The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes
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 <i>mUsp5</i> 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 <i>hUSP5</i> 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
- Rolf Schröder (ORCID: https://orcid.org/0000-0002-2772-2615)
- André Schneider (ORCID: https://orcid.org/0000-0001-5421-0909)
- Manfred Richter (ORCID: https://orcid.org/0000-0002-6239-3503)
- Mareike S. Poetsch (ORCID: https://orcid.org/0000-0003-1353-5525)
- Ay Lin Kho (ORCID: https://orcid.org/0000-0002-9753-2091)
- Christoph S. Clemen (ORCID: https://orcid.org/0000-0002-1291-4219)
- Ulrich Gaertner
- Thomas Braun (ORCID: https://orcid.org/0000-0002-6165-4804)
- Mathias Gautel (ORCID: https://orcid.org/0000-0003-4027-9803)
- Benjamin Meder (ORCID: https://orcid.org/0000-0003-0741-2633)
- Kai Guo (ORCID: https://orcid.org/0000-0002-4291-4439)
- Michael Potente (ORCID: https://orcid.org/0000-0002-5689-0036)
- Hendrik Milting (ORCID: https://orcid.org/0000-0001-9722-0007)
- Silke Meiners (ORCID: https://orcid.org/0000-0003-3678-7995)
- Yvonne Eibach (ORCID: https://orcid.org/0009-0002-5345-6418)
- Silke Kreher (ORCID: https://orcid.org/0009-0001-0890-2979)
Institutions
- University of Cologne (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- King's College London (GB)
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- Heart and Diabetes Center North Rhine-Westphalia (DE)
- Deutsches Zentrum für Luft- und Raumfahrt e. V. (DLR) (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Humboldt-Universität zu Berlin (DE)
- Max Planck Institute for Heart and Lung Research (DE)
- German Centre for Cardiovascular Research (DE)
- German Center for Lung Research (DE)
- Kerckhoff Klinik (DE)
- Giessen School of Theology (DE)
- Cardio-Pulmonary Institute (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2025-01-22
- DOI
- https://doi.org/10.1126/sciadv.ado3852
- Citations
- 5
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Medical Research Council
- Biotechnology and Biological Sciences Research Council