Department of Chemistry, Wayne State University, Detroit, MI, 48202, USA.
Department of Physiology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
Nat Commun. 2018 Oct 18;9(1):4341. doi: 10.1038/s41467-018-06786-x.
Reactive oxygen species (ROS) contribute to the etiology of multiple muscle-related diseases. There is emerging evidence that cellular stress can lead to destabilization of sarcomeres, the contractile unit of muscle. However, it is incompletely understood how cellular stress induces structural destabilization of sarcomeres. Here we report that glutathionylation of SMYD2 contributes to a loss of myofibril integrity and degradation of sarcomeric proteins mediated by MMP-2 and calpain 1. We used a clickable glutathione approach in a cardiomyocyte cell line and found selective glutathionylation of SMYD2 at Cys13. Biochemical analysis demonstrated that SMYD2 upon oxidation or glutathionylation at Cys13 loses its interaction with Hsp90 and N2A, a domain of titin. Upon dissociation from SMYD2, N2A or titin is degraded by activated MMP-2, suggesting a protective role of SMYD2 in sarcomere stability. Taken together, our results support that SMYD2 glutathionylation is a novel molecular mechanism by which ROS contribute to sarcomere destabilization.
活性氧（ROS）是多种与肌肉相关疾病的病因之一。有新的证据表明，细胞应激会导致肌节（肌肉的收缩单位）不稳定。然而，细胞应激如何导致肌节的结构不稳定还不完全清楚。在这里，我们报告谷胱甘肽化的 SMYD2 会导致肌原纤维完整性丧失和肌节蛋白的降解，这是由 MMP-2 和钙蛋白酶 1 介导的。我们在心肌细胞系中使用了一种可点击的谷胱甘肽方法，发现 SMYD2 的 Cys13 处有选择性的谷胱甘肽化。生化分析表明，SMYD2 氧化或 Cys13 处的谷胱甘肽化会使其失去与 Hsp90 和 N2A（肌联蛋白的一个结构域）的相互作用。从 SMYD2 上解离后，N2A 或肌联蛋白被激活的 MMP-2 降解，这表明 SMYD2 在肌节稳定性中具有保护作用。总之，我们的结果支持 ROS 导致肌节不稳定的一种新的分子机制是 SMYD2 谷胱甘肽化。
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