《Journal of Cell Biology》：内质网扩大相关的基因被
The Journal of Cell Biology, Volume 167, Number 1, 35-41
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: email@example.com
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.
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).
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).
作者:admin@医学,生命科学 2011-02-16 05:11