Intracellular clusterin causes juxtanuclear aggregate formation and mitochondrial alteration

L Debure, J Vayssière, V Rincheval… - Journal of Cell …, 2003 - journals.biologists.com
L Debure, J Vayssière, V Rincheval, F Loison, Y Le Dréan, D Michel
Journal of Cell Science, 2003journals.biologists.com
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 α-chain region strongly
accumulated in an ubiquitinated form in juxtanuclear aggregates meeting the main criterions …
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 α-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.
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