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| Item Type: | Preprint |
|---|---|
| Title: | SUMOylation of HSF1 orchestrates transcriptional and splicing programs during the proteotoxic stress response |
| Creators: |
Mueller, Stefan  ORCID: https://orcid.org/0000-0002-8792-7700, Patra, Upayan, Kuska, Svenja, Mosler, Thorsten ORCID: https://orcid.org/0000-0003-1800-2680, Makarov, Timur, Mukhopadhyay, Urbi, Münch, Christian ORCID: https://orcid.org/0000-0003-3832-090X, Keller, Ulrich ORCID: https://orcid.org/0000-0002-8485-1958, Müller-McNicoll, Michaela ORCID: https://orcid.org/0000-0002-7174-8310 and Wirth, Matthias ORCID: https://orcid.org/0000-0002-8340-0872
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| Abstract: | Proteotoxic stress poses a significant threat to cellular homeostasis. To maintain proteostasis, cells activate a multi-layered adaptive program that rewires translation, transcription, and splicing. However, the signaling events that coordinate this program are incompletely understood. Here we inhibited the ubiquitin-like SUMO pathway, subjected cells to transient heat stress, and performed integrative quantitative proteomic and transcriptomic analyses. Remarkably, in cells recovering from proteotoxic stress, inhibition of SUMO conjugation led to sustained activation of Heat Shock Factor 1 (HSF1). Mechanistically, loss of HSF1 SUMOylation promoted the persistent clustering of HSF1 at the promoters of its target genes and maintained its interaction with the general transcription machinery and transcriptional co-activators. This not only drives enhanced expression of canonical heat shock proteins, but also triggers persistent expression of long non-coding HSATIII RNAs that function as scaffolds for nuclear stress bodies (nSBs). Consequently, SUMO inhibition impaired the disassembly of nSBs and trapped splicing factors within these molecular condensates, thereby disrupting recovery of normal splicing patterns upon stress release. Altogether, we define SUMOylation of HSF1 as a central regulatory node for restoration of proteostasis. Our data highlight the critical role of SUMO signaling in regulating the dynamics of a molecular condensate for ensuring timely resolution of the stress response and functional re-establishment of cellular homeostasis. |
| Source: | Research Square |
| Publisher: | Research Square |
| Article Number: | rs.3.rs-10283915/v1 |
| Date: | 16 July 2026 |
| Official Publication: | https://doi.org/10.21203/rs.3.rs-10283915/v1 |
| Related to: |
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