Stroke Branch, National Institute of Neurological Disease and Stroke, National Institutes of Health (NINDS/NIH), Bldg10/Rm5B06, MSC 1401, 10 Center Drive, Bethesda, MD, 20892, USA,
Neuromolecular Med. 2013 Dec;15(4):771-81. doi: 10.1007/s12017-013-8239-9. Epub 2013 Jun 18.
Hibernating squirrels slow blood flow to a crawl, but sustain no damage to brain or other tissues. This phenomenon provides an excellent model of natural tolerance to ischemia. Small ubiquitin-like modifier (SUMO) is a 100-residue peptide that modifies other proteins by being attached to the epsilon amino group of specific lysine residues. The discovery of massive SUMOylation (by both SUMO-1 and SUMO-2/3) occurring in the brains of 13-lined ground squirrels (Ictidomys tridecemlineatus) during hibernation torpor had opened the door to the studies on SUMO and ischemic tolerance reviewed here. Ischemic stress was shown to increase the levels of SUMO conjugation, especially SUMO-2/3, mostly during reperfusion in animal models and during restoration of oxygen and glucose in cell culture systems. Over-expression or depletion of SUMOs and/or Ubc9 (the SUMO E2 conjugating enzyme) increases or decreases (respectively) the levels of SUMO conjugates. Elevated global SUMO conjugations were shown to cytoprotect from ischemic insults; conversely, depressed SUMOylation sensitized cells. Global protein conjugation not only by SUMOs, but also by other ubiquitin-like modifiers (ULMs) including NEDD8, ISG15, UFM1 and FUB1 was shown to be significantly increased in the brains of hibernating ground squirrels during torpor. These increases in multiple ULM conjugations may orchestrate the cellular events in hibernating ground squirrels that induce a state of natural tolerance through their multipronged effects. Certain miRNAs such as the miR-200 family and the miR-182 family were shown, at least partly, to control the levels of these ULM conjugations. Lowering the levels of these miRNAs leads to an increase in global SUMOylation/ULM conjugation, thereby providing the tolerance to ischemia. This suggests that these miRNAs may be good targets for therapeutic intervention in stroke.
冬眠松鼠会使血液流动减缓，但大脑和其他组织不会受到损伤。这种现象为天然耐受缺血提供了一个极好的模型。小泛素样修饰物 (SUMO) 是一种 100 个残基的肽，通过连接到特定赖氨酸残基的 ε 氨基基团来修饰其他蛋白质。在 13 线地松鼠 (Ictidomys tridecemlineatus) 冬眠蛰伏期间，大脑中大量 SUMO 化（SUMO-1 和 SUMO-2/3 都有）的发现，为这里综述的 SUMO 与缺血耐受的研究开辟了道路。在动物模型中，缺血应激被证明会增加 SUMO 连接的水平，尤其是 SUMO-2/3，主要是在再灌注期间，以及在细胞培养系统中恢复氧和葡萄糖时。SUMO 和/或 Ubc9（SUMO E2 连接酶）的过表达或耗竭会增加或减少（分别）SUMO 连接物的水平。研究表明，升高的全局 SUMO 连接可保护细胞免受缺血损伤；相反，SUMO 化降低会使细胞敏感。在冬眠地松鼠的大脑中，不仅 SUMO，还包括其他泛素样修饰物（ULM），如 NEDD8、ISG15、UFM1 和 FUB1 的全局蛋白连接都被证明在蛰伏期间显著增加。这些多种 ULM 连接物的增加可能协调了冬眠地松鼠细胞内的事件，通过其多方面的作用诱导天然耐受状态。某些 miRNA，如 miR-200 家族和 miR-182 家族，至少部分控制这些 ULM 连接物的水平。降低这些 miRNA 的水平会导致全局 SUMO 化/ULM 连接增加，从而提供对缺血的耐受。这表明这些 miRNA 可能是中风治疗干预的良好靶点。
