SCS3 and YFT2 link transcription of phospholipid biosynthetic genes to ER stress and the UPR.
SCS3 and YFT2 link transcription of phospholipid biosynthetic genes to ER stress and the UPR.
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DOI：
10.1371/journal.pgen.1002890
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发表时间：
2012-08
期刊：
影响因子：
4.5
通讯作者：
Willis IM
中科院分区：
文献类型：
--
作者：
Moir RD;Gross DA;Silver DL;Willis IM
在脂滴中储存营养的能力是一种古老的功能，在营养不足时期和两餐之间提供代谢能量的主要来源。脂肪储存诱导跨膜蛋白(FIT)是一种保守的内质网驻留蛋白，通过将能量丰富的甘油三酯分配到低密度脂蛋白中来促进脂肪储存。FIT2是最早在哺乳动物中发现的FIT基因家族的古老同源基因，在酿酒酵母(SCS3和YFT2)和其他酵母属真菌中有两个同源基因。尽管这些基因经过了1.7亿多年的共同进化以及它们与高等真核生物的差异，SCS3、YFT2和人类FIT2基因仍然保留了一些共同的功能：酵母基因在人胚胎肾细胞系中的表达促进了LD的形成，而人FIT2在酵母中的表达挽救了缺乏SCS3的菌株的肌醇营养不良以及化学和遗传表型。为了更好地了解SCS3和YFT2的功能，我们调查了其中一个或两个基因缺失的菌株的化学敏感性，并针对活性酵母基因缺失集合鉴定了合成的遗传交互作用。我们发现，SCS3和YFT2具有共同和独特的功能，连接着对细胞生长至关重要的主要生物合成过程。这些包括脂类代谢、囊泡运输、磷脂生物合成基因的转录和蛋白质合成。遗传数据表明，最佳菌株适合性需要磷脂合成和蛋白质合成之间的平衡，而SCS3和YFT2的缺失会影响协调这些过程的调节机制。这一机制的一部分涉及SCS3在内质网变化(例如，由于低肌醇)与Opi1调节的磷脂生物合成基因转录之间的联系。我们的结论是，SCS3和YFT2是正常的内质网膜生物合成所必需的，以响应脂代谢和内质网应激的扰动。形成脂滴的能力是真核细胞的一种保守特性，它允许以一种易于获取的形式存储多余的代谢能量。在脂肪组织中，将多余的卡路里储存在脂滴中通常会保护其他组织免受脂肪毒性和胰岛素抵抗的影响，但这种保护随着慢性营养过剩而丧失。脂肪储存诱导跨膜蛋白(FIT)是近年来发现的一个保守的蛋白质家族，存在于内质网的脂质双层中，与脂滴的形成密切相关。在这项工作中，我们证明了FIT蛋白的特定功能在酵母和人类之间是保守的，并且哺乳动物FIT2的酵母同源物SCS3和YFT2是连接脂代谢、囊泡运输、转录和蛋白质合成的大型遗传相互作用网络的一部分。根据这些相互作用，我们确定缺乏SCS3和YFT2的酵母菌株对慢性内质网应激的反应存在缺陷，并且不能诱导未折叠的蛋白质反应途径或低肌醇中磷脂生物合成基因的转录。我们的发现表明，哺乳动物Fit基因可能在内质网应激途径中发挥重要作用，而内质网应激途径与肥胖和2型糖尿病有关。
The ability to store nutrients in lipid droplets (LDs) is an ancient function that provides the primary source of metabolic energy during periods of nutrient insufficiency and between meals. The Fat storage-Inducing Transmembrane (FIT) proteins are conserved ER–resident proteins that facilitate fat storage by partitioning energy-rich triglycerides into LDs. FIT2, the ancient ortholog of the FIT gene family first identified in mammals has two homologs in Saccharomyces cerevisiae (SCS3 and YFT2) and other fungi of the Saccharomycotina lineage. Despite the coevolution of these genes for more than 170 million years and their divergence from higher eukaryotes, SCS3, YFT2, and the human FIT2 gene retain some common functions: expression of the yeast genes in a human embryonic kidney cell line promotes LD formation, and expression of human FIT2 in yeast rescues the inositol auxotrophy and chemical and genetic phenotypes of strains lacking SCS3. To better understand the function of SCS3 and YFT2, we investigated the chemical sensitivities of strains deleted for either or both genes and identified synthetic genetic interactions against the viable yeast gene-deletion collection. We show that SCS3 and YFT2 have shared and unique functions that connect major biosynthetic processes critical for cell growth. These include lipid metabolism, vesicular trafficking, transcription of phospholipid biosynthetic genes, and protein synthesis. The genetic data indicate that optimal strain fitness requires a balance between phospholipid synthesis and protein synthesis and that deletion of SCS3 and YFT2 impacts a regulatory mechanism that coordinates these processes. Part of this mechanism involves a role for SCS3 in communicating changes in the ER (e.g. due to low inositol) to Opi1-regulated transcription of phospholipid biosynthetic genes. We conclude that SCS3 and YFT2 are required for normal ER membrane biosynthesis in response to perturbations in lipid metabolism and ER stress. The ability to form lipid droplets is a conserved property of eukaryotic cells that allows the storage of excess metabolic energy in a form that can be readily accessed. In adipose tissue, the storage of excess calories in lipid droplets normally protects other tissues from lipotoxicity and insulin resistance, but this protection is lost with chronic over-nutrition. The FAT storage-inducing transmembrane (FIT) proteins were recently identified as a conserved family of proteins that reside in the lipid bilayer of the endoplasmic reticulum and are implicated in lipid droplet formation. In this work we show that specific functions of the FIT proteins are conserved between yeast and humans and that SCS3 and YFT2, the yeast homologs of mammalian FIT2, are part of a large genetic interaction network connecting lipid metabolism, vesicle trafficking, transcription, and protein synthesis. From these interactions we determined that yeast strains lacking SCS3 and YFT2 are defective in their response to chronic ER stress and cannot induce the unfolded protein response pathway or transcription of phospholipid biosynthetic genes in low inositol. Our findings suggest that the mammalian FIT genes may play an important role in ER stress pathways, which are linked to obesity and type 2 diabetes.
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影响因子：
4.8
作者：
BACHHAWAT, N;OUYANG, QA;HENRY, SA
通讯作者：
HENRY, SA
影响因子：
3.1
作者：
Dettmann, Anne;Jaeschke, Yvonne;Schueller, Hans-Joachim
通讯作者：
Schueller, Hans-Joachim
DOI：
10.1016/j.bbrc.2007.07.109
发表时间：
2007-10-05
影响因子：
3.1
作者：
Ford, Jason;Odeyale, Oluwafemi;Shen, Chang-Hui
通讯作者：
Shen, Chang-Hui
DOI：
10.1083/jcb.201010111
发表时间：
2011-03-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Adeyo O;Horn PJ;Lee S;Binns DD;Chandrahas A;Chapman KD;Goodman JM
通讯作者：
Goodman JM
影响因子：
3.9
作者：
Daum, G.;Wagner, A.;Athenstaedt, K.
通讯作者：
Athenstaedt, K.