Chevallier Julien, Chamoun Zeina, Jiang Guowei, Prestwich Glenn, Sakai Naomi, Matile Stefan, Parton Robert G, Gruenberg Jean
Biochemistry, University of Geneva, 30 Quai E. Ansermet, 1211 Geneva 4, Switzerland.
Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84108-1257.
J Biol Chem. 2008 Oct 10;283(41):27871-27880. doi: 10.1074/jbc.M801463200. Epub 2008 Jul 21.
Most cell types acquire cholesterol by endocytosis of circulating low density lipoprotein, but little is known about the mechanisms of intra-endosomal cholesterol transport and about the primary cause of its aberrant accumulation in the cholesterol storage disorder Niemann-Pick type C (NPC). Here we report that lysobisphosphatidic acid (LBPA), an unconventional phospholipid that is only detected in late endosomes, regulates endosomal cholesterol levels under the control of Alix/AlP1, which is an LBPA-interacting protein involved in sorting into multivesicular endosomes. We find that Alix down-expression decreases both LBPA levels and the lumenal vesicle content of late endosomes. Cellular cholesterol levels are also decreased, presumably because the storage capacity of endosomes is affected and thus cholesterol clearance accelerated. Both lumenal membranes and cholesterol can be restored in Alix knockdown cells by exogenously added LBPA. Conversely, we also find that LBPA becomes limiting upon pathological cholesterol accumulation in NPC cells, because the addition of exogenous LBPA, but not of LBPA isoforms or analogues, partially reverts the NPC phenotype. We conclude that LBPA controls the cholesterol capacity of endosomes.
大多数细胞类型通过内吞循环中的低密度脂蛋白来获取胆固醇，但关于内体胆固醇转运机制以及其在胆固醇储存障碍尼曼-皮克C型（NPC）中异常积累的主要原因，人们了解甚少。在此我们报告，溶血双磷脂酸（LBPA）是一种仅在内体晚期被检测到的非常规磷脂，它在Alix/AlP1的控制下调节内体胆固醇水平，Alix/AlP1是一种与LBPA相互作用的蛋白，参与多泡内体的分选。我们发现Alix表达下调会降低LBPA水平以及内体晚期的腔内囊泡含量。细胞胆固醇水平也会降低，推测是因为内体的储存能力受到影响，从而加速了胆固醇清除。通过外源添加LBPA，Alix敲低细胞中的腔内膜和胆固醇都可以恢复。相反，我们还发现，在NPC细胞中病理性胆固醇积累时，LBPA会变得有限，因为添加外源LBPA（而非LBPA异构体或类似物）可部分逆转NPC表型。我们得出结论，LBPA控制内体的胆固醇容量。
