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Reversible ubiquitination regulates HSF1 phase separation in response to proteotoxic stress
Yue Zhu1, Jianhua Wang2, Shuhong Tang2
1The Fifth People's Hospital of Dalian, Dalian Medical University, Dalian, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Life Sciences
|January 24, 2026
Summary
Ubiquitination drives heat shock factor 1 (HSF1) condensation during proteotoxic stress. STUB1 promotes HSF1 phase separation, while USP13 and ATXN3 inhibit it, revealing key regulatory roles.
Area of Science:
- Cellular Biology
- Molecular Biology
- Stress Response
Background:
- Heat shock factor 1 (HSF1) forms nuclear condensates under proteotoxic stress, influencing cell fate.
- Protein ubiquitination is a critical post-translational modification involved in liquid-liquid phase separation.
- The precise role of ubiquitination in HSF1 condensation remains largely unknown.
Purpose of the Study:
- To investigate how ubiquitination regulates HSF1 phase separation in cells experiencing proteotoxic stress.
- To identify specific ubiquitin ligases and deubiquitinating enzymes involved in HSF1 condensation.
Main Methods:
- Immunofluorescence assays to detect HSF1 condensate formation.
- Fluorescence recovery after photobleaching (FRAP) to analyze HSF1 phase separation dynamics.
- Western blotting, immunoprecipitation, and mutagenesis to identify regulatory enzymes and ubiquitination sites.
Main Results:
- Proteasome inhibitor PS341 induced time-dependent HSF1 nuclear condensate formation.
- E3 ubiquitin ligase STUB1 promoted HSF1 phase separation via enhanced ubiquitination.
- Deubiquitinating enzymes (DUBs) USP13 and ATXN3 negatively regulated HSF1 condensation.
- Mutations at HSF1 ubiquitination sites significantly inhibited condensate formation.
Conclusions:
- Ubiquitination at multiple lysine residues is essential for driving HSF1 phase separation under proteotoxic stress.
- HSF1 phase separation is coordinately regulated by the E3 ubiquitin ligase STUB1 and DUBs USP13 and ATXN3.
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