Data from: 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 the
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 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.