Oxidative stress destabilizes protein arginine methyltransferase 4 via glycogen synthase kinase 3β to impede lung epithelial cell migration
Oxidative stress destabilizes protein arginine methyltransferase 4 via glycogen synthase kinase 3β to impede lung epithelial cell migration
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DOI：
10.1152/ajpcell.00073.2017
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发表时间：
2017-09-01
影响因子：
5.5
通讯作者：
Zou, Chunbin
中科院分区：
文献类型：
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作者：
Li, Xiuying;Lai, Yandong;Zou, Chunbin
氧化应激影响正常的细胞功能，导致包括肺部疾病在内的各种疾病的发病机制。蛋白质精氨酸甲基转移酶4（PRMT 4）对于正常肺泡上皮细胞发育至关重要;然而，PRMT 4在此类肺部疾病中的调节尚未阐明。使用生物化学方法，我们发现过氧化氢（H2 O2）处理降低了PRMT 4蛋白在小鼠肺上皮（MLE 12）细胞中的稳定性，从而阻碍了细胞迁移。蛋白激酶糖原合成酶激酶3 β（GSK-3 β）与PRMT 4相互作用并催化PRMT 4 T132磷酸化，其保护PRMT 4免于泛素蛋白酶体降解。H2 O2下调GSK-3 β以在蛋白水平上减少PRMT 4。PRMT 4促进细胞迁移，H2 O2降解PRMT 4以抑制肺上皮细胞迁移。这些观察结果表明，氧化应激通过GSK-3 β信号传导使PRMT 4不稳定，从而阻碍肺上皮细胞迁移，这可能阻碍肺修复和再生过程。
Oxidative stress impacts normal cellular function leading to the pathogenesis of various diseases including pulmonary illnesses. Protein arginine methyltransferase 4 (PRMT4) is critical for normal lung alveolar epithelial cell development; however, the regulation of PRMT4 within such pulmonary diseases has yet to be elucidated. Using biochemical approaches, we uncovered that peroxide (H2O2) treatment decreases PRMT4 protein stability in murine lung epithelial (MLE12) cells to impede cell migration. Protein kinase glycogen synthase kinase 3 beta (GSK-3 beta) interacts with PRMT4 and catalyzes PRMT4 T132 phosphorylation that protects PRMT4 from ubiquitin proteasomal degradation. H2O2 downregulates GSK-3 beta to reduce PRMT4 at protein level. PRMT4 promotes cell migration and H2O2 degrades PRMT4 to inhibit lung epithelial cell migration. These observations demonstrate that oxidative stress destabilizes PRMT4 via GSK-3 beta signaling to impede lung epithelial cell migration that may hinder the lung repair and regeneration process.