A functional proteome is of paramount importance for all cells and organisms. The cellular pathways involved in maintaining the integrity of the proteome are collectively referred to as the proteostasis network. This network coordinates protein synthesis, folding, localization, modification, assembly, and turnover. Quality control mechanisms ensure the degradation of misfolded protein to prevent aggregation and deleterious effects of dysfunctional proteins. The proteostasis network dynamically adapts to meet the requirements of the cell. Conditions that lead to an increase in protein misfolding, such as heat shock, trigger stress response pathways, which typically reduce protein synthesis and increase the cellular capacity for protein folding and degradation. In addition to this homeostatic function, stress response pathways can trigger apoptosis in response to prolonged stress.
The proteostasis network is also challenged or rewired in a wide range of disease states, including cancer and neurodegenerative diseases, making it an attractive therapeutic target. However, the network’s size, complexity, dynamic nature and partial redundancy present formidable barriers to investigation with traditional methods. The functional genomics platform we pioneered positions us uniquely to address this challenge and to elucidate mechanisms and therapeutic targets in the proteostasis network.