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Restoration of mutant hERG stability by inhibition of HDAC6. | LitMetric

Restoration of mutant hERG stability by inhibition of HDAC6.

J Mol Cell Cardiol

Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University, 86-1, Nishimachi, Yonago, Tottori 683-8503, Japan.

Published: February 2018

AI Article Synopsis

  • The human ether-a-go-go-related gene (hERG) is responsible for encoding a potassium channel, and mutations in this gene lead to long QT syndrome type 2 (LQT2).
  • The study investigated how histone deacetylase 6 (HDAC6) affects both normal and mutant hERG proteins, revealing that inhibiting HDAC6 increases the protein levels and activity of hERG channels.
  • Results suggest that targeting HDAC6 may provide a new therapeutic strategy for treating LQT2 by enhancing the expression and functionality of hERG proteins through increased acetylation.

Article Abstract

The human ether-a-go-go-related gene (hERG) encodes the α subunit of a rapidly activating delayed-rectifier potassium (I) 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 (I) 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 I, 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.

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Source
http://dx.doi.org/10.1016/j.yjmcc.2018.01.009DOI Listing

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