title: Coordinate regulation of phospholipid biosynthesis and secretory pathway gene expression in XBP-1(S)-induced endoplasmic reticulum biogenesis.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA.
authors.forename: Rungtawan
authors.initials: R
authors.lastname: Sriburi
authors.forename: Hemamalini
authors.initials: H
authors.lastname: Bommiasamy
authors.forename: Gerald L
authors.initials: GL
authors.lastname: Buldak
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Robbins
authors.forename: Matthew
authors.initials: M
authors.lastname: Frank
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jackowski
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Brewer
mesh_terms: D000818:Animals; D019916:Choline-Phosphate Cytidylyltransferase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D002798:Diacylglycerol Cholinephosphotransferase / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology*; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000502:physiology*; D010743:Phospholipids / Q000096:biosynthesis*; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010743:Phospholipids; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D019916:Choline-Phosphate Cytidylyltransferase; D002798:Diacylglycerol Cholinephosphotransferase