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Widespread remodeling of proteome solubility in response to different protein homeostasis stresses

Significance The protein homeostasis system prevents proteins from misfolding and aggregation. It is unclear, however, how this system is organized to fulfil this role under different insults. To investigate this problem, we examined how six different stresses affected proteome solubility in a mouse neuroblastoma cell line. We found that, although different stresses substantially changed the solubility of many proteins, no proteins substantially aggregated in common. Instead, each stress distinctly remodeled protein–ligand networks involved in key cellular processes, notably SG formation and metabolism. We conclude that cells are endowed with a wide range of regulatory responses, which are tailored for distinct stresses and buffer against widespread protein aggregation. The accumulation of protein deposits in neurodegenerative diseases has been hypothesized to depend on a metastable subproteome vulnerable to aggregation. To investigate this phenomenon and the mechanisms that regulate it, we measured the solubility of the proteome in the mouse Neuro2a cell line under six different protein homeostasis stresses: 1) Huntington’s disease proteotoxicity, 2) Hsp70, 3) Hsp90, 4) proteasome, 5) endoplasmic reticulum (ER)-mediated folding inhibition, and 6) oxidative stress. Overall, we found that about one-fifth of the proteome changed solubility with almost all of the increases in insolubility were counteracted by increases in solubility of other proteins. Each stress directed a highly specific pattern of change, which reflected the remodeling of protein complexes involved in adaptation to perturbation, most notably, stress granule (SG) proteins, which responded differently to different stresses. These results indicate that the protein homeostasis system is organized in a modular manner and aggregation patterns were not correlated with protein folding stability (ΔG). Instead, distinct cellular mechanisms regulate assembly patterns of multiple classes of protein complexes under different stress conditions.