SUMO1-dependent modulation of SERCA2a in heart failure.
SUMO1-dependent modulation of SERCA2a in heart failure.
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DOI：
10.1038/nature10407
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发表时间：
2011-09-07
期刊：
影响因子：
64.8
通讯作者：
Hajjar, Roger J.
中科院分区：
文献类型：
--
作者：
Kho, Changwon;Lee, Ahyoung;Jeong, Dongtak;Oh, Jae Gyun;Chaanine, Antoine H.;Kizana, Eddy;Park, Woo Jin;Hajjar, Roger J.
SR Ca2+ ATPase 2A（SERCA2A）是在激发触发偶联过程中负责Ca2+再摄取的关键ATPase。 SR Ca2+摄取受损，导致表达降低和SERCA2A活性降低是心力衰竭（HF）的标志。因此，事实证明，通过基因转移对SERCA2A表达的恢复可以有效改善HF患者和动物模型中的心脏功能。小型泛素相关的修饰剂（SUMO）可以与靶蛋白的赖氨酸残基相结合，该残基参与了大多数细胞过程。在这里，我们表明SERCA2A在赖氨酸480和585上是sumoyl的，并且这种Sumoylation对于保留SERCA2A ATPase活性和稳定性至关重要。在失败的心脏中，SEMO1的水平和SERCA2A本身的Sumoylation量大大降低了。 SUMO1通过腺相关病毒介导的基因递送恢复，可维持SERCA2A的蛋白质丰度，并在HF小鼠中显着改善了心脏功能。这种作用与SERCA2A基因递送相当。此外，SUMO1在孤立的心肌细胞中的过表达增加了收缩力并加速了Ca2+衰减。转基因介导的SUMO1过表达救出了压力超负荷引起的心脏功能障碍，而SERCA2A功能也随之增加。相比之下，使用shRNA加速压力超负荷诱导心脏功能恶化的SUMO1下调，并伴随SERCA2A功能降低。然而，SERCA2A的敲低导致体外和体内严重的收缩功能障碍，而SUMO1的过表达并未挽救。综上所述，我们的数据表明，sumoylation是一种关键的翻译后修改，可调节SERCA2A功能，并为HF设计新型治疗策略提供了一个平台。
SR Ca2+ ATPase 2a (SERCA2a) is a critical ATPase responsible for Ca2+ re-uptake during excitation-contraction coupling. Impaired SR Ca2+ uptake resulting from decreased expression and reduced activity of SERCA2a is a hallmark of heart failure (HF). Accordingly, restoration of SERCA2a expression by gene transfer has proven to be effective in improving cardiac function in HF patients as well as in animal models. The small ubiquitin-related modifier (SUMO) can be conjugated to lysine residues of target proteins, which is involved in most cellular process. 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 Ca2+ 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.
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DOI：
10.1073/pnas.95.9.5251
发表时间：
1998-04-28
影响因子：
11.1
作者：
Hajjar, RJ;Schmidt, U;Rosenzweig, A
通讯作者：
Rosenzweig, A
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
4.8
作者：
Wang, J;Feng, XH;Schwartz, RJ
通讯作者：
Schwartz, RJ
影响因子：
4.8
作者：
Drewett, V;Devitt, A;Shaw, PE
通讯作者：
Shaw, PE
影响因子：
64.8
作者：
Baba, D;Maita, N;Shirakawa, M
通讯作者：
Shirakawa, M