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

• 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
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M807338200

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.