Special Issue "Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: 20 January 2022.

Special Issue Editor

Dr. Alexander E. Kabakov
E-Mail Website
Guest Editor
Department of Radiation Biochemistry, A. Tsyb Medical Radiological Research Center, Obninsk, Russia
Interests: heat shock proteins; molecular chaperones; cellular stress; protein folding; cancer; cancer stem cells; radiotherapy; hyperthermia; tumor radioresistance; radiosensitizers; anticancer drugs; DNA damage response; apoptosis; hypoxia in tumors.

Special Issue Information

Dear Colleagues,

In recent decades, it has been established that some heat shock proteins (HSPs) play a protective role under pathophysiological states such as ischemia/reperfusion, atrial fibrillation, aberrant amyloid accumulation, and acute inflammation. Consequently, HSPs are considered as endogenous tools for the curation of ischemic insult, heart failure, neurodegenerative diseases, etc. At the same time, it has been revealed that HSPs may promote autoimmune disorders and cancer. HSPs are one of the drivers of tumorigenesis, contributing to both unlimited tumor growth and tumor resistance to therapeutics. Therefore, HSPs seem to be promising targets for cancer treatment. Attempts have been made to develop HSP-based anticancer vaccines and HSP-based methods of clinical diagnostics/prognostics. However, HSPs are yet to be used in clinical settings, neither as tools nor as targets. A deeper understanding of the molecular mechanisms of the expression, functioning, and regulation of HSPs in normal and affected cells/tissues would help to adopt HSPs as targets or tools for therapy more quickly. The main goals of this Special Issue are to (1) summarize the most recent advances in molecular studies in the field of HSPs that may be significant for curative or diagnostic medicine and (2) review novel approaches to the development of HSP-based therapy. We welcome research articles and reviews covering such topics as HSPs and ischemia, HSPs and heart failure, HSPs and neurodegenerative diseases, HSPs and cancer, HSP-based vaccines, and HSP-based therapy or diagnostics.

I look forward to receiving your contributions and compiling this exciting Special Issue.

Dr. Alexander E. Kabakov
Guest Editor

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Keywords

  • heat shock proteins (HSPs)
  • heat shock factor 1 (HSF1)
  • molecular chaperones
  • proteostasis
  • cancer
  • therapy
  • theranostics

Published Papers (11 papers)

