RATIONALE: Impairment of proteasomal function is pathogenic in several cardiac 
proteinopathies and can eventually lead to heart failure. Loss of proteasomal 
activity often results in the accumulation of large protein aggregates. The 
ubiquitin proteasome system (UPS) is primarily responsible for cellular protein 
degradation, and although the role of ubiquitination in this process is well 
studied, the function of an ancillary post-translational modification, 
SUMOylation, in protein quality control is not fully understood.
OBJECTIVE: To determine the role of ubiquitin-conjugating enzyme 9 (UBC9), a 
small ubiquitin-like modifier-conjugating enzyme, in cardiomyocyte protein 
quality control.
METHODS AND RESULTS: Gain- and loss-of-function approaches were used to 
determine the importance of UBC9. Overexpression of UBC9 enhanced UPS function 
in cardiomyocytes, whereas knockdown of UBC9 by small interfering RNA caused 
significant accumulations of aggregated protein. UPS function and relative 
activity was analyzed using a UPS reporter protein consisting of a short degron, 
CL1, fused to the COOH-terminus of green fluorescent protein (GFPu). 
Subsequently, the effects of UBC9 on UPS function were tested in a proteotoxic 
model of desmin-related cardiomyopathy, caused by cardiomyocyte-specific 
expression of a mutated αB crystallin, CryAB(R120G). CryAB(R120G) expression 
leads to aggregate formation and decreased proteasomal function. Coinfection of 
UBC9-adenovirus with CryAB(R120G) virus reduced the proteotoxic sequelae, 
decreasing overall aggregate concentrations. Conversely, knockdown of UBC9 
significantly decreased UPS function in the model and resulted in increased 
aggregate levels.
CONCLUSIONS: UBC9 plays a significant role in cardiomyocyte protein quality 
control, and its activity can be exploited to reduce toxic levels of misfolded 
or aggregated proteins in cardiomyopathy.