Human «ether-a-go-go» related gene trafficking is dependent on a cytosolic chaperone network

Long QT Syndrome is a cardiac disorder associated with ventricular arrhythmias that can lead to syncope and sudden death.Loss of function mutations in the human ether-a-go-go related gene (hERG/KCNH2) potassium channel underlie type 2 long-QT syndrome (LQT2).Most often this loss of function is a consequence of defective trafficking of hERG mutants to the cell surface, with channel retention and degradation at the endoplasmic reticulum.This study began with a proteomics screen conducted to search for hERGinteracting proteins that were important for its folding, trafficking, and degradation.The resulting list of putative interactors was huge and included several known components of the cytosolic chaperone network which became the focus of this work.Among them were Hsc70 (70 kDa heat shock cognate protein), Hsp90 (90 kDa heat shock protein), DJA1, Hop (Hsp-organizing protein) and Bag-2 (BCL-associated athanogene 2) as well as the membrane-bound FKBP38 (38 kDa FK506-binding protein; FKBP8).We first demonstrate that FKBP38 immunoprecipitates and co-localizes with hERG in our cellular system and that siRNA knockdown of FKBP38 causes a reduction in hERG trafficking.Next, we identify DJA1 (DNAJA1) and DJA2 (DNAJA2) as key modulators of hERG degradation.Overexpression of the DJAs reduces hERG trafficking List of Abbreviations AC adenylyl cyclase Aha1 activator of Hsp90 ATPase 1 aLQTS acquired long QT syndrome AR adrenergic receptor Bag-2 BCL-associated athanogene 2 CaM calmodulin cAMP cyclic adenosine monophosphate CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator CG core glycosylated CHIP C-terminal of Hsp70 interacting protein CL C-linker CNBD cyclic nucleotide binding domain CT carboxyl terminus DAG diacyl glycerol EAG ether-a-go-go gene ECG electrocardiogram EDEM ER degradation-enhancing mannosidase-like protein ER endoplasmic reticulum ERAD ER associated degradation FG fully glycosylated FKBP38 38 kDa FK506-binding protein GA geldanamycin GRP glucose-regulated protein GFP green fluorescent protein GT glucosyltransferase HA hemagglutinin hERG human ether-a-go-go-related gene HCN2 Hyperpolarization activated cyclic nucleotide-gated potassium channel 2 Hop Hsp-organizing protein Hsc70 70 kDa heat shock cognate protein Hsp90 90 kDa heat shock protein ICD implantable cardiac defibrillator IP3 1,4,5 inositol triphosphate J-LN Jervell and Lange-Nielson syndrome XIV LCSD left cardiac sympathetic nerve denervation LQTS long QT syndrome MiRP1 minK-related peptide 1 MSD membrane spanning domain NBD nucleotide binding domain PAS Per-Arnt-Sim PIP2 phosphatidyl-4,5-bisphosphate PKA protein kinase A PKC protein kinase C PPI peptidylprolyl cis/trans isomerase QC quality control RRL rabbit reticulocyte lysate RW Romano-Ward syndrome SCD sudden cardiac death SHR steroid hormone receptor TCC tetramerizing coiled coil TPR tetratricopeptide repeat UBL ubiquitin-like domain WT wild type XV

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