The Dual Roles of Clusterin in Extracellular and Intracellular Proteostasis

Emerging evidence suggests that, uniquely amongst chaperones, CLU may play important roles in maintaining proteostasis across all organismal body fluids, both within and outside cells and tissues. The mechanism(s) underlying the stress-induced appearance of the normally secreted chaperone CLU in the cytosol and non-secretory organelles are contentious. Published studies have shown that endoplasmic reticulum stress induces the release of CLU from the endoplasmic reticulum/Golgi to the cytosol, and we propose that this is the primary mechanism by which CLU appears outside the secretory system in cells. Insufficient evidence has been produced to support the existence of cytoplasmic stress-induced CLU protein isoforms arising from alternative mechanisms of transcription/translation. We present a model in which cell stress induces the release of CLU from the secretory system to the cytosol, where it facilitates the safe disposal of misfolded proteins via both autophagy and the proteasome to preserve organismal viability. Clusterin (CLU) was the first reported secreted mammalian chaperone and impacts on serious diseases associated with inappropriate extracellular protein aggregation. Many studies have described intracellular CLU in locations outside the secretory system and recent work has shown that CLU can be released into the cytosol during cell stress. In this article, we critically evaluate evidence relevant to the proposed origins of cellular CLU found outside the secretory system, and advance the hypothesis that the cytosolic release of CLU induced by stress serves to facilitate the trafficking of misfolded proteins to the proteasome and autophagy for degradation. We also propose future research directions that could help establish CLU as a unique chaperone performing critical and synergic roles in both intracellular and extracellular proteostasis. Clusterin (CLU) was the first reported secreted mammalian chaperone and impacts on serious diseases associated with inappropriate extracellular protein aggregation. Many studies have described intracellular CLU in locations outside the secretory system and recent work has shown that CLU can be released into the cytosol during cell stress. In this article, we critically evaluate evidence relevant to the proposed origins of cellular CLU found outside the secretory system, and advance the hypothesis that the cytosolic release of CLU induced by stress serves to facilitate the trafficking of misfolded proteins to the proteasome and autophagy for degradation. We also propose future research directions that could help establish CLU as a unique chaperone performing critical and synergic roles in both intracellular and extracellular proteostasis. insoluble protein aggregates that lack any specific structure. insoluble protein aggregates with highly ordered beta-sheet rich fibrillar structure (from normally soluble proteins). a major cytoplasmic process for the proteolytic degradation of unwanted proteins and organelles in autophagosomes. an ATP-independent chaperone that can hold aggregation-prone proteins in a soluble state and inhibit further aggregation, but lacks any ability itself to refold proteins. behavioural test often used for rodents in neuroscience studies to study spatial memory and animal learning. a family of enzymes that together regulate fibrin degradation, matrix turnover, and cell invasion. the second major cytoplasmic protein degradation system, which recognises and degrades polyubiquitinated intracellular proteins. the total set of proteins that are present in a cell, tissue or organism at a given time. all those processes that act together to homeostatically control protein synthesis, folding, localisation, and degradation.