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However, the underlying molecular interactions that drive aging remain enigmatic. Here, we develop quantitative time-resolved crosslinking mass spectrometry to monitor protein interactions and dynamics inside condensates formed by the protein fused in sarcoma (FUS). We identify misfolding of the RNA recognition motif of FUS as a key driver of condensate aging. We demonstrate that the small heat shock protein HspB8 partitions into FUS condensates via its intrinsically disordered domain and prevents condensate hardening via condensate-specific interactions that are mediated by its \u03b1-crystallin domain (\u03b1CD). These \u03b1CD-mediated interactions are altered in a disease-associated mutant of HspB8, which abrogates the ability of HspB8 to prevent condensate hardening. We propose that stabilizing aggregation-prone folded RNA-binding domains inside condensates by molecular chaperones may be a general mechanism to prevent aberrant phase transitions.<\/jats:p>","DOI":"10.7554\/elife.69377","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T14:11:39Z","timestamp":1630937499000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.69377","source":"Crossref","is-referenced-by-count":102,"title":["HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain"],"prefix":"10.7554","volume":"10","author":[{"given":"Edgar E","family":"Boczek","sequence":"first","affiliation":[{"name":"Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany"},{"name":"Dewpoint Therapeutics GmbH, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius","family":"F\u00fcrsch","sequence":"additional","affiliation":[{"name":"University of Konstanz, Department of 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