Phosphatidic acid metabolism regulates the intracellular trafficking and retrotranslocation of CFTR
Phosphatidic acid metabolism regulates the intracellular trafficking and retrotranslocation of CFTR
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DOI：
10.1016/j.bbamcr.2007.08.011
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发表时间：
2008-01-01
影响因子：
5.1
通讯作者：
Kai, Hirofumi
中科院分区：
文献类型：
--
作者：
Hashimoto, Yasuaki;Okiyoneda, Tsukasa;Kai, Hirofumi
囊性纤维化跨膜电导调节因子(CFTR)通过高尔基体从内质网(ER)转运到质膜。对这些贩运事件至关重要的不仅是蛋白质因素的作用，而且还有膜脂的作用。然而，磷脂等脂类对CFTR贩运的监管在很大程度上还没有被探索过。在这里，我们表明，异丁醇抑制磷脂酶D(PLD)介导的磷脂酸(PA)的形成，抑制了CFTR的成熟和从内质网输出。外源添加的PA逆转了这些效应。此外，小干扰RNA下调PLD_1基因后，成熟期CFTR的表达下降。有趣的是，在PA磷酸酶抑制剂存在的情况下，通过添加过量的PA来维持PA的水平，可以减弱CFTR从高尔基体到质膜的运输以及Delta F508 CFTR到细胞质的逆行运输，这是Delta F508 CFTR与ER相关的降解的必要步骤。这些结果表明，PA的代谢调节了CFTR的胞内动力学和转运。(C)2007 Elsevier B.V.保留所有权利。
The cystic fibrosis transmembrane conductance regulator (CFTR) is transported to the plasma membrane from endoplasmic reticulum (ER) through the Golgi. Crucial to these trafficking events is the role of not only the proteinous factors but also the membrane lipids. However, the involvement of lipids, such as phospholipids, on the regulation of CFTR trafficking has been largely unexplored. Here, we show that the inhibition of phospholipase D (PLD)-mediated phosphatidic acid (PA) formation by I-butanol inhibited the maturation and export of CFTR from the ER. Exogenously added PA reversed these effects. Moreover, knock down of PLD1 by small interfering RNA decreased the expression of mature CFTR. Interestingly, sustaining the level of PA, by the addition of excess PA in the presence of PA phosphatase inhibitor, attenuated the transport of CFTR from the Golgi to plasma membrane and the retrograde transport of Delta F508 CFTR to the cytoplasm, a necessary step for the ER-associated degradation of Delta F508 CFTR. These results indicated that the metabolism of PA modulated the intracellular dynamics and trafficking of CFTR. (C) 2007 Elsevier B.V. All rights reserved.