Yang Wei, Sheng Huaxin, Warner David S, Paschen Wulf
Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Cereb Blood Flow Metab. 2008 Feb;28(2):269-79. doi: 10.1038/sj.jcbfm.9600523. Epub 2007 Jun 13.
A new group of proteins, small ubiquitin-like modifier (SUMO) proteins, has recently been identified and protein sumoylation has been shown to play a major role in various signal transduction pathways. Here, we report that transient global cerebral ischemia induces a marked increase in protein sumoylation. Mice were subjected to 10 mins severe forebrain ischemia followed by 3 or 6 h of reperfusion. Transient cerebral ischemia induced a massive increase in protein sumoylation by SUMO2/3 both in the hippocampus and cerebral cortex. SUMO2/3 conjugation was associated with a decrease in levels of free SUMO2/3. After ischemia, protein levels of the SUMO-conjugating enzyme Ubc9 were transiently decreased in the cortex but not in the hippocampus. We also exposed HT22 cells to arsenite, a respiratory poison that impairs cytoplasmic function and induces oxidative stress. Arsenite exposure induced a marked rise in protein sumoylation, implying that impairment of cytoplasmic function and oxidative stress may be involved in the massive post-ischemic activation of SUMO conjugation described here. Sumoylation of transcription factors has been shown to block their activation, with some exceptions such as the heat-shock factor and the hypoxia-responsive factor, where sumoylation blocks their degradation, and the nuclear factor-kappaB (NF-kappaB) essential modulator where sumoylation leads to an activation of NF-kappaB. Because protein sumoylation is known to be involved in the regulation of various biologic processes, the massive post-ischemic increase in protein sumoylation may play a critical role in defining the final outcome of neurons exposed to transient ischemia.
最近，一组新的蛋白质，即小泛素样修饰物（SUMO）蛋白被发现，并且蛋白质SUMO化已被证明在各种信号转导途径中起主要作用。在此，我们报告短暂性全脑缺血会导致蛋白质SUMO化显著增加。对小鼠进行10分钟的严重前脑缺血，随后再灌注3或6小时。短暂性脑缺血在海马体和大脑皮层中均诱导SUMO2/3介导的蛋白质SUMO化大量增加。SUMO2/3缀合与游离SUMO2/3水平的降低相关。缺血后，SUMO缀合酶Ubc9的蛋白质水平在皮层中短暂降低，但在海马体中未降低。我们还将HT22细胞暴露于亚砷酸盐，一种损害细胞质功能并诱导氧化应激的呼吸毒物。亚砷酸盐暴露诱导蛋白质SUMO化显著升高，这意味着细胞质功能受损和氧化应激可能参与了此处描述的缺血后SUMO缀合的大量激活。转录因子的SUMO化已被证明会阻断其激活，但有一些例外，如热休克因子和缺氧反应因子，其中SUMO化会阻断其降解，以及核因子-κB（NF-κB）必需调节剂，其中SUMO化会导致NF-κB激活。由于已知蛋白质SUMO化参与各种生物过程的调节，缺血后蛋白质SUMO化的大量增加可能在确定暴露于短暂性缺血的神经元的最终结局中起关键作用。