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Research

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Article
CDK1-Mediated Phosphorylation of BAG3 Promotes Mitotic Cell Shape Remodeling and the Molecular Assembly of Mitotic p62 Bodies
Cells 2021, 10(10), 2638; https://doi.org/10.3390/cells10102638 - 02 Oct 2021
Viewed by 274
Abstract
The cochaperone BCL2-associated athanogene 3 (BAG3), in complex with the heat shock protein HSPB8, facilitates mitotic rounding, spindle orientation, and proper abscission of daughter cells. BAG3 and HSPB8 mitotic functions implicate the sequestosome p62/SQSTM1, suggesting a role for protein quality control. However, the [...] Read more.
The cochaperone BCL2-associated athanogene 3 (BAG3), in complex with the heat shock protein HSPB8, facilitates mitotic rounding, spindle orientation, and proper abscission of daughter cells. BAG3 and HSPB8 mitotic functions implicate the sequestosome p62/SQSTM1, suggesting a role for protein quality control. However, the interplay between this chaperone-assisted pathway and the mitotic machinery is not known. Here, we show that BAG3 phosphorylation at the conserved T285 is regulated by CDK1 and activates its function in mitotic cell shape remodeling. BAG3 phosphorylation exhibited a high dynamic at mitotic entry and both a non-phosphorylatable BAG3T285A and a phosphomimetic BAG3T285D protein were unable to correct the mitotic defects in BAG3-depleted HeLa cells. We also demonstrate that BAG3 phosphorylation, HSPB8, and CDK1 activity modulate the molecular assembly of p62/SQSTM1 into mitotic bodies containing K63 polyubiquitinated chains. These findings suggest the existence of a mitotically regulated spatial quality control mechanism for the fidelity of cell shape remodeling in highly dividing cells. Full article
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Article
HSPB1 Is Essential for Inducing Resistance to Proteotoxic Stress in Beta-Cells
Cells 2021, 10(9), 2178; https://doi.org/10.3390/cells10092178 - 24 Aug 2021
Viewed by 377
Abstract
During type 1 diabetes mellitus (T1DM) development, beta-cells undergo intense endoplasmic reticulum (ER) stress that could result in apoptosis through the failure of adaptation to the unfolded protein response (UPR). Islet transplantation is considered an attractive alternative among beta-cell replacement therapies for T1DM. [...] Read more.
During type 1 diabetes mellitus (T1DM) development, beta-cells undergo intense endoplasmic reticulum (ER) stress that could result in apoptosis through the failure of adaptation to the unfolded protein response (UPR). Islet transplantation is considered an attractive alternative among beta-cell replacement therapies for T1DM. To avoid the loss of beta-cells that will jeopardize the transplant’s outcome, several strategies are being studied. We have previously shown that prolactin induces protection against proinflammatory cytokines and redox imbalance-induced beta-cell death by increasing heat-shock protein B1 (HSPB1) levels. Since the role of HSPB1 in beta cells has not been deeply studied, we investigated the mechanisms involved in unbalanced protein homeostasis caused by intense ER stress and overload of the proteasomal protein degradation pathway. We tested whether HSPB1-mediated cytoprotective effects involved UPR modulation and improvement of protein degradation via the ubiquitin-proteasome system. We demonstrated that increased levels of HSPB1 attenuated levels of pro-apoptotic proteins such as CHOP and BIM, as well as increased protein ubiquitination and the speed of proteasomal protein degradation. Our data showed that HSPB1 induced resistance to proteotoxic stress and, thus, enhanced cell survival via an increase in beta-cell proteolytic capacity. These results could contribute to generate strategies aimed at the optimization of beta-cell replacement therapies. Full article
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Article
Phosphorylation in the Charged Linker Modulates Interactions and Secretion of Hsp90β
Cells 2021, 10(7), 1701; https://doi.org/10.3390/cells10071701 - 05 Jul 2021
Viewed by 402
Abstract
Hsp90β is a major chaperone involved in numerous cellular processes. Hundreds of client proteins depend on Hsp90β for proper folding and/or activity. Regulation of Hsp90β is critical to coordinate its tasks and is mediated by several post-translational modifications. Here, we focus on two [...] Read more.
Hsp90β is a major chaperone involved in numerous cellular processes. Hundreds of client proteins depend on Hsp90β for proper folding and/or activity. Regulation of Hsp90β is critical to coordinate its tasks and is mediated by several post-translational modifications. Here, we focus on two phosphorylation sites located in the charged linker region of human Hsp90β, Ser226 and Ser255, which have been frequently reported but whose function remains unclear. Targeted measurements by mass spectrometry indicated that intracellular Hsp90β is highly phosphorylated on both sites (>90%). The level of phosphorylation was unaffected by various stresses (e.g., heat shock, inhibition with drugs) that impact Hsp90β activity. Mutating the two serines to alanines increased the amount of proteins interacting with Hsp90β globally and increased the sensitivity to tryptic cleavage in the C-terminal domain. Further investigation revealed that phosphorylation on Ser255 and to a lesser extent on Ser226 is decreased in the conditioned medium of cultured K562 cells, and that a non-phosphorylatable double alanine mutant was secreted more efficiently than the wild type. Overall, our results show that phosphorylation events in the charged linker regulate both the interactions of Hsp90β and its secretion, through changes in the conformation of the chaperone. Full article
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Article
Inhibition of the Heat Shock Protein A (HSPA) Family Potentiates the Anticancer Effects of Manumycin A
Cells 2021, 10(6), 1418; https://doi.org/10.3390/cells10061418 - 07 Jun 2021
Viewed by 999
Abstract
