Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation

Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. Here we show that in budding yeast, Hsf1 basally associates with the chaperone Hsp70 and this association is transiently disrupted by heat shock, providing the first evidence that a chaperone repressor directly regulates Hsf1 activity. We develop and experimentally validate a mathematical model of Hsf1 activation by heat shock in which unfolded proteins compete with Hsf1 for binding to Hsp70. Surprisingly, we find that Hsf1 phosphorylation, previously thought to be required for activation, in fact only positively tunes Hsf1 and does so without affecting Hsp70 binding. Our work reveals two uncoupled forms of regulation - an ON/OFF chaperone switch and a tunable phosphorylation gain - that allow Hsf1 to flexibly integrate signals from the proteostasis network and cell signaling pathways.

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Invited Review: Interplay between molecular chaperones and signaling pathways in survival of heat shock

Journal of Applied Physiology ◽

10.1152/japplphysiol.01101.2001 ◽

2002 ◽

Vol 92 (4) ◽

pp. 1743-1748 ◽

Cited By ~ 122

Author(s):

Vladimir L. Gabai ◽

Michael Y. Sherman

Keyword(s):

Cell Death ◽

Heat Shock ◽

Signaling Pathways ◽

Molecular Chaperones ◽

Mammalian Cells ◽

Survival Pathways ◽

Extracellular Signal ◽

A Cell ◽

Stress Kinase ◽

Nonapoptotic Cell Death

Heat shock of mammalian cells causes protein damage and activates a number of signaling pathways. Some of these pathways enhance the ability of cells to survive heat shock, e.g., induction of molecular chaperones [heat shock protein (HSP) HSP72 and HSP27], activation of the protein kinases extracellular signal-regulated kinase and Akt, and phosphorylation of HSP27. On the other hand, heat shock can activate a stress kinase, c-Jun NH2-terminal kinase, thus triggering both apoptotic and nonapoptotic cell death programs. Recent data indicate that kinases activated by heat shock can regulate synthesis and functioning of the molecular chaperones, and these chaperones modulate activity of the cell death and survival pathways. Therefore, the overall balance of the pathways and their interplay determine whether a cell exposed to heat shock will die or survive and become stress tolerant.

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Roles of the nucleotide exchange factor and chaperone Hsp110 in cellular proteostasis and diseases of protein misfolding

Biological Chemistry ◽

10.1515/hsz-2018-0209 ◽

2018 ◽

Vol 399 (10) ◽

pp. 1215-1221 ◽

Cited By ~ 7

Author(s):

Unekwu M. Yakubu ◽

Kevin A. Morano

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Molecular Chaperones ◽

Protein Misfolding ◽

Recent Progress ◽

Cellular Protein ◽

Protein Homeostasis ◽

Nucleotide Exchange ◽

Exchange Factor ◽

Nucleotide Exchange Factor

Abstract Cellular protein homeostasis (proteostasis) is maintained by a broad network of proteins involved in synthesis, folding, triage, repair and degradation. Chief among these are molecular chaperones and their cofactors that act as powerful protein remodelers. The growing realization that many human pathologies are fundamentally diseases of protein misfolding (proteopathies) has generated interest in understanding how the proteostasis network impacts onset and progression of these diseases. In this minireview, we highlight recent progress in understanding the enigmatic Hsp110 class of heat shock protein that acts as both a potent nucleotide exchange factor to regulate activity of the foldase Hsp70, and as a passive chaperone capable of recognizing and binding cellular substrates on its own, and its integration into the proteostasis network.

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Comparative docking studies of rosmarinic acid and sinesitin to inhibit HSP70

International Journal of Engineering Technology and Sciences ◽

10.15282/ijets.v6i1.2242 ◽

2019 ◽

Vol 6 (1) ◽

pp. 115-119

Author(s):

Mansoureh Nazari V. ◽

Syed Mahmood ◽

Subashini Raman

Keyword(s):

Heat Shock ◽

Cancer Cells ◽

Molecular Chaperones ◽

Rosmarinic Acid ◽

Poor Prognosis ◽

Docking Studies ◽

Protein Homeostasis ◽

Hsp70 Family ◽

Adenosine Triphosphatases ◽

Shock Proteins

The HSP70 family of heat shock proteins consists of molecular chaperones of approximately 70kDa in size that serve critical roles in protein homeostasis. These adenosine triphosphatases unfold misfolded or denatured proteins and can keep these proteins in an unfolded, folding-competent state. They also protect nascently translating proteins, promote the cellular or organellar transport of proteins, reduce proteotoxic protein aggregates and serve general housekeeping roles in maintaining protein homeostasis. The HSP70 family is the most conserved in evolution, and all eukaryotes contain multiple members. the HSP70 family of proteins can be thought of as a potent buffering system for cellular stress either from extrinsic (physiological, viral and environmental) or intrinsic (replicative or oncogenic) stimuli. Not surprisingly, cancer cells rely heavily on this buffering system for survival. The overwhelming majority of human tumours overexpress HSP70 family members, and expression of these proteins is typically a marker for poor prognosis.

