Chapter 5: Nuclear CLU (nCLU) and the fate of the cell.

The possible biological role played by Clusterin (CLU) has been puzzling researchers for a long time since its first discovery and characterization. CLU has been often described as an "enigmatic" gene, a clear indication that too many aspects of this issue have been obscure or difficult to interpret for long. The good news is that this is certainly no longer true. Since the beginning, CLU was believed to play important roles in nearly all most important biological phenomena. The diversity, sometime the contradictions, of its biological action is now likely explained by the existence of different protein products all generated by the same single copy CLU gene. The relatively recent discovery that CLU can be retained inside the cell and targeted to many intracellular sites and organelles, including the nucleus, provided us a very different view from that solely deriving from its possible role in the outer cellular environment. In particular, nuclear localization of CLU (nCLU) was found to trigger cell death in many systems. In this chapter, a critical review of previous work will enable us to reinterpret old data and observations in the attempt to progressively unravelling the CLU "enigma" by considering its localization inside and outside the cell. The final picture would supposedly reconciliate different or alternative hypothesis. Starting with an "historical" approach demonstrating that nCLU was right under our eyes since the beginning, up to the more recent contributions we will describe which stimuli would inhibit secretion and maturation of CLU leading at least one protein product to target the nucleus and kill the cell. A better understanding of this complex issue is not an easy work, considering the thoughtfulness in reviewing the existing literature and the known controversial reports. We hope that the information contained in this article will be useful for the reader to enlighten this field.