Manumycin A (MA) is a well-tolerated natural antibiotic showing pleiotropic anticancer effects in various preclinical in vitro and in vivo models. Anticancer drugs may themselves act as stressors to induce the cellular adaptive mechanism that can minimize their cytotoxicity. Heat shock proteins (HSPs) [...] Read more.
Manumycin A (MA) is a well-tolerated natural antibiotic showing pleiotropic anticancer effects in various preclinical in vitro and in vivo models. Anticancer drugs may themselves act as stressors to induce the cellular adaptive mechanism that can minimize their cytotoxicity. Heat shock proteins (HSPs) as cytoprotective factors can counteract the deleterious effects of various stressful stimuli. In this study, we examined whether the anticancer effects of MA can be counteracted by the mechanism related to HSPs belonging to the HSPA (HSP70) family. We found that MA caused cell type-specific alterations in the levels of HSPAs. These changes included concomitant upregulation of the stress-inducible (HSPA1 and HSPA6) and downregulation of the non-stress-inducible (HSPA2) paralogs. However, neither HSPA1 nor HSPA2 were necessary to provide protection against MA in lung cancer cells. Conversely, the simultaneous repression of several HSPA paralogs using pan-HSPA inhibitors (VER-155008 or JG-98) sensitized cancer cells to MA. We also observed that genetic ablation of the heat shock factor 1 (HSF1) transcription factor, a main transactivator of HSPAs expression, sensitized MCF7 cells to MA treatment. Our study reveals that inhibition of HSF1-mediated heat shock response (HSR) can improve the anticancer effect of MA. These observations suggest that targeting the HSR- or HSPA-mediated adaptive mechanisms may be a promising strategy for further preclinical developments. Full article
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Article
Regional Differences in Heat Shock Protein 25 Expression in Brain and Spinal Cord Astrocytes of Wild-Type and SOD1 G93A Mice
Cells 2021, 10(5), 1257; https://doi.org/10.3390/cells10051257 - 19 May 2021
Cited by 1 | Viewed by 788
Abstract
Heterogeneity of glia in different CNS regions may contribute to the selective vulnerability of neuronal populations in neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). Here, we explored regional variations in the expression of heat shock protein 25 in glia under conditions of [...] Read more.
Heterogeneity of glia in different CNS regions may contribute to the selective vulnerability of neuronal populations in neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). Here, we explored regional variations in the expression of heat shock protein 25 in glia under conditions of acute and chronic stress. Hsp27 (Hsp27; murine orthologue: Hsp25) fulfils a number of cytoprotective functions and may therefore be a possible therapeutic target in ALS. We identified a subpopulation of astrocytes in primary murine mixed glial cultures that expressed Hsp25. Under basal conditions, the proportion of Hsp25-positive astrocytes was twice as high in spinal cord cultures than in cortical cultures. To explore the physiological role of the elevated Hsp25 expression in spinal cord astrocytes, we exposed cortical and spinal cord glia to acute stress, using heat stress and pro-inflammatory stimuli. Surprisingly, we observed no stress-induced increase in Hsp25 expression in either cortical or spinal cord astrocytes. Similarly, exposure to endogenous stress, as modelled in glial cultures from SOD1 G93A-ALS mice, did not increase Hsp25 expression above that observed in astrocytes from wild-type mice. In vivo, Hsp25 expression was greater under conditions of chronic stress present in the spinal cord of SOD1 G93A mice than in wild-type mice, although this increase in expression is likely to be due to the extensive gliosis that occurs in this model. Together, these results show that there are differences in the expression of Hsp25 in astrocytes in different regions of the central nervous system, but Hsp25 expression is not upregulated under acute or chronic stress conditions. Full article
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Article
Heat Shock Protein 27 Is an Emerging Predictor of Contrast-Induced Acute Kidney Injury on Patients Subjected to Percutaneous Coronary Interventions
Cells 2021, 10(3), 684; https://doi.org/10.3390/cells10030684 - 19 Mar 2021
Cited by 1 | Viewed by 498
Abstract
Contrast-induced acute kidney injury (CI-AKI) is a serious complication associated with considerable morbidity and mortality. Heat-shock protein 27 (HSP27) plays a role in the defense of the kidney tissue against various forms of cellular stress, including hypoxia and oxydative stress, both features associated [...] Read more.
Contrast-induced acute kidney injury (CI-AKI) is a serious complication associated with considerable morbidity and mortality. Heat-shock protein 27 (HSP27) plays a role in the defense of the kidney tissue against various forms of cellular stress, including hypoxia and oxydative stress, both features associated with CI-AKI. The aim of our study was to evaluate a potential predictive value of HSP27 for CI-AKI in patients subjected to percutaneous coronary interventions (PCI). Included were 343 selected patients subjected to PCI. Exclusion criteria were conditions that potentially might influence HSP27 levels. HSP27 serum levels were evaluated prior to PCI, together with serum creatinine, the concentration of which was also evaluated twice at 48 and 72 h post PCI. CI-AKI was diagnosed in 9.3% of patients. Patients in whom CI-AKI was diagnosed were older (p < 0.001), were more often females (p = 0.021), had higher prevalence of diabetes (p = 0.011), hypotension during PCI (p < 0.001), albuminuria (p = 0.004) as well as multivessel disease (p = 0.002), received higher contrast volume (p = 0.006), more often received contrast volume (CV) above the maximum allowed contrast dose (MACD) (p < 0.001), and had lower HSP27 level (p < 0.001). On multivariate analysis, CV > MACD (OR 1.23, p = 0.001), number of diseased vessels (OR 1.27, p = 0.006), and HSP27 (OR 0.81, p = 0.001) remained independent predictors of CI-AKI. Low concentration of HSP27 is an emerging, strong and independent predictor of CI-AKI in patients subjected to PCI. Full article
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Review

