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XBP1(S) and the mechanism of phospholipid biosynthesis
Author(s) -
Sriburi Rungtawan,
Jackowski Suzanne,
Mori Kazutoshi,
Brewer Joseph W
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a952-b
Subject(s) - xbp1 , phosphocholine , diacylglycerol kinase , endoplasmic reticulum , chemistry , unfolded protein response , microbiology and biotechnology , choline , phosphatidylcholine , enzyme , biochemistry , phospholipid , biology , rna splicing , rna , protein kinase c , membrane , gene
When mature B‐lymphocytes differentiate into antibody‐secreting plasma cells, synthesis of phosphatidylcholine (PtdCho) increases and the endoplasmic reticulum (ER) expands. Plasma cell development requires the active form of X‐box binding protein 1 [pXBP1(S)], a bZIP factor regulated by the Unfolded Protein Response (UPR) pathway. We previously showed that enforced expression of pXBP1(S) in NIH‐3T3 fibroblasts is sufficient to up‐regulate PtdCho synthesis and expand the rough ER. Furthermore, the activities of CDP:phosphocholine cytidylyltransferase (CCT), the rate‐limiting enzyme that produces CDP‐choline in the CDP‐choline pathway of PtdCho biosynthesis, and diacylglycerol:cholinephosphotransferase (CPT), an enzyme that acts upon CDP‐choline and diacylglycerol (DAG) to yield PtdCho, are increased in XBP1(S)‐transduced cells. We now show that increased CPT activity, achieved by over‐expression of CPT and/or CEPT, is not sufficient to up‐regulate PtdCho synthesis in fibroblasts. Consistent with the enhanced CCT activity, the steady‐state level of CCT enzyme and the CDP‐choline product are increased in XBP1(S)‐transduced cells. By contrast, the level of DAG is unchanged. Thus, the key mechanism by which XBP1(S) regulates PtdCho biosynthesis appears to center on the CCT‐catalyzed rate‐limiting step in the CDP‐choline pathway. [NIH Grant GM61970 to J.W.B, NIH Grant GM45737 to S.J. and ALSAC]