Date of Graduation
Genes and Development
Doctor of Philosophy (PhD)
Robert J. Schwartz
Edward T.H. Yeh
James F. Martin
A Novel cardiac function of SUMO2/3 and SENP5 dependent pathway and its physiologic impact on congestive cardiomyopathy
Eun Young Kim, M.S.
Supervisory professor: Robert J. Schwartz, Ph.D.
SUMOylation regulates diverse cellular processes including transcription, cell cycle, protein stability, and apoptosis. Although SUMO1 has been extensively studied so far, relevance of SUMO2/3 is unclear, especially in heart. Here we show that failing heart induces SUMO2/3 conjugation. Increased SUMO2/3-dependent modification leads to congestive heart disease such as cardiac hypertrophy by promoting cardiac cell death. Calpain2 and Calpastatin as a novel SUMO2 targets have been known to be involved in mitochondrial-independent cell death pathway in heart. These SUMOylations of Calpain2 and Calpastatin facilitate activation of Calpain2 by reducing inhibitory role of Calpastatin. These findings identify a SUMO2/3-dependent modification as a novel posttranslational modification that controls Calpain2-Calpastatin system resulting in cardiac protein degradation. On the other hand, transgenic mice overexpressing SENP5, SUMO2/3-specific deconjugation enzyme in the heart, developed dilated cardiomyopathy. This unexpected phenotype mimics human heart failure, which has elevated SENP5 protein levels. Dilated hearts of SENP5 transgenic mice showed markedly reduced functions of mitochondrial complexes due to almost complete loss of mitochondrial cristae, and compromised cardiac energy metabolism. These hearts also showed increased deSUMOylation of mitochondrial proteins including dynamin related protein (Drp1), which leads to nuclear translocation of mitochondrial apoptosis inducing factor (AIF). This induces massive loss of cardiomyocytes via caspase-independent apoptotic pathway. These findings identify a novel SENP5-mediated deSUMOylation pathway that controls mitochondrial structure and pathological remodeling of the heart. Thus, inhibiting SENP5 might be beneficial to dilated cardiomyopathy and heart failure.
SUMO, cardiomyopathy, apoptosis, calpain 2, calpastatin, SENP