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First published online 10 June 2003
doi: 10.1242/jcs.00619

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.00619v1 116/15/3109    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Debure, L. Articles by Michel, D. Search for Related Content PubMed PubMed Citation Articles by Debure, L. Articles by Michel, D.

Intracellular clusterin causes juxtanuclear aggregate formation and mitochondrial alteration

¹ Information et Programmation Cellulaire, UMR6026 CNRS-Université de Rennes 1, Campus de Beaulieu, Bat. 13, 35042 Rennes Cedex, France
² CNRS-UPRES-A 8087, Laboratoire de génétique moléculaire et physiologique de l'EPHE, Université de Versailles/Saint-Quentin, Bâtiment Fermat, 45 avenue des Etats-Unis, 78035 Versailles Cedex, France

^* Author for correspondence (e-mail: laure.debure{at}univ-rennes1.fr)

Accepted 15 April 2003

Clusterin is a puzzling protein upregulated in many diseased tissues, presented as either a survival or a death protein. The role of clusterin might depend on the final maturation and localization of the protein, which can be secreted or reside inside cells, either after in situ synthesis or uptake of extracellular clusterin. We studied the biological effects of intracellular clusterin and observed that clusterin forms containing the -chain region strongly accumulated in an ubiquitinated form in juxtanuclear aggregates meeting the main criterions of aggresomes and leading to profound alterations of the mitochondrial network. The viability of cells transfected by intracellular forms of clusterin was improved by overexpression of Bcl-2, and caspase inhibition was capable of rescuing cells expressing clusterin, which presented an altered mitochondrial permeability. We propose that, although it might be an inherently pro-survival and anti-apoptotic protein expressed by cells under stress in an attempt to protect themselves, clusterin can become highly cytotoxic when accumulated in the intracellular compartment. This activity might reconcile the opposite purported influences of clusterin on cell survival and explain how clusterin can be causally involved in neurodegeneration.

Key words: Clusterin, Heat-shock protein, Aggresome, Mitochondria, Apoptosis, _m

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