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J. Biol. Chem., Vol. 280, Issue 8, 6663-6668, February 25, 2005

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Intracellular Retention of Caveolin 1 in Presenilin-deficient Cells^*

Douglas R. Wood, Jeffrey S. Nye, Ned J. C. Lamb¶, Anne Fernandez¶, and Magali Kitzmann||**

From the Department of Urology, Northwestern University, Chicago, Illinois 60611, Johnson and Johnson Pharmaceutical Research and Development, Titusville, New Jersey 08560, ^¶Cell Biology Unit, Institut de Génétique Humaine, UPR 1142 CNRS, 141 Rue de la Cardonille, Montpellier Cedex 05, F34396, and ^||Muscle Stem Cells and Facio Scapulo Humeral Dystrophy Unit, Centre de Recherche en Biochimie Macromoleculaire, FRE 2593, 1919 Route de Mende, 34293 Montpellier Cedex 5, France

Mutations in genes encoding presenilins (PS1 and PS2) are responsible for the majority of early onset familial Alzheimer's disease. PS, a critical component of -secretase, is responsible for the intramembranous cleavage of amyloid precursor protein and Notch. Other physiological functions have been assigned to PS without any clear identification of the mechanisms underlying these multiple biological roles. The early embryonic lethality of PS1 and PS2 double knock-out (PS1/2 null) mice prevents the evaluation of physiological roles of PS. To investigate new functions for presenilins, we performed a proteomic approach by using cells derived from PS1/2 null blastocysts and wild type controls. We identified a presenilin-dependent cell-surface binding of albumin. Binding of albumin depends on intact caveolae on the cellular surface. Abnormal caveolin 1 localization in PS1/2 null cells was associated with a loss of caveolae and an absence of caveolin 1 expression within lipid rafts. Expressing PS1 or PS2 but not the intracellular form of Notch1 in PS1/2 null cells restored normal caveolin 1 localization, demonstrating that presenilins are required for the subcellular trafficking of caveolin 1 independently from Notch activity. Despite an expression of both caveolin 1 and PS1 within lipid raft-enriched fractions after sucrose density centrifugation in wild type cells, no direct interaction between these two proteins was detected, implying that presenilins affect caveolin 1 trafficking in an indirect manner. We conclude that presenilins are required for caveolae formation by controlling transport of intracellular caveolin 1 to the plasma membrane.

Received for publication, September 9, 2004 , and in revised form, December 1, 2004.

^* This work was supported by a Human Frontier Science Program Long Term Fellowship LT-00052/2000-M (to M. K.) and by ARC Grant 4459 (to N. J. C. L.). 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.

^** To whom correspondence should be addressed: CRBM, FRE2593, 1919 Route de Mende, 34293 Montpellier Cedex 5, France. Tel.: 33-467-61-33-62; Fax: 33-4-67-52-15-59; E-mail: magali.kitzmann{at}crbm.cnrs.fr.

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