CTP:phosphocholine cytidylyltransferase alpha 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. CCTalpha is the predominant isoform expressed in mammalian cells. To investigate the role of CCTalpha in the development and function of B-lymphocytes, mice with B-lymphocytes that selectively lacked CCTalpha were derived using the CD19-driven Cre/loxP system. When challenged with a T-cell-dependent antigen, the animals harboring CCTalpha-deficient B-cells exhibited a hyper-IgM secretion phenotype coupled with a lack of IgG production. The inability of CCTalpha-/- 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 CCTalpha-/- 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.
Fagone
Paolo
P
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.
Gunter
Christopher
C
Sage
Christopher R
CR
Gunn
Kathryn E
KE
Brewer
Joseph W
JW
Jackowski
Suzanne
S
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D019916:Choline-Phosphate Cytidylyltransferase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000502:physiology*; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; D007527:Isoenzymes; D008070:Lipopolysaccharides; D010713:Phosphatidylcholines; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D019916:Choline-Phosphate Cytidylyltransferase; C500611:Pcyt1a protein, mouse