Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Biochimie. 2020 Mar;170:212-218. doi: 10.1016/j.biochi.2020.01.014. Epub 2020 Feb 1.
SUMOylation, covalent conjugation of small ubiquitin-related modifier (SUMO), has been emerging as a critical posttranslational modification of developmental transcription factors, as well as key regulators in the adult heart. Identifying the SUMOylated targets within cardiac transcription factors will facilitate to unravel the roles of SUMOylation in heart development and disease. Here, we show that Gata6, an essential cardiac transcription factor, can be modified by SUMO in vivo. Mutation of potential SUMOylation sites reveals that a lysine residue at amino acid position 12 of Gata6 serves as the major attachment site for SUMO. Pias1, as an E3 SUMO ligase, preferentially enhances the conjugation of SUMO1 to Gata6 through its RING finger domain. Functional analyses with SUMOylation-deficient mutant indicate that SUMOylation does not affect the subcellular localization but instead represses Gata6 transcriptional activity. Our data suggest that posttranslational modification of Gata6 by SUMO conjugation provides a novel mechanism to regulate Gata6 activity.
SUMOylation，即小泛素相关修饰物（SUMO）的共价连接，已成为发育转录因子以及成年心脏中关键调节因子的一种重要翻译后修饰方式。鉴定心脏转录因子中的 SUMOylated 靶标将有助于揭示 SUMOylation 在心脏发育和疾病中的作用。在这里，我们发现 Gata6，一种必需的心脏转录因子，可以在体内被 SUMO 修饰。潜在 SUMOylation 位点的突变表明，Gata6 氨基酸位置 12 上的一个赖氨酸残基是 SUMO 的主要附着位点。作为一种 E3 SUMO 连接酶，Pias1 通过其 RING 指结构域优先增强 SUMO1 与 Gata6 的结合。SUMOylation 缺陷突变体的功能分析表明，SUMOylation 不会影响亚细胞定位，而是抑制 Gata6 的转录活性。我们的数据表明，SUMO 连接对 Gata6 的翻译后修饰提供了一种调节 Gata6 活性的新机制。
