Plasmalogen biosynthesis is spatiotemporally regulated by sensing plasmalogens in the inner leaflet of plasma membranes.
Plasmalogen biosynthesis is spatiotemporally regulated by sensing plasmalogens in the inner leaflet of plasma membranes.
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DOI：
10.1038/srep43936
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发表时间：
2017-03-08
影响因子：
4.6
通讯作者：
Fujiki Y
中科院分区：
文献类型：
--
作者：
Honsho M;Abe Y;Fujiki Y
烯基醚磷脂是乙醇胺-和胆碱-磷脂的主要亚类，其中长链脂肪醇通过乙烯基醚键连接在sn-1位。含乙醇胺的烯基醚磷脂（缩醛磷脂）的生物合成通过调节脂肪酰辅酶A还原酶1（Far 1）的稳定性来调节，其方式取决于细胞缩醛磷脂的水平。然而，对缩醛磷脂合成调控的精确分子机制仍知之甚少。在这里，我们表明，通过抑制发动蛋白，Src激酶，或flotillin-1介导的内吞作用，而不增加细胞水平的缩醛磷脂的降解Far 1加速。相比之下，Far 1通过用制霉菌素螯合胆固醇而稳定。此外，通过降低编码翻转酶β亚基的CDC 50 A的表达来消除缩醛磷脂在质膜中的不对称分布，提高了Far 1的表达水平和缩醛磷脂合成，而不降低缩醛磷脂的总细胞水平。总之，这些结果支持了一个模型，即位于质膜内小叶的缩醛磷脂被感知用于细胞中的缩醛磷脂稳态，从而表明缩醛磷脂合成是通过监测缩醛磷脂的细胞水平来时空调节的。
Alkenyl ether phospholipids are a major sub-class of ethanolamine- and choline-phospholipids in which a long chain fatty alcohol is attached at the sn-1 position through a vinyl ether bond. Biosynthesis of ethanolamine-containing alkenyl ether phospholipids, plasmalogens, is regulated by modulating the stability of fatty acyl-CoA reductase 1 (Far1) in a manner dependent on the level of cellular plasmalogens. However, precise molecular mechanisms underlying the regulation of plasmalogen synthesis remain poorly understood. Here we show that degradation of Far1 is accelerated by inhibiting dynamin-, Src kinase-, or flotillin-1-mediated endocytosis without increasing the cellular level of plasmalogens. By contrast, Far1 is stabilized by sequestering cholesterol with nystatin. Moreover, abrogation of the asymmetric distribution of plasmalogens in the plasma membrane by reducing the expression of CDC50A encoding a β-subunit of flippase elevates the expression level of Far1 and plasmalogen synthesis without reducing the total cellular level of plasmalogens. Together, these results support a model that plasmalogens localised in the inner leaflet of the plasma membranes are sensed for plasmalogen homeostasis in cells, thereby suggesting that plasmalogen synthesis is spatiotemporally regulated by monitoring cellular level of plasmalogens.