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Published online June 16, 2008
doi:10.1083/jcb.200706152
The Journal of Cell Biology, Vol. 181, No. 6, 945-957
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Tian et al.
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Article

 Cytokine secretion requires phosphatidylcholine synthesis

Yong Tian1, Caroline Pate1, Alberto Andreolotti1,3, Limin Wang1, Elaine Tuomanen1, Kelli Boyd2, Enrique Claro3, and Suzanne Jackowski1

1 Department of Infectious Diseases and 2 Animal Resource Center, St. Jude Children's Research Hospital, Memphis, TN 38105
3 Institut de Neurociències i Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain

Correspondence to Suzanne Jackowski: suzanne.jackowski{at}stjude.org

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-1β 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.

Y. Tian and C. Pate contributed equally to this paper.

L. Wang's present address is Department of Internal Medicine, University of California, Davis, Davis, CA 95616.

Abbreviations used in this paper: ApoE, apolipoprotein E; CCT, cytidylyltransferase; CDP–Cho, cytidine diphosphocholine; C/EPT, choline/ethanolamine phosphotransferase; CPT, choline phosphotransferase; ERGIC-53, ER–Golgi intermediate compartment 53-kD protein; edelfosine, Et-18-OCH3; fMLP, formyl-methionylleucylphenylalanine; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IL-1β, interleukin-1β; IL-6, interleukin-6; LCM, L cell–conditioned medium; LPS, lipopolysaccharide; lysoPC, lysophosphatidylcholine; PEMT, phosphatidylethanolamine methyltransferase; PGE2, prostaglandin E2; PLD1, phospholipase D1; pro-TNF{alpha}, precursor form of TNF{alpha}; PtdCho, phosphatidylcholine; PtdEtn, phosphatidylethanolamine; PtdOH, phosphatidic acid; P'tse, phosphatase; qRT-PCR, quantitative RT-PCR; SM, sphingomyelin; TAPI, N-(D,L-[2-(hydroxyaminocarbonyl)methyl]-4-methylpentanoyl)-L-3-(2'naphthyl)-alanyl-L-alanine, 2-aminoethylamide; TACE, TNF{alpha}-converting enzyme.

© 2008 Tian et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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