The E3 ubiquitin ligase Asb2β is downregulated in a mouse model of hypertrophic cardiomyopathy and targets desmin for proteasomal degradation

TY - JOUR

T1 - The E3 ubiquitin ligase Asb2β is downregulated in a mouse model of hypertrophic cardiomyopathy and targets desmin for proteasomal degradation

AU - Thottakara, Tilo

AU - Friedrich, Felix W

AU - Reischmann, Silke

AU - Braumann, Simon

AU - Schlossarek, Saskia

AU - Krämer, Elisabeth

AU - Juhr, Denise

AU - Schlüter, Hartmut

AU - van der Velden, Jolanda

AU - Münch, Julia

AU - Patten, Monica

AU - Eschenhagen, Thomas

AU - Moog-Lutz, Christel

AU - Carrier, Lucie

N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/10

Y1 - 2015/10

N2 - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disease with mutations in genes encoding sarcomeric proteins. Previous findings suggest deregulation of the ubiquitin proteasome system (UPS) in HCM in humans and in a mouse model of HCM (Mybpc3-targeted knock-in (KI) mice). In this study we investigated transcript levels of several muscle-specific E3 ubiquitin ligases in KI mice and aimed at identifying novel protein targets.METHODS AND RESULTS: Out of 9 muscle-specific E3 ligases, Asb2β was found with the lowest mRNA level in KI compared to wild-type (WT) mice. After adenoviral-mediated Asb2β transduction of WT neonatal mouse cardiomyocytes with either a WT or inactive Asb2β mutant, desmin was identified as a new target of Asb2β by mass spectrometry, co-immunoprecipitation and immunoblotting. Immunofluorescence analysis revealed a co-localization of desmin with Asb2β at the Z-disk of the sarcomere. Knock-down of Asb2β in cardiomyocytes resulted in higher desmin protein levels. Furthermore, desmin levels were higher in ventricular samples of HCM mice and patients than controls.CONCLUSIONS: This study identifies desmin as a new Asb2β target for proteasomal degradation in cardiomyocytes and suggests that accumulation of desmin could contribute to UPS impairment in HCM mice and patients.

AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disease with mutations in genes encoding sarcomeric proteins. Previous findings suggest deregulation of the ubiquitin proteasome system (UPS) in HCM in humans and in a mouse model of HCM (Mybpc3-targeted knock-in (KI) mice). In this study we investigated transcript levels of several muscle-specific E3 ubiquitin ligases in KI mice and aimed at identifying novel protein targets.METHODS AND RESULTS: Out of 9 muscle-specific E3 ligases, Asb2β was found with the lowest mRNA level in KI compared to wild-type (WT) mice. After adenoviral-mediated Asb2β transduction of WT neonatal mouse cardiomyocytes with either a WT or inactive Asb2β mutant, desmin was identified as a new target of Asb2β by mass spectrometry, co-immunoprecipitation and immunoblotting. Immunofluorescence analysis revealed a co-localization of desmin with Asb2β at the Z-disk of the sarcomere. Knock-down of Asb2β in cardiomyocytes resulted in higher desmin protein levels. Furthermore, desmin levels were higher in ventricular samples of HCM mice and patients than controls.CONCLUSIONS: This study identifies desmin as a new Asb2β target for proteasomal degradation in cardiomyocytes and suggests that accumulation of desmin could contribute to UPS impairment in HCM mice and patients.

U2 - 10.1016/j.yjmcc.2015.08.020

DO - 10.1016/j.yjmcc.2015.08.020

M3 - SCORING: Journal article

C2 - 26343497

VL - 87

SP - 214

EP - 224

JO - J MOL CELL CARDIOL

JF - J MOL CELL CARDIOL

SN - 0022-2828

ER -