Heat shock factor 2 is required for maintaining proteostasis against febrile-range thermal stress and polyglutamine aggregation

Heat shock response is characterized by the induction of heat shock proteins (HSPs), which facilitate protein folding, and non-HSP proteins with diverse functions, including protein degradation, and is regulated by heat shock factors (HSFs). HSF1 is a master regulator of HSP expression during heat shock in mammals, as is HSF3 in avians. HSF2 plays roles in development of the brain and reproductive organs. However, the fundamental roles of HSF2 in vertebrate cells have not been identified. Here we find that vertebrate HSF2 is activated during heat shock in the physiological range. HSF2 deficiency reduces threshold for chicken HSF3 or mouse HSF1 activation, resulting in increased HSP expression during mild heat shock. HSF2-null cells are more sensitive to sustained mild heat shock than wild-type cells, associated with the accumulation of ubiquitylated misfolded proteins. Furthermore, loss of HSF2 function increases the accumulation of aggregated polyglutamine protein and shortens the lifespan of R6/2 Huntington's disease mice, partly through αB-crystallin expression. These results identify HSF2 as a major regulator of proteostasis capacity against febrile-range thermal stress and suggest that HSF2 could be a promising therapeutic target for protein-misfolding diseases.

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Thermal manipulation during broiler chicken embryogenesis increases basal mRNA levels and alters production dynamics of heat shock proteins 70 and 60 and heat shock factors 3 and 4 during thermal stress

Poultry Science ◽

10.3382/ps/pey225 ◽

2018 ◽

Vol 97 (10) ◽

pp. 3661-3670 ◽

Cited By ~ 7

Author(s):

M.B. Al-Zghoul

Keyword(s):

Thermal Stress ◽

Heat Shock ◽

Heat Shock Proteins ◽

Broiler Chicken ◽

Mrna Levels ◽

Heat Shock Factors ◽

Shock Proteins ◽

Production Dynamics ◽

Thermal Manipulation

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Induction and phosphorylation of the small heat shock proteins HspB1/Hsp25 and HspB5/αB-crystallin in the rat retina upon optic nerve injury

Cell Stress and Chaperones ◽

10.1007/s12192-015-0650-8 ◽

2015 ◽

Vol 21 (1) ◽

pp. 167-178 ◽

Cited By ~ 5

Author(s):

Thomas Schmidt ◽

Dietmar Fischer ◽

Anastasia Andreadaki ◽

Britta Bartelt-Kirbach ◽

Nikola Golenhofen

Keyword(s):

Optic Nerve ◽

Heat Shock ◽

Heat Shock Proteins ◽

Nerve Injury ◽

Small Heat Shock Proteins ◽

Optic Nerve Injury ◽

Rat Retina ◽

Αb Crystallin ◽

Shock Proteins

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The Effect of Oxidized Dopamine on the Structure and Molecular Chaperone Function of the Small Heat-Shock Proteins, αB-Crystallin and Hsp27

International Journal of Molecular Sciences ◽

10.3390/ijms22073700 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3700

Author(s):

Junna Hayashi ◽

Jennifer Ton ◽

Sparsh Negi ◽

Daniel E. K. M. Stephens ◽

Dean L. Pountney ◽

...

Keyword(s):

Heat Shock ◽

Protein Aggregation ◽

Molecular Chaperone ◽

Cross Linking ◽

Αb Crystallin ◽

The Cross ◽

Shock Proteins ◽

And Function

Oxidation of the neurotransmitter, dopamine (DA), is a pathological hallmark of Parkinson’s disease (PD). Oxidized DA forms adducts with proteins which can alter their functionality. αB-crystallin and Hsp27 are intracellular, small heat-shock molecular chaperone proteins (sHsps) which form the first line of defense to prevent protein aggregation under conditions of cellular stress. In vitro, the effects of oxidized DA on the structure and function of αB-crystallin and Hsp27 were investigated. Oxidized DA promoted the cross-linking of αB-crystallin and Hsp27 to form well-defined dimer, trimer, tetramer, etc., species, as monitored by SDS-PAGE. Lysine residues were involved in the cross-links. The secondary structure of the sHsps was not altered significantly upon cross-linking with oxidized DA but their oligomeric size was increased. When modified with a molar equivalent of DA, sHsp chaperone functionality was largely retained in preventing both amorphous and amyloid fibrillar aggregation, including fibril formation of mutant (A53T) α-synuclein, a protein whose aggregation is associated with autosomal PD. In the main, higher levels of sHsp modification with DA led to a reduction in chaperone effectiveness. In vivo, DA is sequestered into acidic vesicles to prevent its oxidation and, intracellularly, oxidation is minimized by mM levels of the antioxidant, glutathione. In vitro, acidic pH and glutathione prevented the formation of oxidized DA-induced cross-linking of the sHsps. Oxidized DA-modified αB-crystallin and Hsp27 were not cytotoxic. In a cellular context, retention of significant chaperone functionality by mildly oxidized DA-modified sHsps would contribute to proteostasis by preventing protein aggregation (particularly of α-synuclein) that is associated with PD.

