Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation
Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation
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DOI：
10.1074/jbc.m506182200
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发表时间：
2006-03-31
影响因子：
4.8
通讯作者：
Codogno, P
中科院分区：
文献类型：
--
作者：
Lavieu, G;Scarlatti, F;Codogno, P
鞘脂神经酰胺在癌细胞中诱导具有自噬特征的巨自噬（这里称为自噬）和细胞死亡。在这里，我们表明，鞘氨醇激酶1（SK 1），负责生产鞘氨醇1-磷酸（S1 P）的酶，在MCF- 7细胞中的过表达刺激自噬通过增加LC 3阳性自噬体的形成和自噬抑制剂3-甲基腺嘌呤敏感的蛋白水解率。自噬被阻断的二甲基鞘氨醇，SK活性的抑制剂的存在下，并在细胞中表达的催化失活形式的SK 1。然而，在SK 1（wt）过表达细胞中，自噬对神经酰胺合成酶抑制剂伏马菌素B1不敏感。与神经酰胺诱导的自噬相反，SK 1（S1 P）诱导的自噬的特征在于（i）抑制哺乳动物靶雷帕霉素信号传导，独立于Akt/蛋白激酶B信号传导臂，和（ii）缺乏自噬蛋白Beclin 1的稳健积累。此外，营养饥饿诱导自噬和SK活性的刺激。通过siRNA敲低自噬蛋白Atg 7或SK 1的表达，消除了饥饿诱导的自噬，并增加了具有凋亡标志的细胞死亡。总之，这些结果表明，SK 1（S1 P）诱导的自噬保护细胞在营养饥饿期间免于死亡，具有凋亡特征。
The sphingolipid ceramide induces macroautophagy ( here called autophagy) and cell death with autophagic features in cancer cells. Here we show that overexpression of sphingosine kinase 1 ( SK1), an enzyme responsible for the production of sphingosine 1- phosphate ( S1P), in MCF- 7 cells stimulates autophagy by increasing the formation of LC3- positive autophagosomes and the rate of proteolysis sensitive to the autophagy inhibitor 3- methyladenine. Autophagy was blocked in the presence of dimethylsphingosine, an inhibitor of SK activity, and in cells expressing a catalytically inactive form of SK1. In SK1(wt)- overexpressing cells, however, autophagy was not sensitive to fumonisin B1, an inhibitor of ceramide synthase. In contrast to ceramide- induced autophagy, SK1( S1P)- induced autophagy is characterized by ( i) the inhibition of mammalian target of rapamycin signaling independently of the Akt/ protein kinase B signaling arm and ( ii) the lack of robust accumulation of the autophagy protein Beclin 1. In addition, nutrient starvation induced both the stimulation of autophagy and SK activity. Knocking down the expression of the autophagy protein Atg7 or that of SK1 by siRNA abolished starvation- induced autophagy and increased cell death with apoptotic hallmarks. In conclusion, these results show that SK1( S1P)- induced autophagy protects cells from death with apoptotic features during nutrient starvation.