Abstract：
SET domain protein 3 (SETD3) is an actin-specific methyltransferase, a rare post-translational modification with limited known biological functions. Till now, the function of SETD3 in cerebral ischemia-reperfusion (I/R)-induced injury remains unknown. Here, we show that the protein level of SETD3 is decreased in rat neurons after cerebral I/R injury. SETD3 promotes neuronal survival after both glucose and oxygen deprivation/reoxygenation (OGD/R) and cerebral I/R injury, and knockdown of SETD3 increases OGD/R-induced neuronal death. We further show that OGD/R-induced downregulation of SETD3 leads to the decrease of cellular ATP level, the reduction of mitochondrial electric potential and the increase of ROS production, thereby promoting mitochondrial dysfunction. We found that SETD3 reduction-induced mitochondrial dysfunction is mediated by the suppression of actin polymerization after OGD/R. Furthermore, we demonstrate that I/R-induced upregulation of PTEN leads to the downregulation of SETD3, and suppressing PTEN protects against ischemic neuronal death through downregulation of SETD3 and enhancement of actin polymerization. Together, this study provides the first evidence suggesting that I/R-induced downregulation of SETD3 mediates PTEN upregulation-induced ischemic neuronal death through downregulation of SETD3 and subsequent suppression of actin polymerization. Thus, upregulating SETD3 is a potential approach for the development of ischemic stroke therapy.
摘要：
SET结构域蛋白3（SETD3）是一种肌动蛋白特异性甲基转移酶，一种罕见的翻译后修饰，具有有限的已知生物学功能。到现在为止,SETD3在脑缺血再灌注损伤中的作用尚不清楚。这里,我们表明，在脑I/R损伤后，大鼠神经元中SETD3的蛋白水平降低。SETD3促进葡萄糖和氧剥夺/复氧（OGD/R）和脑I/R损伤后的神经元存活，SETD3的敲除增加了OGD/R诱导的神经元死亡。我们进一步表明，OGD/R诱导的SETD3下调导致细胞ATP水平降低，线粒体电位的降低和ROS产生的增加，从而促进线粒体功能障碍。我们发现SETD3还原诱导的线粒体功能障碍是由OGD/R后肌动蛋白聚合的抑制介导的。此外，我们证明，I/R诱导的PTEN上调导致SETD3下调，抑制PTEN通过下调SETD3和增强肌动蛋白聚合保护缺血性神经元死亡。一起,这项研究提供了第一个证据,表明I/R诱导的SETD3下调通过下调SETD3和随后抑制肌动蛋白聚合介导PTEN上调诱导的缺血性神经元死亡.因此，上调SETD3是开发缺血性卒中治疗的潜在方法。
