The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes

Eibach Y, Kreher S, Poetsch MS, Kho AL, Gaertner U, Clemen CS, Schröder R, Guo K, Milting H, Meder B, Potente M, Richter M, Schneider A, Meiners S, Gaute M, Braun T (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Science Advances American Association for the Advancement of Science

Book Volume: 11

Article Number: eado3852

Journal Issue: 4

DOI: 10.1126/sciadv.ado3852

Abstract

Protein homeostasis is crucial for maintaining cardiomyocyte (CM) function. Disruption of proteostasis results in accumulation of protein aggregates causing cardiac pathologies such as hypertrophy, dilated cardiomyopathy (DCM), and heart failure. Here, we identify ubiquitin-specific peptidase 5 (USP5) as a critical determinant of protein quality control (PQC) in CM. CM-specific loss of mUsp5 leads to the accumulation of polyubiquitin chains and protein aggregates, cardiac remodeling, and eventually DCM. USP5 interacts with key components of the proteostasis machinery, including PSMD14, and the absence of USP5 increases activity of the ubiquitin-proteasome system and autophagic flux in CMs. Cardiac-specific hUSP5 overexpression reduces pathological remodeling in pressure-overloaded mouse hearts and attenuates protein aggregate formation in titinopathy and desminopathy models. Since CMs from humans with end-stage DCM show lower USP5 levels and display accumulation of ubiquitinated protein aggregates, we hypothesize that therapeutically increased USP5 activity may reduce protein aggregates during DCM. Our findings demonstrate that USP5 is essential for ubiquitin turnover and proteostasis in mature CMs.

Authors with CRIS profile

Rolf Schröder Professur für Neuropathologie

Involved external institutions

Max Planck Institute for Heart and Lung Research / Max-Planck-Institut für Herz- und Lungenforschung DE Germany (DE) King’s College London GB United Kingdom (GB) Justus-Liebig-Universität Gießen DE Germany (DE) Deutsches Zentrum für Luft- und Raumfahrt e.V. (DLR) / German Aerospace Center DE Germany (DE) Forschungszentrum Borstel - Leibniz-Zentrum für Medizin und Biowissenschaften / Research Center Borstel - Leibniz-Center for Medicine and Biosciences DE Germany (DE) Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch DE Germany (DE) Herz- und Diabeteszentrum Nordrhein-Westfalen DE Germany (DE) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) DE Germany (DE) Berliner Institut für Gesundheitsforschung (BIH) DE Germany (DE) Kerckhoff-Klinik DE Germany (DE)

How to cite

APA:

Eibach, Y., Kreher, S., Poetsch, M.S., Kho, A.L., Gaertner, U., Clemen, C.S.,... Braun, T. (2025). The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes. Science Advances, 11(4). https://doi.org/10.1126/sciadv.ado3852

MLA:

Eibach, Yvonne, et al. "The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes." Science Advances 11.4 (2025).

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