Cellular Strategies for Regulating Functional and Nonfunctional Protein Aggregation

Growing evidence suggests that aggregation-prone proteins are both harmful and functional for a cell. How do cellular systems balance the detrimental and beneficial effect of protein aggregation? We reveal that aggregation-prone proteins are subject to differential transcriptional, translational, and degradation control compared to nonaggregation-prone proteins, which leads to their decreased synthesis, low abundance, and high turnover. Genetic modulators that enhance the aggregation phenotype are enriched in genes that influence expression homeostasis. Moreover, genes encoding aggregation-prone proteins are more likely to be harmful when overexpressed. The trends are evolutionarily conserved and suggest a strategy whereby cellular mechanisms specifically modulate the availability of aggregation-prone proteins to (1) keep concentrations below the critical ones required for aggregation and (2) shift the equilibrium between the monomeric and oligomeric/aggregate form, as explained by Le Chatelier’s principle. This strategy may prevent formation of undesirable aggregates and keep functional assemblies/aggregates under control. [Display omitted] ► mRNA encoding aggregation-prone proteins is complex, suggesting greater translational regulation ► Aggregation-prone proteins are present in low abundance and for short periods of time ► Tight control is evolutionarily conserved and provides robustness against aggregation ► Aggregation-prone proteins are subject to tight regulation Although deposits of protein aggregates are the hallmark of various neurodegenerative diseases, recent studies have demonstrated that protein aggregation is exploited in different physiological processes. These observations raise the question of how cells balance the detrimental and beneficial effects of aggregation. Gsponer and Babu reveal that aggregation-prone structured and disordered proteins are subject to differential regulation compared to non-aggregation-prone proteins. Their results provide a unifying framework for understanding the control of functional and nonfunctional protein aggregation in cells.