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Chaperoning signaling pathways: molecular chaperones as stress-sensing`heat shock' proteins

Journal of Cell Science ◽

10.1242/jcs.115.14.2809 ◽

2002 ◽

Vol 115 (14) ◽

pp. 2809-2816 ◽

Cited By ~ 10

Author(s):

Ellen A. A. Nollen ◽

Richard I. Morimoto

Keyword(s):

Cell Death ◽

Heat Shock ◽

Heat Shock Proteins ◽

Signaling Pathways ◽

Molecular Chaperones ◽

Growth Control ◽

Normal Function ◽

Stress Sensing ◽

As Stress ◽

Shock Proteins

Heat shock proteins interact with multiple key components of signaling pathways that regulate growth and development. The molecular relationships between heat shock proteins, various signaling proteins and partner proteins appear to be critical for the normal function of signal transduction pathways. The relative levels of these proteins may be important, as too little or too much Hsp70 or Hsp90 can result in aberrant growth control, developmental malformations and cell death. Although the functions of heat shock proteins as molecular chaperones have been well characterized, their complementary role as a `stress-induced' proteins to monitor changes and alter the biochemical environment of the cell remains elusive. Genetic and molecular interactions between heat shock proteins, their co-chaperones and components of signaling pathways suggest that crosstalk between these proteins can regulate proliferation and development by preventing or enhancing cell growth and cell death as the levels of heat shock proteins vary in response to environmental stress or disease.

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Heat Shock Factor (HSF): The Promoter of Chaperone Genes. A Mini Review

Current Proteomics ◽

10.2174/1570164615666180713095309 ◽

2018 ◽

Vol 16 (1) ◽

pp. 22-30 ◽

Cited By ~ 1

Author(s):

Natália Galdi Quel ◽

Carlos H.I. Ramos

Keyword(s):

Heat Shock ◽

Molecular Chaperones ◽

Protein Quality ◽

Cell Function ◽

Heat Shock Factor ◽

Protein Homeostasis ◽

General Knowledge ◽

Protein Quality Control System ◽

Shock Proteins ◽

And Function

Protein homeostasis, or proteostasis, is required for proper cell function and thus must be under tight maintenance in all circumstances. In crowded cell conditions, protein folding is sometimes unfavorable, and this condition is worsened during stress situations. Cells cope with such stress through the use of a Protein Quality Control system, which uses molecular chaperones and heat shock proteins as its major players. This system aids with folding, avoiding misfolding and/or reversing aggregation. A pivotal regulator of the response to heat stress is Heat Shock Factor, which is recruited to the promoters of the chaperone genes, inducting their expression. This mini review aims to cover our general knowledge on the structure and function of this factor.

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Molecular Chaperone HSP70 and Key Regulators of Apoptosis - A Review

Current Molecular Medicine ◽

10.2174/1566524019666190326114720 ◽

2019 ◽

Vol 19 (5) ◽

pp. 315-325 ◽

Cited By ~ 7

Author(s):

Rabih Roufayel ◽

Seifedine Kadry

Keyword(s):

Heat Shock ◽

Molecular Chaperone ◽

Vital Role ◽

Unfolded Proteins ◽

Cellular Survival ◽

Protein Biogenesis ◽

Molecular Chaperon ◽

Multiple Levels ◽

Hsp70 Synthesis ◽

Chaperone Hsp70

Identified as a molecular chaperone constitutively being synthesized due to enhanced elevated temperature change, this heat shock protein HSP70 has shown to be intimately involved in many protein biogenesis, facilitating the synthesis and folding of proteins and trafficking of nascent peptides during cell growth. HSP70 also plays a vital role in protein assembly, regulation and interaction with a wide variety of proteins. Stress-induced cell death is under the control of the Bcl-2 family of apoptotic regulators and display either pro-apoptotic or anti-apoptotic activities. Subjected to stress conditions such as heat shock, cells have been reported to express elevated expressions of HSP70. Moreover, this molecular chaperon has shown to act at multiple levels to suppress stressed-induced apoptotic signals of some Bcl-2 members by repairing, re-synthesizing damaged proteins, and stabilizing unfolded proteins. Therefore, HSP70 synthesis can act as an essential recovery mode for cellular survival and adaptation during lethal conditions.

