TY - JOUR TI - HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain AU - Boczek, Edgar E AU - Fürsch, Julius AU - Niedermeier, Marie Laura AU - Jawerth, Louise AU - Jahnel, Marcus AU - Ruer-Gruß, Martine AU - Kammer, Kai-Michael AU - Heid, Peter AU - Mediani, Laura AU - Wang, Jie AU - Yan, Xiao AU - Pozniakovski, Andrej AU - Poser, Ina AU - Mateju, Daniel AU - Hubatsch, Lars AU - Carra, Serena AU - Alberti, Simon AU - Hyman, Anthony A AU - Stengel, Florian A2 - Dötsch, Volker A2 - Urlaub, Henning A2 - Benesch, Justin LP A2 - Dötsch, Volker VL - 10 PY - 2021 DA - 2021/09/06 SP - e69377 C1 - eLife 2021;10:e69377 DO - 10.7554/eLife.69377 UR - https://doi.org/10.7554/eLife.69377 AB - Aberrant liquid-to-solid phase transitions of biomolecular condensates have been linked to various neurodegenerative diseases. 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 α-crystallin domain (αCD). These αCD-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. KW - molecular condensates KW - RRM KW - chaperones KW - time-resolved quantitative XL-MS KW - FUS KW - aging JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -