CTP:Phosphocholine Cytidylyltransferase α Is Required for B-cell Proliferation and Class Switch Recombination

CTP:phosphocholine cytidylyltransferase (CCT) is a key rate-controlling enzyme in the biosynthetic pathway leading to the principle membrane phospholipid, phosphatidylcholine. CCTα is the predominant isoform expressed in mammalian cells. To investigate the role of CCTα in the development and functio...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-03, Vol.284 (11), p.6847-6854
Main Authors: Fagone, Paolo, Gunter, Christopher, Sage, Christopher R., Gunn, Kathryn E., Brewer, Joseph W., Jackowski, Suzanne
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
Cell Proliferation
Choline-Phosphate Cytidylyltransferase - genetics
Choline-Phosphate Cytidylyltransferase - immunology
Choline-Phosphate Cytidylyltransferase - metabolism
DNA-Binding Proteins - biosynthesis
DNA-Binding Proteins - genetics
DNA-Binding Proteins - immunology
Immunoglobulin Class Switching - drug effects
Immunoglobulin Class Switching - physiology
Immunoglobulin M - genetics
Immunoglobulin M - immunology
Immunoglobulin M - metabolism
Isoenzymes - genetics
Isoenzymes - immunology
Isoenzymes - metabolism
Lipopolysaccharides - pharmacology
Mice
Mice, Knockout
Phosphatidylcholines - biosynthesis
Phosphatidylcholines - genetics
Phosphatidylcholines - immunology
Regulatory Factor X Transcription Factors
Transcription Factors - biosynthesis
Transcription Factors - genetics
Transcription Factors - immunology
X-Box Binding Protein 1
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Summary:CTP:phosphocholine cytidylyltransferase (CCT) is a key rate-controlling enzyme in the biosynthetic pathway leading to the principle membrane phospholipid, phosphatidylcholine. CCTα is the predominant isoform expressed in mammalian cells. To investigate the role of CCTα in the development and function of B-lymphocytes, mice with B-lymphocytes that selectively lacked CCTα were derived using the CD19-driven Cre/loxP system. When challenged with a T-cell-dependent antigen, the animals harboring CCTα-deficient B-cells exhibited a hyper-IgM secretion phenotype coupled with a lack of IgG production. The inability of CCTα-/- B-cells to undergo class switch recombination correlated with a proliferation defect in vivo and in vitro in response to antigenic and mitogenic stimuli. Lipopolysaccharide stimulation of CCTα-/- B-cells resulted in an early trigger of the unfolded protein response-mediated splicing of Xbp-1 mRNA, and this was accompanied by accelerated kinetics of IgM secretion and higher incidence of IgM-secreting cells. Thus, the inability of stimulated B-cells to produce enough phosphatidylcholine prevents proliferation and class switch recombination but leads to unfolded protein response activation and a hyper-IgM secretion phenotype.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M807338200