Ubiquitination-dependent quality control of hERG K⁺ channel with acquired and inherited conformational defect at the plasma membrane

Abstract

The role of the plasma membrane quality control machinery is demonstrated in the development of the long QT syndrome phenotype, caused by acquired and inherited conformational defects of the hERG potassium channel in multiple expression systems, including cardiac myocytes.

The endosomal trafficking factors CORVET and ESCRT suppress plasma membrane residence of the renal outer medullary potassium channel (ROMK)

“…Our findings build upon related work on the inwardly-rectifying potassium channel Kir2.1 (27), the calcium-gated potassium channel KCa3.1 (96), and the voltage-gated potassium channel hERG (97,98), adding ROMK to a growing list of channels and transporters regulated by post-endocytic transport (99). Previous studies of ROMK in yeast focused instead on the identification of ROMK-interaction partners from human cDNA libraries via the yeast two hybrid (100, 101).…”

Protein Homeostasis at the Plasma Membrane

“…Intriguingly, the Rsp5-dependent ubiquitination and elimination of unfolded Fur4p could not be substituted by Ubr1 or San1 E3 ligases that can recognize unfolded cytosolic and nuclear client protein (152). The possible redundancy of PM QC ligases is supported by the observation that CHIP ablation only partially inhibits the proteolytic downregulation of unfolded ⌬F508-CFTR, DRD4, V2R, and hERG, whereas depletion of other E3 Ub-ligases (e.g., Hrd1 and Gp78) also impeded CFTR clearance from the PM (1,2,95). Similarly, at least two E3 ligases (Cullin5 and CHIP) are responsible for the geldanamycin-induced ubiquitination and lysosomal downregulation of ErbB2 (HER2/neu) (34, 153).…”

Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels

“…Bag1 Promotes Degradation of Immature hERG-Degradation of immature CG hERG is by proteasomes at the ER, whereas mature FG hERG is degraded by the endosome-lysosome pathway (36). The effects of Bag1 were restored by proteasome inhibition, suggesting that the degradation is mostly of CG hERG, which would decrease the amount able to traffic and mature to FG hERG.…”

“…Bag1 could be affecting the quality control clearance of mature hERG, which involves Hsp70 and CHIP (36). We therefore performed cycloheximide chase experiments to determine the effects of Bag1.…”