摘要
胆固醇是真核细胞中含量非常丰富的一类脂质小分子,其主要生物学功能是掺入到磷脂双分子层中,调节膜的性质。胆固醇在细胞内不同膜上的分布极不均匀而且高度动态运输,这对维持细胞的正常生命活动至关重要。然而,细胞内胆固醇运输的机制一直不清楚。针对这一胆固醇代谢领域的重要问题,同时也是一个基本的细胞生物学问题,通过巧妙设计、全基因组筛选,鉴定出341个参与细胞内胆固醇转运的候选基因,其中,过氧化物酶体相关基因被显著富集。进而发现溶酶体通过和过氧化物酶体相互接触,将胆固醇转移给后者。而介导该接触的分子分别是溶酶体上的Synaptotagmin VII(Syt7)和过氧化物酶体膜上的PI(4,5)P2磷脂。将这种新发现的溶酶体–过氧化物酶体膜接触命名为LPMC(lysosome-peroxisome membrane contacts)。过氧化物酶体功能缺失会导致一大类相关疾病—过氧化物酶体紊乱疾病,表现为发育和神经系统功能障碍,目前还没有有效的治疗手段。该工作第一次揭示在这些病人和小鼠模型的细胞中有大量胆固醇堆积,且该现象的出现大大早于神经症状,提示胆固醇堆积是过氧化物酶体紊乱疾病的发病原因之一。这项研究工作的意义在于:(1)发现了细胞内胆固醇运输的新途径;(2)揭示了过氧化物酶体这一细胞器的新功能;(3)证明胆固醇运输异常是导致过氧化物酶体紊乱疾病的病因之一,为治疗该类疾病提供了全新的思路。
Cholesterol is an essential lipid for eukaryotic cells. Its major function is regulating membrane characters. Cholesterol is not evenly distributed among different organelles and is dynamically transported in the cell. However, the mechanism underlying intracellular cholesterol transport has remained largely unknown. We established an amphotericin B-based assay enabling a genome-wide sh RNA screen for delayed LDL-cholesterol transport, and identified 341 hits with particular enrichment of peroxisome genes, suggesting a previously unappreciated pathway for cholesterol transport. We showed dynamic membrane contact between peroxisome and lysosome, which was mediated by lysosomal Synaptotagmin VII binding to the lipid PI（4,5）P2 on peroxisomal membrane. LDL-cholesterol enhances such contact and cholesterol is transported from lysosome to peroxisome. Disruption of critical peroxisome genes leads to cholesterol accumulation in lysosome. Together, these findings reveal an unexpected role of peroxisome in intracellular cholesterol transport. We further demonstrate massive cholesterol accumulation in human patient cells and mouse model of peroxisomal disorders, suggesting a contribution of abnormal cholesterol accumulation to the diseases.
出处
《中国细胞生物学学报》
CAS
CSCD
2015年第6期759-763,共5页
Chinese Journal of Cell Biology
