Manish K Gupta1, Patrick M McLendon1, James Gulick1, Jeanne James1, Kamel Khalili1, Jeffrey Robbins2. 1. From the Department of Neuroscience, Temple University, Philadelphia, PA (M.K.G., K.K.); and Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, Cincinnati, OH (P.M.M., J.G., J.J, J.R.). 2. From the Department of Neuroscience, Temple University, Philadelphia, PA (M.K.G., K.K.); and Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, Cincinnati, OH (P.M.M., J.G., J.J, J.R.). jeff.robbins@cchmc.org.
Abstract
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.
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 enzymeUBC9 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.
Authors: Marty L Montpetit; Patrick J Stocker; Tara A Schwetz; Jean M Harper; Sarah A Norring; Lana Schaffer; Simon J North; Jihye Jang-Lee; Timothy Gilmartin; Steven R Head; Stuart M Haslam; Anne Dell; Jamey D Marth; Eric S Bennett Journal: Proc Natl Acad Sci U S A Date: 2009-08-07 Impact factor: 11.205
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Authors: Manish K Gupta; Rafal Kaminski; Brian Mullen; Jennifer Gordon; Tricia H Burdo; Joseph Y Cheung; Arthur M Feldman; Muniswamy Madesh; Kamel Khalili Journal: Sci Rep Date: 2017-08-17 Impact factor: 4.379