title: The role of the cytosolic HSP70 chaperone system in diseases caused by misfolding and aberrant trafficking of ion channels.
abstract: Protein-folding diseases are an ongoing medical challenge. Many diseases within this group are genetically determined, and have no known cure. Among the examples in which the underlying cellular and molecular mechanisms are well understood are diseases driven by misfolding of transmembrane proteins that normally function as cell-surface ion channels. Wild-type forms are synthesized and integrated into the endoplasmic reticulum (ER) membrane system and, upon correct folding, are trafficked by the secretory pathway to the cell surface. Misfolded mutant forms traffic poorly, if at all, and are instead degraded by the ER-associated proteasomal degradation (ERAD) system. Molecular chaperones can assist the folding of the cytosolic domains of these transmembrane proteins; however, these chaperones are also involved in selecting misfolded forms for ERAD. Given this dual role of chaperones, diseases caused by the misfolding and aberrant trafficking of ion channels (referred to here as ion-channel-misfolding diseases) can be regarded as a consequence of insufficiency of the pro-folding chaperone activity and/or overefficiency of the chaperone ERAD role. An attractive idea is that manipulation of the chaperones might allow increased folding and trafficking of the mutant proteins, and thereby partial restoration of function. This Review outlines the roles of the cytosolic HSP70 chaperone system in the best-studied paradigms of ion-channel-misfolding disease--the CFTR chloride channel in cystic fibrosis and the hERG potassium channel in cardiac long QT syndrome type 2. In addition, other ion channels implicated in ion-channel-misfolding diseases are discussed.
authors.affiliation: McGill University, Department of Biochemistry, Groupe de Recherche Axé sur la Structure des Protéines, 3649 Promenade Sir William Osler, Montreal, QC H3G 0B1, Canada.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Young
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D021381:Protein Transport; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D018840:HSP70 Heat-Shock Proteins; D007473:Ion Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: Chaperone; Cystic fibrosis; Degradation; Intracellular trafficking; Long QT syndrome; Protein folding