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J Biol Chem. 2017 Feb 10;292(6):2287-2300. doi: 10.1074/jbc.M116.752618. Epub 2016 Dec 20.

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

Author information

1
From the Departments of Physiology and.
2
Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, Quebec H3G 0B1, Canada.
3
Biochemistry and.
4
From the Departments of Physiology and alvin.shrier@mcgill.ca.
5
Biochemistry and jason.young2@mcgill.ca.

Abstract

Cardiac long QT syndrome type 2 is caused by mutations in the human ether a go-go-related gene (hERG) potassium channel, many of which cause misfolding and degradation at the endoplasmic reticulum instead of normal trafficking to the cell surface. The Hsc70/Hsp70 chaperones assist the folding of the hERG cytosolic domains. Here, we demonstrate that the Hsp70 nucleotide exchange factor Bag1 promotes hERG degradation by the ubiquitin-proteasome system at the endoplasmic reticulum to regulate hERG levels and channel activity. Dissociation of hERG complexes containing Hsp70 and the E3 ubiquitin ligase CHIP requires the interaction of Bag1 with Hsp70, but this does not involve the Bag1 ubiquitin-like domain. The interaction with Bag1 then shifts hERG degradation to the membrane-anchored E3 ligase TRC8 and its E2-conjugating enzyme Ube2g2, as determined by siRNA screening. TRC8 interacts through the transmembrane region with hERG and decreases hERG functional expression. TRC8 also mediates degradation of the misfolded hERG-G601S disease mutant, but pharmacological stabilization of the mutant structure prevents degradation. Our results identify TRC8 as a previously unknown Hsp70-independent quality control E3 ligase for hERG.

KEYWORDS:

E3 ubiquitin ligase; chaperone; chaperone DnaK (DnaK); endoplasmic reticulum-associated protein degradation (ERAD); intracellular trafficking; potassium channel

PMID:
27998983
PMCID:
PMC5313101
DOI:
10.1074/jbc.M116.752618
[Indexed for MEDLINE]
Free PMC Article

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