Gallardo-Chamizo Francisco, González-Prieto Román, Jafari Vahid, Luna-Peláez Noelia, Vertegaal Alfred C O, García-Domínguez Mario
Andalusian Centre for Molecular Biology and Regenerative Medicine-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain.
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands.
Cell Death Discov. 2025 May 10;11(1):230. doi: 10.1038/s41420-025-02513-w.
Because limited oxygen and glucose supply to tissues is a serious challenge that cells must properly measure to decide between surviving or triggering cell death, organisms have developed accurate mechanisms for sensing and signaling these conditions. In recent years, signaling through posttranslational modification of proteins by covalent attachment of the Small Ubiquitin-like Modifier (SUMO) is gaining notoriety. Enhanced sumoylation in response to oxygen and glucose deprivation (OGD) constitutes a safeguard mechanism for cells and a new avenue for therapeutic intervention. However, indiscriminate global sumoylation can limit the therapeutic potential that a more precise action on selected targets would have. To clear up this, we have conducted a proteomic approach in P19 cells to identify specific SUMO targets responding to OGD and to investigate the potential that these targets and their sumoylation have in preserving cells from death. Proteins undergoing sumoylation in response to OGD are mostly related to transcription and RNA processing, and the majority of them are rapidly desumoylated when restoring oxygen and glucose (ROG), confirming the high dynamics of this modification. Since OGD is linked to brain ischemia, we have also studied cells differentiated into neurons. However, no major differences have been observed between the SUMO-proteomes of proliferating and differentiated cells. We show that the overexpression of the transcription factor SOX2 or the SUMO ligase PIAS4 has a manifest cell protective effect largely depending on their sumoylation, and that maintaining the sumoylation capacity of the coregulator NAB2 is also important to face OGD. Conversely, sumoylation of the pluripotency factor OCT4, which is sumoylated under OGD, and is a target of the SUMO protease SENP7 for desumoylation after ROG, seems to block its cell survival-promoting capacity. Thus, better outcomes in cell protection would rely on the appropriate combination of sumoylated and non-sumoylated forms of selected factors.
由于组织中氧气和葡萄糖供应有限是细胞必须妥善衡量以决定是存活还是触发细胞死亡的严峻挑战，生物体已开发出精确的机制来感知和传递这些状况。近年来，通过小泛素样修饰物（SUMO）共价连接对蛋白质进行翻译后修饰的信号传导正受到关注。响应于氧和葡萄糖剥夺（OGD）而增强的SUMO化构成了细胞的一种保护机制以及治疗干预的新途径。然而，不加区分的全局SUMO化可能会限制对选定靶点采取更精确作用所具有的治疗潜力。为了弄清楚这一点，我们在P19细胞中进行了蛋白质组学研究，以鉴定响应OGD的特定SUMO靶点，并研究这些靶点及其SUMO化在保护细胞免于死亡方面的潜力。响应OGD而发生SUMO化的蛋白质大多与转录和RNA加工有关，并且当恢复氧气和葡萄糖（ROG）时，它们中的大多数会迅速去SUMO化，这证实了这种修饰的高度动态性。由于OGD与脑缺血有关，我们还研究了分化为神经元的细胞。然而，在增殖细胞和分化细胞的SUMO蛋白质组之间未观察到重大差异。我们表明，转录因子SOX2或SUMO连接酶PIAS4的过表达具有明显的细胞保护作用，这在很大程度上取决于它们的SUMO化，并且维持共调节因子NAB2的SUMO化能力对于应对OGD也很重要。相反，多能性因子OCT4在OGD下被SUMO化，并且是ROG后去SUMO化的SUMO蛋白酶SENP7的靶点，其SUMO化似乎会阻断其促进细胞存活的能力。因此，细胞保护方面更好的结果将依赖于选定因子的SUMO化和非SUMO化形式的适当组合。