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Intercellular chaperone transmission via exosomes contributes to maintenance of protein homeostasis at the organismal level

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1412651112 ◽

2015 ◽

Vol 112 (19) ◽

pp. E2497-E2506 ◽

Cited By ~ 88

Author(s):

Toshihide Takeuchi ◽

Mari Suzuki ◽

Nobuhiro Fujikake ◽

H. Akiko Popiel ◽

Hisae Kikuchi ◽

...

Keyword(s):

Heat Shock ◽

Molecular Chaperones ◽

Molecular Mechanisms ◽

Cultured Cells ◽

Physiological Role ◽

Transcriptional Response ◽

Cell Types ◽

Protein Homeostasis ◽

Stressful Environment ◽

Elevated Expression

The heat shock response (HSR), a transcriptional response that up-regulates molecular chaperones upon heat shock, is necessary for cell survival in a stressful environment to maintain protein homeostasis (proteostasis). However, there is accumulating evidence that the HSR does not ubiquitously occur under stress conditions, but largely depends on the cell types. Despite such imbalanced HSR among different cells and tissues, molecular mechanisms by which multicellular organisms maintain their global proteostasis have remained poorly understood. Here, we report that proteostasis can be maintained by molecular chaperones not only in a cell-autonomous manner but also in a non–cell-autonomous manner. We found that elevated expression of molecular chaperones, such as Hsp40 and Hsp70, in a group of cells improves proteostasis in other groups of cells, both in cultured cells and in Drosophila expressing aggregation-prone polyglutamine proteins. We also found that Hsp40, as well as Hsp70 and Hsp90, is physiologically secreted from cells via exosomes, and that the J domain at the N terminus is responsible for its exosome-mediated secretion. Addition of Hsp40/Hsp70-containing exosomes to the culture medium of the polyglutamine-expressing cells results in efficient suppression of inclusion body formation, indicating that molecular chaperones non-cell autonomously improve the protein-folding environment via exosome-mediated transmission. Our study reveals that intercellular chaperone transmission mediated by exosomes is a novel molecular mechanism for non–cell-autonomous maintenance of organismal proteostasis that could functionally compensate for the imbalanced state of the HSR among different cells, and also provides a novel physiological role of exosomes that contributes to maintenance of organismal proteostasis.

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Temporal requirements of SKN-1/NRF as a regulator of lifespan and proteostasis in Caenorhabditis elegans

PLoS ONE ◽

10.1371/journal.pone.0243522 ◽

2021 ◽

Vol 16 (7) ◽

pp. e0243522

Author(s):

Danielle Grushko ◽

Hana Boocholez ◽

Amir Levine ◽

Ehud Cohen

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Caenorhabditis Elegans ◽

Heat Shock ◽

Stress Resistance ◽

Healthy Aging ◽

Early Adulthood ◽

Protein Homeostasis ◽

Heat Shock Factor 1 ◽

Extended Lifespan

Lowering the activity of the Insulin/IGF-1 Signaling (IIS) cascade results in elevated stress resistance, enhanced protein homeostasis (proteostasis) and extended lifespan of worms, flies and mice. In the nematode Caenorhabditis elegans (C. elegans), the longevity phenotype that stems from IIS reduction is entirely dependent upon the activities of a subset of transcription factors including the Forkhead factor DAF-16/FOXO (DAF-16), Heat Shock Factor-1 (HSF-1), SKiNhead/Nrf (SKN-1) and ParaQuat Methylviologen responsive (PQM-1). While DAF-16 determines lifespan exclusively during early adulthood and governs proteostasis in early adulthood and midlife, HSF-1 executes these functions foremost during development. Despite the central roles of SKN-1 as a regulator of lifespan and proteostasis, the temporal requirements of this transcription factor were unknown. Here we employed conditional knockdown techniques and discovered that in C. elegans, SKN-1 is primarily important for longevity and proteostasis during late larval development through early adulthood. Our findings indicate that events that occur during late larval developmental through early adulthood affect lifespan and proteostasis and suggest that subsequent to HSF-1, SKN-1 sets the conditions, partially overlapping temporally with DAF-16, that enable IIS reduction to promote longevity and proteostasis. Our findings raise the intriguing possibility that HSF-1, SKN-1 and DAF-16 function in a coordinated and sequential manner to promote healthy aging.

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