Intracellular clusterin causes juxtanuclear aggregate formation and mitochondrial alteration.
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 alpha-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.
Debure
Laure
L
Information et Programmation Cellulaire, UMR6026 CNRS-Université de Rennes 1, Campus de Beaulieu, Bat 13, 35042 Rennes Cedex, France. laure.debure@univ-rennes1.fr
Vayssiere
Jean-Luc
JL
Rincheval
Vincent
V
Loison
Fabien
F
Le Drean
Yves
Y
Michel
Denis
D
D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002522:Chlorocebus aethiops; D051152:Clusterin; D005434:Flow Cytometry; D019085:Fluorescent Antibody Technique, Direct; D006023:Glycoproteins / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D008928:Mitochondria / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D021122:Protein Subunits / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D051152:Clusterin; D006023:Glycoproteins; D008164:Luminescent Proteins; D018832:Molecular Chaperones; D020033:Protein Isoforms; D021122:Protein Subunits; D019253:Proto-Oncogene Proteins c-bcl-2; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D020169:Caspases