RATIONALE: SUMOylation plays an important role in cardiac function and can be 
protective against cardiac stress. Recent studies show that SUMOylation is an 
integral part of the ubiquitin proteasome system, and expression of the small 
ubiquitin-like modifier (SUMO) E2 enzyme UBC9 improves cardiac protein quality 
control. However, the precise role of SUMOylation on other protein degradation 
pathways, particularly autophagy, remains undefined in the heart.
OBJECTIVE: To determine whether SUMOylation affects cardiac autophagy and 
whether this effect is protective in a mouse model of proteotoxic cardiac 
stress.
METHODS AND RESULTS: We modulated expression of UBC9, a SUMO E2 ligase, using 
gain- and loss-of-function in neonatal rat ventricular cardiomyocytes. UBC9 
expression seemed to directly alter autophagic flux. To confirm this effect in 
vivo, we generated transgenic mice overexpressing UBC9 in cardiomyocytes. These 
mice have an increased level of SUMOylation at baseline and, in confirmation of 
the data obtained from neonatal rat ventricular cardiomyocytes, demonstrated 
increased autophagy, suggesting that increased UBC9-mediated SUMOylation is 
sufficient to upregulate cardiac autophagy. Finally, we tested the protective 
role of SUMOylation-mediated autophagy by expressing UBC9 in a model of cardiac 
proteotoxicity, induced by cardiomyocyte-specific expression of a mutant 
α-B-crystallin, mutant CryAB (CryAB(R120G)), which shows impaired autophagy. 
UBC9 overexpression reduced aggregate formation, decreased fibrosis, reduced 
hypertrophy, and improved cardiac function and survival.
CONCLUSIONS: The data showed that increased UBC9-mediated SUMOylation is 
sufficient to induce relatively high levels of autophagy and may represent a 
novel strategy for increasing autophagic flux and ameliorating morbidity in 
proteotoxic cardiac disease.