Levy Michal, Castillo S Sianna, Goldkorn Tzipora
Signal Transduction Laboratory, Department of Internal Medicine, University of California, School of Medicine, Davis, CA 95616, USA.
Biochem Biophys Res Commun. 2006 Jun 9;344(3):900-5. doi: 10.1016/j.bbrc.2006.04.013. Epub 2006 Apr 19.
We have previously shown that accumulation of ceramide, triggered by hydrogen peroxide (H(2)O(2)), induces apoptosis of human airway epithelial (HAE) cells. Under oxidant exposure, a lung sphingomyelinase (SMase) is activated and displays continued ceramide generation and pro-apoptotic signaling, thus leading to the pathological apoptosis that causes lung injury. In a search for a specific SMase that is modulated by oxidative stress, we recently cloned nSMase2 from monkey lung tissue and HAE cells. Here, we show that this nSMase2 is up-regulated by an oxidant (H(2)O(2)) and is inhibited by an antioxidant (glutathione (GSH)). Moreover, nSMase2 subcellular localization is governed by oxidant exposure, which leads to its preferential trafficking to the plasma membrane, where it generates ceramide and induces apoptosis. On the other hand, exposure to GSH results in nSMase2 trafficking to the nucleus, where it neither generates ceramide nor induces apoptosis.
我们之前已经表明，由过氧化氢（H₂O₂）引发的神经酰胺积累会诱导人气道上皮（HAE）细胞凋亡。在氧化剂暴露下，肺鞘磷脂酶（SMase）被激活，并持续产生神经酰胺和促凋亡信号，从而导致引起肺损伤的病理性凋亡。在寻找受氧化应激调节的特定SMase的过程中，我们最近从猴肺组织和HAE细胞中克隆了nSMase2。在此，我们表明这种nSMase2被氧化剂（H₂O₂）上调，并被抗氧化剂（谷胱甘肽（GSH））抑制。此外，nSMase2的亚细胞定位受氧化剂暴露的控制，这导致其优先转运到质膜，在那里它产生神经酰胺并诱导凋亡。另一方面，暴露于GSH会导致nSMase2转运到细胞核，在那里它既不产生神经酰胺也不诱导凋亡。
