Proteome solubility changes under different proteostasis stresses

The accumulation of aberrant protein aggregates in neurodegenerative diseases is associated with a widespread failure of the protein homeostasis system. To investigate whether there is a subproteome that consistently aggregates under stress and define the broader determinants for protein aggregation at the proteome level we measured the changes in proteome solubility of a mouse neuroblastoma cell line (Neuro2a) under 6 different protein homeostasis stresses, including a Huntington’s disease model, Hsp70, Hsp90, proteasome and ER-mediated folding inhibition, and oxidative stress. By partitioning cell lysates into supernatants and pellets by centrifugation, we found that just over a one-quarter of the proteome extensively changed in solubility upon one or more stresses. Surprisingly, almost all the increases in insolubility were counteracted by increases on solubility of other proteins. Each stress directed a highly specific pattern of change, which reflected the remodelling of protein complexes involved in adaptation to perturbation, most notably stress granule proteins, which were highly enriched but responded differently across the different 2 stresses. The solubility patterns clustered into molecular functions anticipated from stress responses and metabolic pathway hotspots, and indicate a robust rewiring of protein-ligand interactions.