The Molecular Chaperone Apolipoprotein J/Clusterin as a Sensor of Oxidative Stress: Implications in Therapeutic Approaches - A Mini-Review

Abstract

Background: Organisms are constantly exposed to physiological and environmental stresses and therefore require an efficient surveillance of genome and proteome quality in order to prevent disruption of homeostasis. Central to the intra- and extracellular proteome surveillance system are the molecular chaperones that contribute to both proteome maintenance and clearance. The conventional protein product of the apolipoprotein J/clusterin (CLU) gene is a heterodimeric secreted glycoprotein (also termed as sCLU) with a ubiquitous expression in human tissues. CLU exerts a small heat shock protein-like stress-induced chaperone activity and has been functionally implicated in numerous physiological processes as well as in ageing and most age-related diseases including tumorigenesis, neurodegeneration, and cardiovascular and metabolic syndromes. Objective: The CLU gene is differentially regulated by a wide variety of stimuli due to the combined presence of many distinct regulatory elements in its promoter that make it an extremely sensitive cellular biosensor of environmental and/or oxidative stress. Downstream to CLU gene induction, the CLU protein seems to actively intervene in pathological states of increased oxidative injury due to its chaperone-related property to inhibit protein aggregation and precipitation (a main feature of oxidant injury), as well as due to its reported distribution in both extra- and, most likely, intracellular compartments. Conclusion: On the basis of these findings, CLU has emerged as a unique regulator of cellular proteostasis. Nevertheless, it seemingly exerts a dual function in pathology. For instance, in normal cells and during early phases of carcinogenesis, CLU may inhibit tumor progression as it contributes to suppression of proteotoxic stress. In advanced neoplasia, however, it may offer a significant survival advantage in the tumor by suppressing many therapeutic stressors and enhancing metastasis. This review will critically present a synopsis of recent novel findings that relate to the function of this amazing molecule and support the notion that CLU is a biosensor of oxidative injury; a common link between ageing and all pathologies where CLU has been implicated. Potential future perspectives, implications and opportunities for translational research and the development of new therapies will be discussed.

The Chaperone Activity of Clusterin is Dependent on Glycosylation and Redox Environment

“…Hence, we conclude that these hypoglycosylated, intracellular CLU forms can also act as molecular chaperones. It has been discussed that intracellular CLU plays a role in maintaining the cellular homeostasis in pathological processes, such as ischemia, heat shock, ER-stress and other disorders [7,24,32,49]. Our results imply that the chaperone activity could be one mechanism by which intracellular CLU might exert a cytoprotective function as long as at least the core carbohydrates are present.…”

“…The finding that uncleaved sCLU has a high sensitivity towards reducing conditions renders it unlikely to act as a chaperone in a reducing environment. On the basis of these data we postulate that the intracellular CLU forms are inactive in a reducing environment as present in the cytosol and only gain their activity under oxidative stress conditions or in subcellular areas having a varying reduction potential, such as mitochondria [24,26,59]. Hence, under oxidizing conditions, retro-translocated CLU may act as an intracellular molecular chaperone assisting the cell to cope with critical imbalances caused by inflammation and other pathological circumstances [25,59].…”

“…The heat shock response is a cellular defense program triggering the upregulation of a broad spectrum of distinct proteins such as proteolytic enzymes, detoxifying proteins or molecular chaperones [23]. These protect the cell against the devastating effects of UV-light, ionizing radiation or oxidizing reagents, which on their part cause an increase in reactive oxygen species (ROS) and further lead to an accumulation of misfolded proteins [24,25,26]. Such interference in protein homeostasis may result in proteotoxic stress.…”

“…This, in contrast, is believed to be mediated by a few organized regions within the sCLU-protein which can bind to certain receptors of the LRP (lipoprotein receptor-related protein)-receptor family on the surface of vital cells [9,17,38,39,40]. Thereby, sCLU initiates the endocytic uptake and removal of misfolded protein aggregates, thus rendering it a key player during the homeostasis of the proteome, a process which is also termed proteostasis [24,41,42,43]. Furthermore, recent studies suggest that sCLU is an important player for modulating MAPK/Erk and PI3K/Akt signaling pathways.…”

Role of HDL-Associated Proteins and Lipids in the Regulation of Inflammation

“…ApoJ is expressed ubiquitously and is present on small dense HDL3 particles [71][72][73]. It is considered to be an antioxidant due to the presence of disulfide bonds that inhibit ROS-induced injury and preserve mitochondrial function [74].…”