Membrane Phospholipid Asymmetry Counters the Adverse Effects of Sterol Overloading in the Golgi Membrane of Drosophila
Membrane Phospholipid Asymmetry Counters the Adverse Effects of Sterol Overloading in the Golgi Membrane of Drosophila
复制标题
膜磷脂不对称性对抗果蝇高尔基膜中甾醇超载的不利影响
DOI：
10.1534/genetics.111.137687
复制
发表时间：
2012-04-01
期刊：
影响因子：
3.3
通讯作者：
Huang, Xun
中科院分区：
文献类型：
--
作者：
Ma, Zhiguo;Liu, Zhonghua;Huang, Xun
胆固醇和磷脂是所有真核生物细胞膜的结构和功能成分。不同细胞器内和细胞器之间胆固醇和磷脂含量的不均一性是真核膜的一个重要特征。这种异质性是如何实现和协调以维持适当的细胞生理学的，目前还知之甚少。我们先前发现，果蝇氧合固醇结合蛋白(OSBP)的过度表达会导致高尔基体中类固醇的积累。在这里，我们证明了OSBP在一组神经内分泌神经元中的过度表达损害了高尔基体的功能。它损害了神经肽法氏囊的运输，并导致羽化后的行为缺陷，其特征是翅膀未展开。我们进行了基因筛查，以确定抑制未展开的翅膀表型的修饰物。一个可能的磷脂翻转酶编码基因CG33298被证实，这表明膜不对称导向的机制平衡了高尔基膜内的胆固醇混乱。由于在酵母和蠕虫的研究中发现了胆固醇代谢和磷脂翻转酶活性之间的功能联系，我们的发现支持在进化上保守的胆固醇平衡和磷脂不对称之间的因果联系，从而维持正常的细胞生理。
Cholesterol and phospholipids serve as structural and functional components of cellular membranes in all eukaryotes. Heterogeneity in cholesterol and phospholipid content both within and between different organelles is an important characteristic of eukaryotic membranes. How this heterogeneity is achieved and orchestrated to maintain proper cellular physiology remains poorly understood. We previously found that overexpression of the Drosophila oxysterol-binding protein (OSBP) leads to sterol accumulation in the Golgi apparatus. Here, we show that Osbp overexpression in a set of neuroendocrine neurons compromises the function of the Golgi apparatus. It impairs trafficking of the neuropeptide bursicon and results in post-eclosion behavior defects characterized by unexpanded wings. We performed a genetic screen to identify modifiers that suppress the unexpanded wing phenotype. A putative phospholipid flippase-encoding gene, CG33298, was validated, suggesting that a membrane-asymmetry-directed mechanism balances cholesterol chaos within the Golgi membranes. Since the functional connection between cholesterol metabolism and the activity of phospholipid flippase has been implicated in studies in yeast and worms, our findings here support an evolutionarily conserved causal link between cholesterol homeostasis and phospholipid asymmetry that maintains normal cellular physiology.