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《Journal of Cell Biology》：内质网扩大相关的基因被
蛋白质折叠工厂（内质网）的构建之间的这种关连能够确保这两个过程在细胞需要快速制造、折叠和分泌大量特定蛋白时能协调运作。
研究人员发现细胞会产生一种叫做XBP1的分子以满足蛋白质折叠机器不断增长的需要。这种对折叠蛋白需求的增长会导致所谓的未折叠蛋白反应（UPR）以及蛋白质折叠和包装的工厂的膨胀。UPR还能促进细胞产生分子伴侣。
XBP1能够引发细胞产生卵磷脂。卵磷脂是构成内质网（ER）的重要建筑材料。ER中的膜能充当包装已折叠蛋白的包膜。当离开ER后，这个包膜就会融合到细胞膜内侧。一旦融入细胞膜，包膜就会打开并将其内的蛋白质放出细胞外。
通过将分子伴侣的制造和卵磷脂的合成联系起来，XBP1能够协调新ER的构建和装备并以此提高细胞折叠和运送蛋白的能力。
研究人员通过对是小鼠的纤维原细胞的研究发现了这个机制。他们将XBP1基因插入一种病毒并利用这种转基因病毒将这种基因引入纤维原细胞内。XBP1基因使纤维原细胞膜产生有关的关键酶类的活性明显增加。因为，已经知道UPR能够活化XBP1基因，所以这项研究表明XBP1能够将ER的膨胀和增加折叠和包装分泌性蛋白的能力联系在一起。
这项研究解释了细胞能够快速满足增加特定蛋白产量需求的原因，即通过折叠和装配蛋白任务的协同来达成这种任务。而且，这些发现也促进了人们对细胞生物学的进一步了解。
The Journal of Cell Biology, Volume 167, Number 1, 35-41
Report
XBP1 : a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum
Rungtawan Sriburi1, Suzanne Jackowski2, Kazutoshi Mori3, and Joseph W. Brewer1
1 Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153
2 Protein Science Division, Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105
3 Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
Correspondence to Joseph W. Brewer: jbrewer@lumc.edu
Abstract
When the protein folding capacity of the endoplasmic reticulum (ER) is challenged, the unfolded protein response (UPR) maintains ER homeostasis by regulating protein synthesis and enhancing expression of resident ER proteins that facilitate protein maturation and degradation. Here, we report that enforced expression of XBP1(S), the active form of the XBP1 transcription factor generated by UPR-mediated splicing of XBP1 mRNA, is sufficient to induce synthesis of phosphatidylcholine, the primary phospholipid of the ER membrane. Cells overexpressing XBP1(S) exhibit elevated levels of membrane phospholipids, increased surface area and volume of rough ER, and enhanced activity of the cytidine diphosphocholine pathway of phosphatidylcholine biosynthesis. These data suggest that XBP1(S) links the mammalian UPR to phospholipid biosynthesis and ER biogenesis.
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Abbreviations used in this paper: ATF, activating transcription factor; BiP, binding protein; CCT, choline cytidylyltransferase; CDP-choline, cytidine diphosphocholine; CEPT, choline/ethanolaminephosphotransferase; CK, choline kinase; CPT, cholinephosphotransferase; PtdCho, phosphatidylcholine; PtdEtn, phosphatidylethanolamine; UPR, unfolded protein response; XBP1, X-box binding protein 1; XBP1(S), XBP1 (spliced); XBP1(U), XBP1(unspliced).
Introduction
The ER is a dynamic protein-folding compartment that can be expanded according to the demands placed upon the exocytic pathway. This is exemplified by the highly developed ER network present in specialized secretory cells such as insulin-producing ß cells of the pancreas and antibody-secreting plasma cells. Yet, the molecular mechanisms that coordinate the synthesis of protein and lipid components necessary for ER biogenesis remain poorly understood.
Homeostasis of the ER is regulated in large part by the unfolded protein response (UPR), a complex signaling system emanating from the ER membrane that regulates translation and transcription in response to increased demands on the protein folding capacity of the ER (Rutkowski and Kaufman, 2004). One branch of the UPR is directed by the ER membrane-bound activating transcription factor 6 and 6ß (ATF6/ß. Regulated intramembrane proteolysis releases the soluble cytosolic domains of ATF6/ß to function as basic leucine zipper transcription factors that up-regulate expression of various ER resident chaperones and folding enzymes (Haze et al., 1999, 2001).
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作者:admin@医学,生命科学 2011-02-16 05:11
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