MED12 interacts with the heat‐shock transcription factor HSF1 and recruits CDK8 to promote the heat‐shock response in mammalian cells

Srivastava, Pratibha; Takii, Ryosuke; Okada, Mariko; Fujimoto, Mitsuaki; Nakai, Asami

doi:10.1002/1873-3468.14139

Cited by 7 publications

(11 citation statements)

References 60 publications

(115 reference statements)

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“…Mediator components including MED12 co‐localize in HSF1 condensates. Consistent with a previous findings, 88 MED12 strongly promotes the formation of artificial HSF1 condensates in the HSE array of heat‐shocked cells 198 . Thus, some coactivators may enhance HSF1 condensate formation.…”

Section: Formation Of Phase Separated Hsf1 Condensatessupporting

confidence: 92%

“…Similarly, the hyperphosphorylation of Pol II reduces its affinity with SGO2, and may facilitate promoter escape. HSF1 also interacts with and recruits MED12, which forms a complex with CDK8 or CDK19 in the MKM 88 . Importantly, CDK8 and CDK19 phosphorylate HSF1–S326, similar to MEK1/2, p38, AKT1, and mTOR, and/or DYRK2, 115,118–119,184–185 and stabilize the Mediator–PIC complex in heat‐shocked cells (Figure 5).…”

Section: Direct Recruitment Of the Mediator–pic Complexmentioning

confidence: 99%

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Regulation of HSF1 transcriptional complexes under proteotoxic stress

2023

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Environmental, physiological, and pathological stimuli induce the misfolding of proteins, which results in the formation of aggregates and amyloid fibrils. To cope with proteotoxic stress, cells are equipped with adaptive mechanisms that are accompanied by changes in gene expression. The evolutionarily conserved mechanism called the heat shock response is characterized by the induction of a set of heat shock proteins (HSPs), and is mainly regulated by heat shock transcription factor 1 (HSF1) in mammals. We herein introduce the mechanisms by which HSF1 tightly controls the transcription of HSP genes via the regulation of pre‐initiation complex recruitment in their promoters under proteotoxic stress. These mechanisms involve the stress‐induced regulation of HSF1‐transcription complex formation with a number of coactivators, changes in chromatin states, and the formation of phase‐separated condensates through post‐translational modifications.

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Section: Formation Of Phase Separated Hsf1 Condensatessupporting

confidence: 92%

Section: Direct Recruitment Of the Mediator–pic Complexmentioning

confidence: 99%

Regulation of HSF1 transcriptional complexes under proteotoxic stress

2023

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“…HSF1 regulates cellular metabolism in both humans and mice 27–29 . Interestingly, HSF1 also regulates PGC‐1α via transcriptional regulation.…”

Section: Discussionmentioning

confidence: 99%

“…HSF1 regulates cellular metabolism in both humans and mice. [27][28][29] Interestingly, HSF1 also regulates PGC-1α via transcriptional regulation. For example, HSF1 deletion decreases the PGC-1α level and impairs its downstream metabolic activities including glucose/ acid metabolism, mitochondrial biogenesis, fiber switching skeletal muscle, 30,31 suggesting a otal role of the HSF1/PGC-1α axis in regulating energy homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle HSF1 prevents insulin resistance by improving glucose utilization

Lin

et al. 2022

The FASEB Journal

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The regulation of muscle glucose utilization has significant potential for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Heat shock factor 1 (HSF1) is involved in cellular metabolism and regulation of muscle metabolism. However, it is unclear how HSF1 regulates muscle glucose metabolism. In the present study, the development of obesity in mice was associated with HSF1 downregulation. Serum samples and muscle biopsies were obtained from obese and healthy humans. Fasting glucose and insulin levels and the homeostasis model assessment of insulin resistance value showed that obesity was associated with insulin resistance. The skeletal muscle level of HSF1 was decreased in obese and ob/ob mice. HSF1 was selectively over-expressed in the skeletal muscles of high fat diet (HFD)-fed mice. Muscle HSF1 over-expression successfully triggered glycolytic-to-oxidative myofiber switch and increased fatty acid metabolism and insulin sensitivity in the skeletal muscles of HFD-fed mice. Moreover, HSF1 improved energy expenditure and blocked muscle accumulation of triglycerides in HFD-fed mice. Consequently, muscle HSF1 mitigated the impaired muscle insulin signaling and insulin resistance in HFD-fed mice. In conclusion, T2DM and obesity in HFD-fed mice may be treated with selective HSF1-directed programming of exercise-like effects in skeletal muscle. These findings may aid the development of a new therapeutic approach for obesity and T2DM.

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“…Activated and promoter‐bound HSF1 recruits coactivators consisting of chromatin remodelling complexes and histone‐modifying enzymes, and facilitates the formation of the preinitiation complex (PIC) containing RNA polymerase II (Pol II) and general transcription factors [11]. In addition to HSF1‐interacting coactivators, including BRG1, p300, TIP60, GCN5 and MLL1 [12–25], a large number of components in the PIC are assembled on the HSP70 promoters to promote its transcription during heat shock [26,27].…”

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confidence: 99%

The Mediator subunit MED12 promotes formation of HSF1 condensates on heat shock response element arrays in heat‐shocked cells

et al. 2023

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Upon heat shock, activated heat shock transcription factor 1 (HSF1) binds to the heat shock response elements (HSEs) in the promoters of mammalian heat shock protein (HSP)-encoding genes and recruits the preinitiation complex and coactivators, including Mediator. These transcriptional regulators may be concentrated in phase-separated condensates around the promoters, but they are too minute to be characterized in detail. We herein established HSF1 À/À mouse embryonic fibroblasts harbouring HSP72-derived multiple HSE arrays and visualized the condensates of fluorescent protein-tagged HSF1 with liquid-like properties upon heat shock. Using this experimental system, we demonstrate that endogenous MED12, a subunit of Mediator, is concentrated in artificial HSF1 condensates upon heat shock. Furthermore, the knockdown of MED12 markedly reduces the size of condensates, suggesting an important role for MED12 in HSF1 condensate formation.

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MED12 interacts with the heat‐shock transcription factor HSF1 and recruits CDK8 to promote the heat‐shock response in mammalian cells

Cited by 7 publications

References 60 publications

Regulation of HSF1 transcriptional complexes under proteotoxic stress

Regulation of HSF1 transcriptional complexes under proteotoxic stress

Skeletal muscle HSF1 prevents insulin resistance by improving glucose utilization

The Mediator subunit MED12 promotes formation of HSF1 condensates on heat shock response element arrays in heat‐shocked cells

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