SUMO1-dependent modulation of SERCA2a in heart failure

SR Ca(2+) ATPase 2a (SERCA2a) is a critical ATPase responsible for Ca(2+) re-uptake during excitation-contraction coupling. Impaired SR Ca(2+) uptake resulting from decreased expression and reduced activity of SERCA2a is a hallmark of heart failure (HF)(1). Accordingly, restoration of SERCA2a expression by gene transfer has proven to be effective in improving cardiac function in HF patients(2) as well as in animal models(3). The small ubiquitin-related modifier (SUMO) can be conjugated to lysine residues of target proteins(4), which is involved in most cellular process(5). Here, we show that SERCA2a is SUMOylated at lysine 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability. The levels of SUMO1 and SUMOylation of SERCA2a itself were greatly reduced in failing hearts. SUMO1 restitution by adeno-associated virus-mediated gene delivery maintained protein abundance of SERCA2a and significantly improved cardiac function in HF mice. This effect was comparable to SERCA2a gene delivery. Moreover, SUMO1 overexpression in isolated cardiomyocytes augmented contractility and accelerated Ca(2+) decay. Transgene-mediated SUMO1 overexpression rescued pressure overload-induced cardiac dysfunction concomitantly with increased SERCA2a function. By contrast, down-regulation of SUMO1 using 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 provides a platform for the design of novel therapeutic strategies for HF.