Intracellular clusterin causes juxtanuclear aggregate formation and mitochondrial alteration

Abstract

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.

Gene expression correlates of neurofibrillary tangles in Alzheimer's disease

“…Truncated, intracellular forms of APOJ protein have been shown to alter mitochondrial function and, when localized to the nucleus, to induce apoptosis [9,29]. APOJ has been suggested to be both a pro-and anti-apoptotic factor.…”

CRM1 Protein-mediated Regulation of Nuclear Clusterin (nCLU), an Ionizing Radiation-stimulated, Bax-dependent Pro-death Factor

“…Numerous groups have reported accumulation of nCLU in the nuclei of stress-induced cells undergoing apoptotic cell death (4,8,9,10). We previously showed that pnCLU was translated in human cells from an alternatively spliced nCLU mRNA, created by direct splicing of exons I and III (8).…”

Ca2+ depletion induces nuclear clusterin, a novel effector of apoptosis in immortalized human prostate cells

“…These different isoforms of CLU have been suggested to be antiapoptotic 6,13 or proapoptotic. 7,10,12,[14][15][16] These controversial reports on the role of CLU might be related to specific proteomic profiles that are produced by different apoptotic stimuli (i.e. the general protein pattern of CLU and the relative ratio between different CLU isoforms).…”