Human TMEM30a promotes uptake of antitumor and bioactive choline phospholipids into mammalian cells.
Human TMEM30a promotes uptake of antitumor and bioactive choline phospholipids into mammalian cells.
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DOI：
10.4049/jimmunol.1002710
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发表时间：
2011-03-01
期刊：
影响因子：
--
通讯作者：
McIntyre TM
中科院分区：
文献类型：
--
作者：
Chen R;Brady E;McIntyre TM
抗肿瘤烷基磷脂在转化HL-60和Jurkat细胞中启动凋亡，同时保留它们的祖细胞。Edelfosine与其他短链磷脂（炎性血小板活化因子（PAF）和凋亡氧化截断磷脂）一样，被认为具有细胞内作用位点，但这些胆碱磷脂进入哺乳动物细胞的通道尚不明确。雪绒花素也可通过酿酒酵母在需要Lem3p膜蛋白的过程中积累，而人类基因组中含有Lem3p的同源物TMEM30a。我们发现，将胆碱磷脂导入酿酒酵母后，Lem3可以被人TMEM30a和Lem3 -TMEM30a嵌合体部分重建，这表明它们是同源的。TMEM30a- gfp嵌合体在哺乳动物细胞膜和细胞器内表达，异位TMEM30a表达促进外源胆碱和乙醇胺磷脂的摄取。shRNA敲低TMEM30a可减少荧光胆碱磷脂和[3H]PAF的进口。这种低敲还减少了外源性Edelfosine或有丝分裂毒性氧化截断的磷脂azelaoyl磷脂酰胆碱的线粒体去极化，并且低敲减少了对这两种磷脂的凋亡反应。这些结果表明，具有短sn-2残基的细胞外胆碱磷脂可以在细胞内发挥作用和代谢位点，因为它们是TMEM30a磷脂进口系统的运输底物。这种机制的变化可能会限制对短链胆碱磷脂（如Edelfosine， PAF和促凋亡磷脂）的敏感性。
Anti-tumor alkylphospholipids initiate apoptosis in transformed HL-60 and Jurkat cells while sparing their progenitors. Edelfosine like other short-chained phospholipids—inflammatory Platelet-activating Factor (PAF) and apoptotic oxidatively-truncated phospholipids—are proposed to have intracellular sites of action, yet a conduit for these choline phospholipids into mammalian cells is undefined. Edelfosine is also accumulated by Saccharomyces cerevisiae in process requiring the membrane protein Lem3p, and the human genome contains a Lem3p homolog TMEM30a. We show import of choline phospholipids into S. cerevisiae ⊗Lem3 is partially reconstituted by human TMEM30a and by Lem3p-TMEM30a chimeras, showing the proteins are orthologous. TMEM30a-GFP chimeras expressed in mammalian cells localized in plasma membranes, as well as internal organelles, and ectopic TMEM30a expression promoted uptake of exogenous choline and ethanolamine phospholipids. shRNA knockdown of TMEM30a reduced fluorescent choline phospholipid and [3H]PAF import. This knockdown also reduced mitochondrial depolarization from exogenous Edelfosine or the mitotoxic oxidatively truncated phospholipid azelaoyl phosphatidylcholine, and the knockdown reduced apoptosis in response to these two phospholipids. These results show extracellular choline phospholipids with short sn-2 residues can have intracellular roles and sites of metabolism because they are transport substrates for a TMEM30a phospholipid import system. Variation in this mechanism could limit sensitivity to short-chain choline phospholipids such as Edelfosine, PAF, and pro-apoptotic phospholipids.
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影响因子：
4.8
作者：
Kato, U;Emoto, K;Umeda, M
通讯作者：
Umeda, M
DOI：
10.1084/jem.20040213
发表时间：
2004-08-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gajate C;Del Canto-Jañez E;Acuña AU;Amat-Guerri F;Geijo E;Santos-Beneit AM;Veldman RJ;Mollinedo F
通讯作者：
Mollinedo F
影响因子：
4.8
作者：
Chen, Rui;Yang, Lili;McIntyre, Thomas M.
通讯作者：
McIntyre, Thomas M.
影响因子：
20.3
作者：
Cuvillier, O;Mayhew, E;Spiegel, S
通讯作者：
Spiegel, S
影响因子：
3.4
作者：
Devaux, Philippe F.;Lopez-Montero, Ivan;Bryde, Susanne
通讯作者：
Bryde, Susanne