Abstract
The calcium-transporting ATPase ATP2A2, also known as SERCA2a, is a critical ATPase responsible for Ca2+ re-uptake during excitation–contraction coupling. Impaired Ca2+ uptake resulting from decreased expression and reduced activity of SERCA2a is a hallmark of heart failure1. Accordingly, restoration of SERCA2a expression by gene transfer has proved to be effective in improving cardiac function in heart-failure patients2, as well as in animal models3. The small ubiquitin-related modifier (SUMO) can be conjugated to lysine residues of target proteins4, and is involved in many cellular processes5. Here we show that SERCA2a is SUMOylated at lysines 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells. The levels of SUMO1 and the SUMOylation of SERCA2a itself were greatly reduced in failing hearts. SUMO1 restitution by adeno-associated-virus-mediated gene delivery maintained the protein abundance of SERCA2a and markedly improved cardiac function in mice with heart failure. This effect was comparable to SERCA2A gene delivery. Moreover, SUMO1 overexpression in isolated cardiomyocytes augmented contractility and accelerated Ca2+ decay. Transgene-mediated SUMO1 overexpression rescued cardiac dysfunction induced by pressure overload concomitantly with increased SERCA2a function. By contrast, downregulation of SUMO1 using small hairpin RNA (shRNA) accelerated pressure-overload-induced deterioration of cardiac function and was accompanied by decreased SERCA2a function. However, knockdown of SERCA2a resulted in severe contractile dysfunction both in vitro and in vivo, which was not rescued by overexpression of SUMO1. Taken together, our data show that SUMOylation is a critical post-translational modification that regulates SERCA2a function, and provide a platform for the design of novel therapeutic strategies for heart failure.
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Acknowledgements
This work is supported by NIH RO1 HL083156, HL080498, HL093183 and P20HL100396 (R.J.H.). W.J.P. is funded by Global Research Laboratory Program (M6-0605-00-0001) of the Korean Ministry of Science and Technology.
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C.K., A.L. and R.J.H. conceived the project and its design. C.K., A.L., D.J., J.G.O. and A.H.C. performed experiments and data analysis. E.K. aided in experimental design. C.K., A.L., W.J.P. and R.J.H. wrote the manuscript.
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Kho, C., Lee, A., Jeong, D. et al. SUMO1-dependent modulation of SERCA2a in heart failure. Nature 477, 601–605 (2011). https://doi.org/10.1038/nature10407
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DOI: https://doi.org/10.1038/nature10407
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