The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology
The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology
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DOI：
10.1073/pnas.0704154104
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发表时间：
2007-12-26
影响因子：
11.1
通讯作者：
Goodman, Joel M.
中科院分区：
文献类型：
--
作者：
Szymanski, Kimberly M.;Binns, Derk;Goodman, Joel M.
脂肪营养不良是一种以脂肪组织减少为特征的疾病，通常伴有严重的高甘油三酯血症、胰岛素抵抗、糖尿病和脂肪肝。它可以遗传或获得。最严重的遗传形式是 Berardinelli-Seip 先天性脂肪营养不良 2 型，与 BSCL2 基因突变相关。 BSCL2 编码 seipin，其功能完全未知。我们现在报告通过筛选检测对脂滴形态重要的基因来鉴定酵母 BSCL2/seipin。酵母seipin的缺失会导致不规则的脂滴经常聚集在增殖的内质网（ER）旁边；还可以看到巨大的脂滴。 BSCL2 患者的成纤维细胞中也存在许多不规则的小脂滴。人seipin可以在功能上替代酵母seipin，但人seipin中导致脂肪营养不良的错义突变，或酵母基因中的相应突变，使它们无法互补。酵母菌丝蛋白定位于内质网，在那里形成斑点。几乎所有脂滴似乎都位于内质网上，并且在这些连接处发现了seipin。因此，我们假设 seipin 对于液滴维护甚至组装很重要。除了检测seipin之外，筛选还鉴定了58个其他基因，其缺失会导致异常脂滴，其中包括2个编码已知激活lipin（小鼠脂肪营养不良基因座）的蛋白质的基因，以及其他16个参与内体溶酶体运输的基因。我们筛选中鉴定的基因对于理解脂滴生物发生和维持的途径以及某些脂肪营养不良的原因应该具有价值。
Lipodystrophy is a disorder characterized by a loss of adipose tissue often accompanied by severe hypertriglyceridemia, insulin resistance, diabetes, and fatty liver. It can be inherited or acquired. The most severe inherited form is Berardinelli-Seip Congenital Lipodystrophy Type 2, associated with mutations in the BSCL2 gene. BSCL2 encodes seipin, the function of which has been entirely unknown. We now report the identification of yeast BSCL2/seipin through a screen to detect genes important for lipid droplet morphology. The absence of yeast seipin results in irregular lipid droplets often clustered alongside proliferated endoplasmic reticulum (ER); giant lipid droplets are also seen. Many small irregular lipid droplets are also apparent in fibroblasts from a BSCL2 patient. Human seipin can functionally replace yeast seipin, but a missense mutation in human seipin that causes lipodystrophy, or corresponding mutations in the yeast gene, render them unable to complement. Yeast seipin is localized in the ER, where it forms puncta. Almost all lipid droplets appear to be on the ER, and seipin is found at these junctions. Therefore, we hypothesize that seipin is important for droplet maintenance and perhaps assembly. in addition to detecting seipin, the screen identified 58 other genes whose deletions cause aberrant lipid droplets, including 2 genes encoding proteins known to activate lipin, a lipodystrophy locus in mice, and 16 other genes that are involved in endosomallysosomal trafficking. The genes identified in our screen should be of value in understanding the pathway of lipid droplet biogenesis and maintenance and the cause of some lipodystrophies.