ATP8B2-Mediated Asymmetric Distribution of Plasmalogens Regulates Plasmalogen Homeostasis and Plays a Role in Intracellular Signaling.
ATP8B2-Mediated Asymmetric Distribution of Plasmalogens Regulates Plasmalogen Homeostasis and Plays a Role in Intracellular Signaling.
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DOI：
10.3389/fmolb.2022.915457
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发表时间：
2022
影响因子：
5
通讯作者：
中科院分区：
文献类型：
--
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缩醛磷脂是甘油磷脂的一个亚类，在甘油主链的sn-1位含有乙烯基醚键。含乙醇胺的缩醛磷脂（缩醛磷脂）是哺乳动物细胞中细胞膜的主要成分，并且缩醛磷脂的从头合成在很大程度上有助于缩醛磷脂的稳态。缩醛磷脂的生物合成受反馈机制调节，该反馈机制感知质膜内叶中的缩醛磷脂水平并调节脂肪酰辅酶A还原酶1（Far 1）的稳定性，Far 1是缩醛磷脂生物合成的限速酶。然而，缩醛磷脂定位于质膜细胞质小叶的分子机制仍不清楚。为了解决这个问题，我们试图确定一个潜在的转运蛋白的缩醛磷脂从外到内叶质膜的磷脂翻转酶，IV型P-型腺苷三磷酸酶（P4-ATP酶），定位在质膜。我们在此表明，敲低属于1类P4-ATP酶的ATP 8B 2增强了细胞外小叶中的缩醛磷脂而不是磷脂酰乙醇胺的定位，并损害了Far 1的缩醛磷脂依赖性降解。此外，蛋白激酶B（AKT）的磷酸化通过降低ATP 8B 2的表达而下调，这导致细胞生长的抑制。总之，这些结果表明，质膜的细胞质小叶中的缩醛磷脂富集是由ATP 8B 2介导的，并且缩醛磷脂的这种不对称分布是感测缩醛磷脂以及AKT磷酸化所需的。
Plasmalogens are a subclass of glycerophospholipid containing vinyl-ether bond at the sn-1 position of glycerol backbone. Ethanolamine-containing plasmalogens (plasmalogens) are major constituents of cellular membranes in mammalian cells and de novo synthesis of plasmalogens largely contributes to the homeostasis of plasmalogens. Plasmalogen biosynthesis is regulated by a feedback mechanism that senses the plasmalogen level in the inner leaflet of the plasma membrane and regulates the stability of fatty acyl-CoA reductase 1 (Far1), a rate-limiting enzyme for plasmalogen biosynthesis. However, the molecular mechanism underlying the localization of plasmalogens in cytoplasmic leaflet of plasma membrane remains unknown. To address this issue, we attempted to identify a potential transporter of plasmalogens from the outer to the inner leaflet of plasma membrane by focusing on phospholipid flippases, type-IV P-type adenosine triphosphatases (P4-ATPase), localized in the plasma membranes. We herein show that knockdown of ATP8B2 belonging to the class-1 P4-ATPase enhances localization of plasmalogens but not phosphatidylethanolamine in the extracellular leaflet and impairs plasmalogen-dependent degradation of Far1. Furthermore, phosphorylation of protein kinase B (AKT) is downregulated by lowering the expression of ATP8B2, which leads to suppression of cell growth. Taken together, these results suggest that enrichment of plasmalogens in the cytoplasmic leaflet of plasma membranes is mediated by ATP8B2 and this asymmetric distribution of plasmalogens is required for sensing plasmalogens as well as phosphorylation of AKT.
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影响因子：
4.6
作者：
Honsho M;Abe Y;Fujiki Y
通讯作者：
Fujiki Y
DOI：
10.1016/j.bbamcr.2008.05.018
发表时间：
2008-10-01
影响因子：
5.1
作者：
Honsho, Masanori;Yagita, Yuichi;Fujiki, Yukio
通讯作者：
Fujiki, Yukio
影响因子：
4.8
作者：
Bryde, Susanne;Hennrich, Hanka;Holthuis, Joost C. M.
通讯作者：
Holthuis, Joost C. M.
影响因子：
3.7
作者：
Brites P;Ferreira AS;da Silva TF;Sousa VF;Malheiro AR;Duran M;Waterham HR;Baes M;Wanders RJ
通讯作者：
Wanders RJ
影响因子：
15.9
作者：
da Silva, Tiago Ferreira;Eira, Jessica;Brites, Pedro
通讯作者：
Brites, Pedro