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Expression pattern of heat shock proteins during acute thermal stress in the Antarctic sea urchin, Sterechinus neumayeri

Revista chilena de historia natural ◽

10.1186/s40693-016-0052-z ◽

2016 ◽

Vol 89 (1) ◽

Cited By ~ 11

Author(s):

Karina González ◽

Juan Gaitán-Espitia ◽

Alejandro Font ◽

César A. Cárdenas ◽

Marcelo González-Aravena

Keyword(s):

Thermal Stress ◽

Heat Shock ◽

Heat Shock Proteins ◽

Expression Pattern ◽

Sea Urchin ◽

Sterechinus Neumayeri ◽

Shock Proteins ◽

The Antarctic

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Heat Shock Proteins in Alzheimer’s Disease: Role and Targeting

International Journal of Molecular Sciences ◽

10.3390/ijms19092603 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2603 ◽

Cited By ~ 32

Author(s):

Claudia Campanella ◽

Andrea Pace ◽

Celeste Caruso Bavisotto ◽

Paola Marzullo ◽

Antonella Marino Gammazza ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Heat Shock ◽

Heat Shock Proteins ◽

Molecular Chaperones ◽

Protein Misfolding ◽

Point Of View ◽

Toxic Species ◽

Shock Proteins

Among diseases whose cure is still far from being discovered, Alzheimer’s disease (AD) has been recognized as a crucial medical and social problem. A major issue in AD research is represented by the complexity of involved biochemical pathways, including the nature of protein misfolding, which results in the production of toxic species. Considering the involvement of (mis)folding processes in AD aetiology, targeting molecular chaperones represents a promising therapeutic perspective. This review analyses the connection between AD and molecular chaperones, with particular attention toward the most important heat shock proteins (HSPs) as representative components of the human chaperome: Hsp60, Hsp70 and Hsp90. The role of these proteins in AD is highlighted from a biological point of view. Pharmacological targeting of such HSPs with inhibitors or regulators is also discussed.

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Single-molecule fluorescence-based approach reveals novel mechanistic insights into human small heat shock protein chaperone function

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015419 ◽

2020 ◽

pp. jbc.RA120.015419

Author(s):

Caitlin L Johnston ◽

Nicholas R Marzano ◽

Bishnu P Paudel ◽

George Wright ◽

Justin L.P. Benesch ◽

...

Keyword(s):

Heat Shock ◽

Single Molecule ◽

Small Heat Shock Protein ◽

Vital Role ◽

Misfolded Proteins ◽

Single Molecule Fluorescence ◽

Chaperone Function ◽

Αb Crystallin ◽

Client Proteins ◽

Shock Proteins

Small heat shock proteins (sHsps) are a family of ubiquitous intracellular molecular chaperones that are up-regulated under stress conditions and play a vital role in protein homeostasis (proteostasis). It is commonly accepted that these chaperones work by trapping misfolded proteins to prevent their aggregation; however, fundamental questions regarding the molecular mechanism by which sHsps interact with misfolded proteins remain unanswered. The dynamic and polydisperse nature of sHsp oligomers has made studying them challenging using traditional biochemical approaches. Therefore, we have utilized a single-molecule fluorescence-based approach to observe the chaperone action of human αB-crystallin (αBc, HSPB5). Using this approach we have, for the first time, determined the stoichiometries of complexes formed between αBc and a model client protein, chloride intracellular channel 1 (CLIC1). By examining the dispersity and stoichiometries of these complexes over time, and in response to different concentrations of αBc, we have uncovered unique and important insights into a two-step mechanism by which αBc interacts with misfolded client proteins to prevent their aggregation.

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