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J. Biol. Chem., Vol. 283, Issue 15, 10174-10183, April 11, 2008

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Annexin A6-induced Inhibition of Cytoplasmic Phospholipase A₂ Is Linked to Caveolin-1 Export from the Golgi^*

Laia Cubells, Sandra Vilà de Muga, Francesc Tebar, Joseph V. Bonventre, Jesús Balsinde^¶, Albert Pol^||, Thomas Grewal^**1, and Carlos Enrich^||2

From the Departament de Biologia Cel·lular, Facultat de Medicina, and the ^||Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036-Barcelona, Spain, ^**Faculty of Pharmacy, University of Sydney, Sydney, New South Wales 2006, Australia, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, and ^¶Institute of Molecular Biology and Genetics, Spanish Research Council and University of Valladolid School of Medicine, 47003 Valladolid, Spain

The molecular mechanisms regulating the exit of caveolin from the Golgi complex are not fully understood. Cholesterol and sphingolipid availability affects Golgi vesiculation events and involves the activity of cytoplasmic phospholipase A₂ (cPLA₂). We recently demonstrated that high expression levels of annexin A6 (AnxA6) perturb the intracellular distribution of cellular cholesterol, thereby inhibiting caveolin export from the Golgi complex. In the present study we show that in Chinese hamster ovary cells overexpressing AnxA6, sequestration of cholesterol in late endosomes, leading to reduced amounts of cholesterol in the Golgi, inhibits cPLA₂ activity and its association with the Golgi complex. This correlates with the blockage of caveolin export from the Golgi in cells treated with methyl arachidonyl fluorophosphonate, a Ca²⁺-dependent cPLA₂ inhibitor. AnxA6-mediated down-regulation of cPLA₂ activity was overcome upon the addition of exogenous cholesterol or transfection with small interfering RNA targeting AnxA6. These findings indicate that AnxA6 interferes with caveolin transport through the inhibition of cPLA₂.

Received for publication, August 9, 2007 , and in revised form, January 30, 2008.

^* This study was supported by Ministerio de Educación y Ciencia, Spain Grants BFU2006-01151/BMC and GEN2003-20662 and Fellowship PR-2006-0142 (to C. E.) and National Heart Foundation of Australia, Gretl Raymond Foundation Grant G06S2559 (to T. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed. E-mail: tgrewal{at}pharm.usyd.edu.au.

² To whom correspondence may be addressed. E-mail: enrich{at}ub.edu.

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