Non-cell Autonomous Maintenance of Proteostasis by Molecular Chaperones and Its Molecular Mechanism

Molecular chaperones have essential roles in cell survival, to prevent misfolding, aggregation, and aberrant accumulation of cellular proteins, and thus to maintain protein homeostasis (proteostasis). However, recent studies using animal models suggest that transcriptional upregulation of molecular chaperones in response to various types of stresses does not ubiquitously occur in all cells and tissues, but is a cell type-specific event. The imbalanced response to stresses between cells and tissues has been pointed out since more than 30 years ago, but the molecular basis as to how organisms maintain proteostasis in all cells, especially cells deficient for chaperone induction, remains unknown. In this review, I introduce the non-cell autonomous function of molecular chaperones that has been suggested in animal studies, especially focusing on our recent findings, and discuss the possibility that the non-cell autonomous function might provide a potential explanation as to how organisms would maintain proteostasis despite the imbalanced stress response between cells and tissues. Further elucidation of the molecular basis underlying the non-cell autonomous function of molecular chaperones would provide not only better understanding as to how organisms maintain proteostasis but also important insights into the potential development of therapies and diagnostics for the currently intractable neurodegenerative diseases that are associated with protein misfolding and aggregation.