Integral membrane proteins Brr6 and Apq12 link assembly of the nuclear pore complex to lipid homeostasis in the endoplasmic reticulum
Integral membrane proteins Brr6 and Apq12 link assembly of the nuclear pore complex to lipid homeostasis in the endoplasmic reticulum
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DOI：
10.1242/jcs.055046
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Cole, Charles N.
中科院分区：
文献类型：
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作者：
Hodge, Christine A.;Choudhary, Vineet;Cole, Charles N.
缺乏核包膜(NE)-内质网（ER）整体膜蛋白Apq12的酿酒酵母细胞在核孔复合物（NPCs）的组装上存在缺陷，这可能与调节膜流动性的缺陷有关。我们发现编码NE-ER必需的整体膜蛋白的BRR6是apq12 Delta的剂量抑制因子。携带温度敏感的brr6-1等位基因的细胞在核孔蛋白定位、mRNA代谢和核运输方面存在缺陷。电镜显示brr6-1细胞NE明显异常，内质网增生。Brr6-1细胞对影响膜生物物理性质的化合物和脂质生物合成途径抑制剂过敏，并与编码非必需脂质生物合成酶的基因表现出强烈的遗传相互作用。引人注目的是，brr6-1细胞在NE内或NE附近积聚了两类中性脂质的升高水平，即甾酯和三酰基甘油，并且在外源提供时过度积聚了固醇。虽然中性脂合成在野生型细胞中是必不可少的，但brr6-1细胞的生存能力完全依赖于中性脂的产生。这些数据表明Brr6在调节NE-ER中的脂质稳态中具有重要作用，从而影响鼻咽癌的形成和核胞质运输。
Cells of Saccharomyces cerevisiae lacking Apq12, a nuclear envelope (NE)-endoplasmic reticulum ( ER) integral membrane protein, are defective in assembly of nuclear pore complexes (NPCs), possibly because of defects in regulating membrane fluidity. We identified BRR6, which encodes an essential integral membrane protein of the NE-ER, as a dosage suppressor of apq12 Delta. Cells carrying the temperature-sensitive brr6-1 allele have been shown to have defects in nucleoporin localization, mRNA metabolism and nuclear transport. Electron microscopy revealed that brr6-1 cells have gross NE abnormalities and proliferation of the ER. brr6-1 cells were hypersensitive to compounds that affect membrane biophysical properties and to inhibitors of lipid biosynthetic pathways, and displayed strong genetic interactions with genes encoding non-essential lipid biosynthetic enzymes. Strikingly, brr6-1 cells accumulated, in or near the NE, elevated levels of the two classes of neutral lipids, steryl esters and triacylglycerols, and over-accumulated sterols when they were provided exogenously. Although neutral lipid synthesis is dispensable in wild-type cells, viability of brr6-1 cells was fully dependent on neutral lipid production. These data indicate that Brr6 has an essential function in regulating lipid homeostasis in the NE-ER, thereby impacting NPC formation and nucleocytoplasmic transport.