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Clusterin proteins: stress-inducible polypeptides with proposed functions in multiple organ dysfunction

Departments of ¹ Radiation Oncology, ² Pharmacology and ³ Biochemistry, Laboratory of Molecular Stress Responses, Case School of Medicine and the Case Comprehensive Cancer Center, Case Western Reserve University, 2103 Cornell Road WRB 3-531 North, Cleveland, OH 44106-7285, USA

Severe trauma (e.g. whole body ionising radiation (IR)), leads to multiple organ dysfunction (MOD) and death. Although not completely understood, proposed triggering events of MOD include reactive oxygen species (ROS), released Ca²⁺ from endoplasmic reticulum (ER) stores, cell debris resulting from apoptosis and/or necrosis, and liberation of cytokines. Little is known about the defence mechanisms that protect against events that trigger MOD. We propose that the secreted form of clusterin (sCLU) is a major protective factor against trauma-induced MOD. sCLU is induced by IR and by other cytoprotective agents. Interestingly, this secreted protein is cytoprotective in a variety of cell systems following various agents. We demonstrate that sCLU is induced by thapsigargin (TG), a sarcoplasmic-endoplasmic reticulum Ca²⁺ ATPase (SERCA) pump inhibitor, which causes Ca²⁺ release from the ER. sCLU induction was delayed, with the earliest increase in sCLU levels detected at 18–24 h post IR, and peak levels noted at 72–96 h. IR and TG exposures resulted in similar induction kinetics, wherein transcription and translation of sCLU occurred with nearly identical temporal responses. Human CLU promoter activity mimicked induction of sCLU protein levels (p<0.01). Interestingly, cells pre-treated with BAPTA-AM, an intracellular Ca²⁺ chelator, did not prevent sCLU induction or lethality after TG or IR exposures. In fact, high dose exposures of BAPTA-AM induced sCLU responses. Thus, sCLU induction is triggered by ROS, changes in Ca²⁺ homeostasis and lipid peroxidation, factors prominent in triggering MOD. Future studies should directly examine the role(s) of sCLU in preventing MOD, which may be very important in comtermeasures to MOD in accident victims.