biostudies-literatureHunt LCNIA NIH HHSAlzheimer's AssociationNational Institute on Aging110517https://www.ebi.ac.uk/biostudies/studies/S-EPMC12391699biostudies-literatureUnknown301(9)The ubiquitin-proteasome system maintains proteostasis by degrading proteins that unfold and become insoluble upon stress. Some proteins have high insolubility in normal conditions because of their structure, subcellular localization, and interactions but it remains incompletely understood how the ubiquitin-proteasome system regulates them. Here, we utilized mass spectrometry to profile heat-induced solubility changes (insolubilome) and associated post-translational modifications in human cells (http://thermal-stress-insolubilome.stjude.org). We find that the solubility of several protein categories is oppositely modulated by thermal stress. Some proteins become more soluble upon heat shock, whereas others, including several ubiquitin-conjugating enzymes, become more insoluble. By analyzinThe Journal of biological chemistryProteome solubility is differentially reshaped by thermal stress and regulators of ubiquitination.PMC12391699R01 AG075869R21 AG079267RF1 AG068581Poudel SKavdia KPagala VRAlford DDemontis FFu YWang YDYu KHunt LCHigh AAGraca FAStephan AWang WWang XGrime JPeng JfalseProteome solubility is differentially reshaped by thermal stress and regulators of ubiquitination.The ubiquitin-proteasome system maintains proteostasis by degrading proteins that unfold and become insoluble upon stress. Some proteins have high insolubility in normal conditions because of their structure, subcellular localization, and interactions but it remains incompletely understood how the ubiquitin-proteasome system regulates them. Here, we utilized mass spectrometry to profile heat-induced solubility changes (insolubilome) and associated post-translational modifications in human cells (http://thermal-stress-insolubilome.stjude.org). We find that the solubility of several protein categories is oppositely modulated by thermal stress. Some proteins become more soluble upon heat shock, whereas others, including several ubiquitin-conjugating enzymes, become more insoluble. By analyzin2025-01-01T00:00:00Z2025 Jul2026-05-28T04:10:51.676Z2026-05-10T03:07:24.278ZS-EPMC123916994071396410.1016/j.jbc.2025.110517