ID 7076
File
Authors
Li, Peili Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Researchers DB KAKEN
Kurata, Yasutaka Department of Physiology II, Kanazawa Medical University
Mahati, Endang Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University
Ninomiya, Haruaki Department of Biological Regulation, Tottori University Researchers DB KAKEN
Higaki, Katsumi Research Center for Bioscience and Technology, Tottori University Researchers DB KAKEN
Taufiq, Fikri Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University
Morikawa, Kumi Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University KAKEN
Shirayoshi, Yasuaki Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Researchers DB KAKEN
Horie, Minoru Department of Cardiovascular Medicine, Shiga University of Medical Science
Hisatome, Ichiro Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Researchers DB KAKEN
Keywords
hERG
HDAC6
Acetylation
Ubiquitination
LQT2
Abstract
The human ether-a-go-go-related gene (hERG) encodes the α subunit of a rapidly activating delayed-rectifier potassium (IKr) channel. Mutations of the hERG cause long QT syndrome type 2 (LQT2). Acetylation of lysine residues occurs in a subset of non-histone proteins and this modification is controlled by both histone acetyltransferases and deacetylases (HDACs). The aim of this study was to clarify effects of HDAC(s) on wild-type (WT) and mutant hERG proteins. WThERG and two trafficking-defective mutants (G601S and R752W) were transiently expressed in HEK293 cells, which were treated with a pan-HDAC inhibitor Trichostatin A (TSA) or an isoform-selective HDAC6 inhibitor Tubastatin A (TBA). Both TSA and TBA increased protein levels of WThERG and induced expression of mature forms of the two mutants. Immunoprecipitation showed an interaction between HDAC6 and immature forms of hERG. Coexpression of HDAC6 decreased acetylation and, reciprocally, increased ubiquitination of hERG, resulting in its decreased expression. siRNA against HDAC6, as well as TBA, exerted opposite effects. Immunochemistry revealed that HDAC6 knockdown increased expression of the WThERG and two mutants both in the endoplasmic reticulum and on the cell surface. Electrophysiology showed that HDAC6 knockdown or TBA treatment increased the hERG channel current corresponding to the rapidly activating delayed-rectifier potassium current (IKr) in HEK293 cells stably expressing the WT or mutants. Three lysine residues (K116, K495 and K757) of hERG were predicted to be acetylated. Substitution of these lysine residues with arginine eliminated HDAC6 effects. In HL-1 mouse cardiomyocytes, TBA enhanced endogenous ERG expression, increased IKr, and shortened action potential duration. These results indicate that hERG is a substrate of HDAC6. HDAC6 inhibition induced acetylation of hERG which counteracted ubiquitination leading its stabilization. HDAC6 inhibition may be a novel therapeutic option for LQT2.
Publisher
Elsevier
Content Type
Journal Article
Link
ISSN
00222828
Journal Title
Journal of Molecular and Cellular Cardiology
Current Journal Title
Journal of Molecular and Cellular Cardiology
Volume
115
Start Page
158
End Page
169
Published Date
2018-02-28
Publisher-DOI
Text Version
Author
Rights
© 2018 Elsevier Ltd. All rights reserved.
Citation
Li, Peili. Kurata, Yasutaka. Endang, Mahati. et al. Restoration of mutant hERG stability by inhibition of HDAC6. Journal of Molecular and Cellular Cardiology. 115. 158-169. 2018.
Department
Faculty of Medicine/Graduate School of Medical Sciences/University Hospital
Language
English
pii
S0022-2828(18)30018-X