Cytokine secretion requires phosphatidylcholine synthesis.
Choline cytidylyltransferase (CCT) is the rate-limiting enzyme in the phosphatidylcholine biosynthetic pathway. Here, we demonstrate that CCT alpha-mediated phosphatidylcholine synthesis is required to maintain normal Golgi structure and function as well as cytokine secretion from the Golgi complex. CCT alpha is localized to the trans-Golgi region and its expression is increased in lipopolysaccharide (LPS)-stimulated wild-type macrophages. Although LPS triggers transient reorganization of Golgi morphology in wild-type macrophages, similar structural alterations persist in CCT alpha-deficient cells. Pro-tumor necrosis factor alpha and interleukin-6 remain lodged in the secretory compartment of CCT alpha-deficient macrophages after LPS stimulation. However, the lysosomal-mediated secretion pathways for interleukin-1 beta secretion and constitutive apolipoprotein E secretion are unaltered. Exogenous lysophosphatidylcholine restores LPS-stimulated secretion from CCT alpha-deficient cells, and elevated diacylglycerol levels alone do not impede secretion of pro-tumor necrosis factor alpha or interleukin-6. These results identify CCT alpha as a key component in membrane biogenesis during LPS-stimulated cytokine secretion from the Golgi complex.
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Yong
Y
Tian
Caroline
C
Pate
Alberto
A
Andreolotti
Limin
L
Wang
Elaine
E
Tuomanen
Kelli
K
Boyd
Enrique
E
Claro
Suzanne
S
Jackowski
D000818:Animals; D001424:Bacterial Infections / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004075:Diglycerides / Q000096:biosynthesis; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008954:Models, Biological; D009713:Nucleotidyltransferases / Q000172:deficiency; D010713:Phosphatidylcholines / Q000096:biosynthesis*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013109:Sphingomyelins / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015415:Biomarkers; D016207:Cytokines; D004075:Diglycerides; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010713:Phosphatidylcholines; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; D009713:Nucleotidyltransferases