Zhang Hongchen, Shao Shipeng, Zeng Yong, Wang Xiaotian, Qin Yizhi, Ren Qiunan, Xiang Shengqi, Wang Yuxin, Xiao Junyu, Sun Yujie
State Key Laboratory of Membrane Biology, Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China.
National Biomedical Imaging Center, College of Future Technology, Peking University, Beijing, China.
Nat Cell Biol. 2022 Mar;24(3):340-352. doi: 10.1038/s41556-022-00846-7. Epub 2022 Mar 7.
Heat-shock transcription factor 1 (HSF1) orchestrates the fast and vast cellular response to heat shock through increased expression of heat-shock proteins. However, how HSF1 rapidly and reversibly regulates transcriptional reprogramming remains poorly defined. Here by combining super-resolution imaging, in vitro reconstitution and high-throughput sequencing, we reveal that HSF1 forms small nuclear condensates via liquid-liquid phase separation at heat-shock-protein gene loci and enriches multiple transcription apparatuses through co-phase separation to promote the transcription of target genes. Furthermore, the phase-separation capability of HSF1 is fine-tuned through phosphorylation at specific sites within the regulatory domain. Last, we discovered that HSP70 disperses HSF1 condensates to attenuate transcription following the cessation of heat shock and further prevents the gel-like phase transition of HSF1 under extended heat-shock stress. Our work reveals an inducible and reversible phase-separation feedback mechanism for dynamic regulation of HSF1 activity to drive the transcriptional response and maintain protein homeostasis during acute stress.
热休克转录因子1（HSF1）通过增加热休克蛋白的表达来协调细胞对热休克的快速而广泛的反应。然而，HSF1如何快速且可逆地调节转录重编程仍不清楚。在这里，通过结合超分辨率成像、体外重组和高通量测序，我们发现HSF1在热休克蛋白基因位点通过液-液相分离形成小核凝聚物，并通过共相分离富集多种转录装置，以促进靶基因的转录。此外，HSF1的相分离能力通过调节域内特定位点的磷酸化进行微调。最后，我们发现HSP70在热休克停止后分散HSF1凝聚物以减弱转录，并进一步防止HSF1在延长的热休克应激下发生凝胶样相变。我们的工作揭示了一种诱导性和可逆的相分离反馈机制，用于动态调节HSF1活性，以驱动转录反应并在急性应激期间维持蛋白质稳态。
