British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, 77030, USA.
Nat Commun. 2021 Nov 1;12(1):6282. doi: 10.1038/s41467-021-26621-0.
Despite the importance of nitric oxide signaling in multiple biological processes, its role in tissue regeneration remains largely unexplored. Here, we provide evidence that inducible nitric oxide synthase (iNos) translocates to the nucleus during zebrafish tailfin regeneration and is associated with alterations in the nuclear S-nitrosylated proteome. iNos inhibitors or nitric oxide scavengers reduce protein S-nitrosylation and impair tailfin regeneration. Liquid chromatography/tandem mass spectrometry reveals an increase of up to 11-fold in the number of S-nitrosylated proteins during regeneration. Among these, Kdm1a, a well-known epigenetic modifier, is S-nitrosylated on Cys334. This alters Kdm1a binding to the CoRest complex, thus impairing its H3K4 demethylase activity, which is a response specific to the endothelial compartment. Rescue experiments show S-nitrosylation is essential for tailfin regeneration, and we identify downstream endothelial targets of Kdm1a S-nitrosylation. In this work, we define S-nitrosylation as an essential post-translational modification in tissue regeneration.
尽管一氧化氮信号在多种生物过程中具有重要意义，但它在组织再生中的作用在很大程度上仍未得到探索。在这里，我们提供的证据表明，诱导型一氧化氮合酶（iNOS）在斑马鱼尾鳍再生过程中转位到细胞核，并与核内 S-亚硝基化蛋白质组的改变有关。iNOS 抑制剂或一氧化氮清除剂可减少蛋白质 S-亚硝基化并损害尾鳍再生。液相色谱/串联质谱分析显示，在再生过程中，S-亚硝基化蛋白的数量增加了多达 11 倍。在这些蛋白中，Kdm1a 是一种众所周知的表观遗传修饰因子，其 Cys334 发生 S-亚硝基化。这改变了 Kdm1a 与 CoRest 复合物的结合，从而损害其 H3K4 去甲基化酶活性，这是内皮细胞特有的反应。挽救实验表明 S-亚硝基化对于尾鳍再生是必需的，我们确定了 Kdm1a S-亚硝基化的下游内皮靶标。在这项工作中，我们将 S-亚硝基化定义为组织再生中一种必需的翻译后修饰。
