Eukaryotic cells respond to heat shock through several regulatory processes including upregulation of stress responsive chaperones and reversible shutdown cellular activities through formation of protein assemblies. However, the underlying regulatory mechanisms of the recovery of these heat-induced protein assemblies remain largely elusive. Here, we measured the proteome abundance and solubility changes during recovery from severe heat shock in the mouse Neuro2a cell line. We found that prefoldins and translation machinery are rapidly down-regulated as the first step in the heat shock response. Analysis of proteome solubility reveals a rapid mobilization of protein quality control machineries, changes in cellular energy metabolism, changes in translational activity and nucleocytoplasmic transport are fundamental to the early stress responses, while the longer term adaptation to stress involves renewal of core cellular components. Hsp70 inhibition negatively affects the ribosomal machinery and delays the solubility recovery of many nuclear proteins.