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

Journal of Molecular and Cellular Cardiology
Tilo ThottakaraLucie Carrier

Abstract

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. 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. This study identifies desmin as a new Asb2β target for proteasomal degradation in cardiomyocytes and suggests that accumulation of desmin could contribute to UPS i...Continue Reading

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Citations

Sep 12, 2015·Gene·Lucie CarrierFriederike Cuello
Feb 10, 2017·The Journal of Physiology·Jennifer E Gilda, Aldrin V Gomes
Dec 23, 2017·International Journal of Molecular Sciences·Casey CarlisleDave Pilgrim
Oct 13, 2017·Circulation. Heart Failure·Sonia R SinghLucie Carrier
Aug 22, 2017·Frontiers in Physiology·Sabrina StückerFelix W Friedrich
Oct 5, 2018·Frontiers in Physiology·Simon BraumannFelix W Friedrich
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Jun 8, 2018·JCI Insight·Amelia A GlazierSharlene M Day
Nov 21, 2018·Pflügers Archiv : European journal of physiology·Amelia A GlazierSharlene M Day
Feb 1, 2021·Molecular & Cellular Proteomics : MCP·Craig A GoodmanPaul Gregorevic
Sep 14, 2020·Journal of Molecular and Cellular Cardiology·Thomas G Martin, Jonathan A Kirk
Jun 27, 2019·Trends in Molecular Medicine·Karim HniaChristel Moog-Lutz
May 14, 2021·European Journal of Pharmacology·Silke DüsenerFelix W Friedrich

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