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Vol. 14, Issue 8, 3459-3469, August 2003

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Inhibition of a Golgi Complex Lysophospholipid Acyltransferase Induces Membrane Tubule Formation and Retrograde Trafficking

Daniel Drecktrah ^* , Kimberly Chambers ^*, Esther L. Racoosin ^*, Edward B. Cluett , Amy Gucwa ^* , Brian Jackson ^||, and William J. Brown ^* ¶

^* Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853; Biology Department, Ithaca College, Ithaca, New York 14850; and ^|| GlaxoSmithKline Pharmaceuticals Research and Development, Harlow, Essex CM19 5AD, United Kingdom

Submitted November 5, 2002; Revised February 11, 2003; Accepted March 13, 2003
Monitoring Editor: Jennifer Lippincott-Schwartz

Recent studies have suggested that formation of Golgi membrane tubules involves the generation of membrane-associated lysophospholipids by a cytoplasmic Ca²⁺-independent phospholipase A₂ (PLA₂). Herein, we provide additional support for this idea by showing that inhibition of lysophospholipid reacylation by a novel Golgi-associated lysophosphatidylcholine acyltransferase (LPAT) induces the rapid tubulation of Golgi membranes, leading in their retrograde movement to the endoplasmic reticulum. Inhibition of the Golgi LPAT was achieved by 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976), a previously characterized antagonist of acyl-CoA cholesterol acyltransferase. The effect of CI-976 was similar to that of brefeldin A, except that the coatomer subunit -COP remained on Golgi-derived membrane tubules. CI-976 also enhanced the cytosol-dependent formation of tubules from Golgi complexes in vitro and increased the levels of lysophosphatidylcholine in Golgi membranes. Moreover, preincubation of cells with PLA₂ antagonists inhibited the ability of CI-976 to induce tubules. These results suggest that Golgi membrane tubule formation can result from increasing the content of lysophospholipids in membranes, either by stimulation of a PLA₂ or by inhibition of an LPAT. These two opposing enzyme activities may help to coordinately regulate Golgi membrane shape and tubule formation.

Present addresses: Laboratory of Intracellular Parasites, National Institutes of Allergy and Infectious Diseases, Rocky Mountain Laboratory, Hamilton, MT 59840; Perceptive Informatics, Inc., 900 Chelmsford St., Suite 308, Lowell, MA 01851.

^¶ Corresponding author. E-mail address: wjb5{at}cornell.edu.

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