Clusterin is a multifunctional plasma protein which consists of two disulfide-linked chains (α and β) that are both products of one gene. Clusterin is a 70-80-kDa amphiphilic molecule. It has a tendency to aggregate cells, including Sertoli cells and erythrocytes. It binds to the terminal complement complexes and prevents their insertion into cell membranes. The resulting complexes are soluble and unable to induce complement lysis.
Clusterin is constitutively expressed in almost all mammalian tissues, and is a major protein in physiological fluids including plasma, milk, urine, cerebrospinal fluid and semen. Within a given tissue, clusterin may be expressed predominantly in particular cell types-for example, in epithelial cells at tissue-fluid interfaces or in specific sub-populations of neurons.
Unraveling the biological significance of clusterin is complicated by two main characteristics: (1) the propensity of the protein to interact with a wide range of molecules, including itself, lipids, amyloid proteins, components of the complement membrane attack complex, and immunoglobulins; and (2) the ubiquitous upregulated expression of the gene in e.g. developmental remodeling, apoptotic disease states such as neurodegeneration, and in response to injury and other stresses. Clusterin variants additionally may play tissue- or context-specific roles. Is clusterin therefore truly multifunctional, or can a primary role be extracted from the diversity? Earlier hypotheses focused on specific potential roles including cytoprotection at fluid-tissue boundaries, membrane recycling during development and in response to injury, and regulation of complement-mediated membrane attack. More recently, arguments have been advanced proposing clusterin as a form of secreted heat-shock protein or chaperone molecule, in light of its induced expression by thermal, oxidative or mechanical stress, its diverse ligands, its ability to inhibit stress-induced protein precipitation, and its reported activities in in vitro systems as a protectant against cytotoxic agents. In the context of active cell death, these lines of evidence argue against a pro-apoptotic role for clusterin, further supported by failure of targeted overexpression of the gene to cause increased death of photoreceptors in a transgenic model. The posited role of clusterin as a cytoprotective chaperone-like molecule therefore seems compelling. However, not all forms of clusterin exhibit these benign properties. Recently, a truncated 55 kDa form of clusterin induced by irradiation in vitro, has been found targeted to the nucleus where it appears to act as a death signal. Interestingly, investigations of knockout (Clu−/−) mice have also highlighted the two faces of clusterin, since on the one hand absence of clusterin reduces cell death in hypoxia-ischemia-induced brain damage, suggesting that it normally functions to exacerbate neuronal damage in these circumstances, whereas in the same knockout strain, autoimmune myocardial damage is increased, implying a normally protective role. It is possible, therefore, that as with a select few other molecules such as p53 or Bcl-x, clusterin can act either to promote or to inhibit cell death, depending on the cellular context or molecular species.
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