Induction of apoptosis by sphingoid long-chain bases in Aspergillus nidulans
Induction of apoptosis by sphingoid long-chain bases in Aspergillus nidulans
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DOI：
10.1128/mcb.23.1.163-177.2003
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发表时间：
2003-01-01
影响因子：
5.3
通讯作者：
Ye, XS
中科院分区：
文献类型：
--
作者：
Cheng, JJ;Park, TS;Ye, XS
鞘脂代谢在细胞凋亡中起重要作用。在这里，我们表明，二氢鞘氨醇（DHS）和植物鞘氨醇（PHS），两个主要的鞘氨醇碱的真菌，具有强大的杀菌活性与显着高的结构和立体化学特异性对构巢曲霉。事实上，只有自然发生的DHS和PHS是活跃的。进一步的分析表明，DHS和PHS诱导快速的DNA凝聚独立于有丝分裂，大规模的DNA片段化，磷脂酰丝氨酸的暴露，所有常见的形态特征的凋亡，表明DHS和PHS诱导凋亡的A。nidulans。DNA断裂需要蛋白质合成，这意味着一个积极的过程参与，进一步支持这一命题。DHS和PHS诱导细胞凋亡与活性氧（ROS）的快速积累有关。然而，ROS不需要DHS和PHS诱导的细胞凋亡，因为自由基自旋陷阱清除ROS没有效果。我们进一步证明，DHS和PHS诱导的细胞凋亡是独立的metacaspase功能，但需要线粒体功能。总之，结果表明DHS和PHS诱导A.与在哺乳动物系统中观察到的半胱天冬酶非依赖性细胞凋亡最相似。为.由于nidulans在遗传上是易处理的，因此该生物体应该是用于剖析细胞凋亡中的鞘脂信号传导的理想模型系统，并且重要的是，用于进一步阐明半胱天冬酶非依赖性细胞凋亡的分子基础。
Sphingolipid metabolism is implicated to play an important role in apoptosis. Here we show that dihydrosphingosine (DHS) and phytosphingosine (PHS), two major sphingoid bases of fungi, have potent fungicidal activity with remarkably high structural and stereochemical specificity against Aspergillus nidulans. In fact, only naturally occurring DHS and PHS are active. Further analysis revealed that DHS and PHS induce rapid DNA condensation independent of mitosis, large-scale DNA fragmentation, and exposure of phosphatidylserine, all common morphological features characteristic of apoptosis, suggesting that DHS and PHS induce apoptosis in A. nidulans. The finding that DNA fragmentation requires protein synthesis, which implies that an active process is involved, further supports this proposition. The induction of apoptosis by DHS and PHS is associated with the rapid accumulation of reactive oxygen species (ROS). However, ROS are not required for apootosis induced by DHS and PHS, as scavenging of ROS by a free radical spin trap has no effect. We further demonstrate that apoptosis induced by DHS and PHS is independent of metacaspase function but requires mitochondrial function. Together, the results suggest that DHS and PHS induce a type of apoptosis in A. nidulans most similar to the caspase-independent apoptosis observed in mammalian systems. As A. nidulans is genetically tractable, this organism should be an ideal model system for dissecting sphingolipid signaling in apoptosis and, importantly, for further elucidating the molecular basis of caspase-independent apoptosis.