Regulation of Hsf1 and the Heat Shock Response

Pincus, David

doi:10.1007/978-3-030-40204-4_3

Cited by 66 publications

(39 citation statements)

References 79 publications

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“…Efficient recruitment of Hsp70 into the condensate is critical for HSR induction by titrating Hsp70 away from HSF1, consistent with the prevailing model of HSR regulation 16 (Fig. 7b).…”

Section: Discussionsupporting

confidence: 86%

“…Despite previous studies on the kinetics of the HSR 16,20 , the molecular mechanisms adjusting the magnitude and the speed of recovery of the stress response are not well understood. The exact nature of the aberrant protein species critical for HSF1 activation by chaperone titration has been questioned.…”

mentioning

confidence: 98%

“…According to current models, during stress, these chaperone repressors are titrated away from HSF1 by aberrant protein species, thus freeing HSF1 to execute its transcriptional program [12][13][14] . Once sufficiently augmented, chaperones eventually re-bind to HSF1, thus creating a feedback loop for recovery 8,12,15,16 . While the initial activation of the HSR is critical for coping with stress conditions, its shut-off appears to be equally important, as chronic activation of the HSR leads to maladaptation, with an inability to cope with additional stressors and disturbance of biological development in higher organisms [17][18][19] .…”

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confidence: 99%

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Sis1 potentiates the stress response to protein aggregation and elevated temperature

et al. 2020

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Cells adapt to conditions that compromise protein conformational stability by activating various stress response pathways, but the mechanisms used in sensing misfolded proteins remain unclear. Moreover, aggregates of disease proteins often fail to induce a productive stress response. Here, using a yeast model of polyQ protein aggregation, we identified Sis1, an essential Hsp40 co-chaperone of Hsp70, as a critical sensor of proteotoxic stress. At elevated levels, Sis1 prevented the formation of dense polyQ inclusions and directed soluble polyQ oligomers towards the formation of permeable condensates. Hsp70 accumulated in a liquid-like state within this polyQ meshwork, resulting in a potent activation of the HSF1 dependent stress response. Sis1, and the homologous DnaJB6 in mammalian cells, also regulated the magnitude of the cellular heat stress response, suggesting a general role in sensing protein misfolding. Sis1/DnaJB6 functions as a limiting regulator to enable a dynamic stress response and avoid hypersensitivity to environmental changes.

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“…Efficient recruitment of Hsp70 into the condensate is critical for HSR induction by titrating Hsp70 away from HSF1, consistent with the prevailing model of HSR regulation 16 (Fig. 7b).…”

Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 98%

mentioning

confidence: 99%

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Sis1 potentiates the stress response to protein aggregation and elevated temperature

et al. 2020

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“…Specially, HSF1 is found to play an important role in multiple cancers, which promotes cell invasion, migration, and proliferation of tumor cells [ 37 ]. Cancer cells rely on HSR to support their rapid growth and counteract the harmful mutations [ 38 ]. Previous studies have demonstrated that HSF1 is highly expressed in endometrial carcinoma and is closely related to endometrial invasion, which leads to a poor prognosis in estrogen receptor-positive tumors [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

HSF1 promotes endometriosis development and glycolysis by up-regulating PFKFB3 expression

Wang

Xiu

Yang

et al. 2021

Reprod Biol Endocrinol

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Background Endometriosis is a chronic hormonal inflammatory disease characterized by the presence of endometrial tissue outside the uterus. Endometriosis often causes infertility, which brings physical and mental pain to patients and their families. Methods We examined the functions of heat shock factor 1 (HSF1) in endometriosis development through cell count assay, cell-scratch assay and clone formation experiments. We used quantitative real-time PCR (qRT-PCR) and Western blot (WB) to detect HSF1 expression. Glucose and lactate levels were determined using a glucose (GO) assay kit and a lactate assay kit. Furthermore, we used a HSF1 inhibitor-KRIBB11 to establish a mouse model of endometriosis. Results Our data demonstrated that HSF1 promoted endometriosis development. Interestingly, HSF1 enhanced glycolysis via up-regulating PFKFB3 expression in endometriosis cells, which was a key glycolysis enzyme. Consistently, the HSF1 inhibitor KRIBB11 could abrogate endometriosis progression in vivo and in vitro. Conclusions Findings indicate that HSF1 plays an important role in endometriosis development, which might become a new target for the treatment of endometriosis. Electronic supplementary material Supplementary data are available.

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“…HSF1 can be rapidly conformationally activated upon proteotoxic stress such as heat shock, after which it regulates chaperone expression (Anckar and Sistonen, 2011;Mahat et al, 2016;Solís et al, 2016). This chaperone regulation by HSF1 according to fluctuating cellular requirements is preserved among eukaryotes (Pincus, 2020;Kainth et al, 2021). The levels of all Hsp90 chaperones are reduced in AD while HSP70 is overproduced (Koopman and Rüdiger, 2020).…”

Section: Transcription Of Trap1 By Hsf1mentioning

confidence: 99%

The Mitochondrial Hsp90 TRAP1 and Alzheimer’s Disease

Dekker

Rüdiger

2021

Front. Mol. Biosci.

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Alzheimer’s Disease (AD) is the most common form of dementia, characterised by intra- and extracellular protein aggregation. In AD, the cellular protein quality control (PQC) system is derailed and fails to prevent the formation of these aggregates. Especially the mitochondrial paralogue of the conserved Hsp90 chaperone class, tumour necrosis factor receptor-associated protein 1 (TRAP1), is strongly downregulated in AD, more than other major PQC factors. Here, we review molecular mechanism and cellular function of TRAP1 and subsequently discuss possible links to AD. TRAP1 is an interesting paradigm for the Hsp90 family, as it chaperones proteins with vital cellular function, despite not being regulated by any of the co-chaperones that drive its cytosolic paralogues. TRAP1 encloses late folding intermediates in a non-active state. Thereby, it is involved in the assembly of the electron transport chain, and it favours the switch from oxidative phosphorylation to glycolysis. Another key function is that it ensures mitochondrial integrity by regulating the mitochondrial pore opening through Cyclophilin D. While it is still unclear whether TRAP1 itself is a driver or a passenger in AD, it might be a guide to identify key factors initiating neurodegeneration.

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Regulation of Hsf1 and the Heat Shock Response

Cited by 66 publications

References 79 publications

Sis1 potentiates the stress response to protein aggregation and elevated temperature

Sis1 potentiates the stress response to protein aggregation and elevated temperature

HSF1 promotes endometriosis development and glycolysis by up-regulating PFKFB3 expression

The Mitochondrial Hsp90 TRAP1 and Alzheimer’s Disease

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