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J. Biol. Chem., Vol. 282, Issue 10, 7024-7034, March 9, 2007

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Coordinate Regulation of Phospholipid Biosynthesis and Secretory Pathway Gene Expression in XBP-1(S)-induced Endoplasmic Reticulum Biogenesis^*

Rungtawan Sriburi¹, Hemamalini Bommiasamy, Gerald L. Buldak, Gregory R. Robbins, Matthew Frank, Suzanne Jackowski, and Joseph W. Brewer²

From the Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153 and the Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Development of the expansive endoplasmic reticulum (ER) present in specialized secretory cell types requires X-box-binding protein-1 (Xbp-1). Enforced expression of XBP-1(S), a transcriptional activator generated by unfolded protein response-mediated splicing of Xbp-1 mRNA, is sufficient to induce proliferation of rough ER. We previously showed that XBP-1(S)-induced ER biogenesis in fibroblasts correlates with increased production of phosphatidylcholine (PtdCho), the primary phospholipid of the ER membrane, and enhanced activities of the choline cytidylyltransferase (CCT) and cholinephosphotransferase enzymes in the cytidine diphosphocholine (CDP-choline) pathway of PtdCho biosynthesis. Here, we report that the level and synthesis of CCT, the rate-limiting enzyme in the CDP-choline pathway, is elevated in fibroblasts overexpressing XBP-1(S). Furthermore, overexpression experiments demonstrated that raising the activity of CCT, but not cholinephosphotransferase, is sufficient to augment PtdCho biosynthesis in fibroblasts, indicating that XBP-1(S) increases the output of the CDP-choline pathway primarily via its effects on CCT. Finally, fibroblasts overexpressing CCT up-regulated PtdCho synthesis to a level similar to that in XBP-1(S)-transduced cells but exhibited only a small increase in rough ER and no induction of secretory pathway genes. The more robust XBP-1(S)-induced ER expansion was accompanied by induction of a wide array of genes encoding proteins that function either in the ER or at other steps in the secretory pathway. We propose that XBP-1(S) regulates ER abundance by coordinately increasing the supply of membrane phospholipids and ER proteins, the key ingredients for ER biogenesis.

Received for publication, October 10, 2006 , and in revised form, January 8, 2007.

^* This work was supported by National Institutes of Health Grants GM 61970 (to J. W. B.), T32 AI007508 (to H. B. and G. L. B.), and GM 45737 (to S. J.), Cancer Center (CORE) Support Grant CA21765 (to St. Jude Children's Research Hospital), and by the American Lebanese Syrian Associated Charities. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1–S5.

¹ Present address: Dept. of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

² To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, 2160 South First Ave., Maywood, IL 60153. Tel.: 708-216-5816; Fax: 708-216-9574; E-mail: jbrewer{at}lumc.edu.

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