"page":"3787-3804","source":"Crossref","is-referenced-by-count":47,"title":["Ubiquitination-dependent quality control of hERG K<sup>+<\/sup> channel with acquired and inherited conformational defect at the plasma membrane"],"prefix":"10.1091","volume":"24","author":[{"given":"Pirjo M.","family":"Apaja","sequence":"first","affiliation":[{"name":"Department of Physiology and Groupe de Recherche Ax\u00e9 sur la Structure des Prot\u00e9ines, McGill University, Montr\u00e9al, QC H3E 1Y6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Foo","sequence":"additional","affiliation":[{"name":"Department of Physiology and 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