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Review
Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase
Cells 2021, 10(10), 2745; https://doi.org/10.3390/cells10102745 - 14 Oct 2021
Viewed by 178
Abstract
Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an [...] Read more.
Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here, we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), disassembles amyloids of α-synuclein implicated in Parkinson’s disease as well as of other disease-associated proteins such as tau and huntingtin. We highlight recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregase activity. We also discuss whether this chaperone-mediated disassembly mechanism could be used to solubilize other amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies. Full article
Review
The Pathophysiological Role of Heat Shock Response in Autoimmunity: A Literature Review
Cells 2021, 10(10), 2626; https://doi.org/10.3390/cells10102626 - 01 Oct 2021
Viewed by 301
Abstract
Within the last two decades, there has been increasing evidence that heat-shock proteins can have a differential influence on the immune system. They can either provoke or ameliorate immune responses. This review focuses on outlining the stimulatory as well as the inhibitory effects [...] Read more.
Within the last two decades, there has been increasing evidence that heat-shock proteins can have a differential influence on the immune system. They can either provoke or ameliorate immune responses. This review focuses on outlining the stimulatory as well as the inhibitory effects of heat-shock proteins 27, 40, 70, 65, 60, and 90 in experimental and clinical autoimmune settings. Full article
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Review
Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases
Cells 2021, 10(10), 2596; https://doi.org/10.3390/cells10102596 - 29 Sep 2021
Viewed by 316
Abstract
The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, [...] Read more.
The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, assisting with intracellular transport, and interfering with protein aggregation or degradation. Heat shock protein 70 kDa (Hsp70) and 90 kDa (Hsp90) are two of the most important chaperones whose functions are dependent on ATP hydrolysis and collaboration with their co-chaperones. Numerous studies implicate Hsp70, Hsp90, and their co-chaperones in neurodegenerative diseases. Targeting the specific protein–protein interactions between chaperones and their particular partner co-chaperones with small molecules provides an opportunity to specifically modulate Hsp70 or Hsp90 function for neurodegenerative diseases. Here, we review the roles of co-chaperones in Hsp70 or Hsp90 chaperone cycles, the impacts of co-chaperones in neurodegenerative diseases, and the development of small molecules modulating chaperone/co-chaperone interactions. We also provide a future perspective of drug development targeting chaperone/co-chaperone interactions for neurodegenerative diseases. Full article
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Review
Heat Shock Proteins: Connectors between Heart and Kidney
Cells 2021, 10(8), 1939; https://doi.org/10.3390/cells10081939 - 30 Jul 2021
Viewed by 926
Abstract
Over the development of eukaryotic cells, intrinsic mechanisms have been developed in order to provide the ability to defend against aggressive agents. In this sense, a group of proteins plays a crucial role in controlling the production of several proteins, guaranteeing cell survival. [...] Read more.
Over the development of eukaryotic cells, intrinsic mechanisms have been developed in order to provide the ability to defend against aggressive agents. In this sense, a group of proteins plays a crucial role in controlling the production of several proteins, guaranteeing cell survival. The heat shock proteins (HSPs), are a family of proteins that have been linked to different cellular functions, being activated under conditions of cellular stress, not only imposed by thermal variation but also toxins, radiation, infectious agents, hypoxia, etc. Regarding pathological situations as seen in cardiorenal syndrome (CRS), HSPs have been shown to be important mediators involved in the control of gene transcription and intracellular signaling, in addition to be an important connector with the immune system. CRS is classified as acute or chronic and according to the first organ to suffer the injury, which can be the heart (CRS type 1 and type 2), kidneys (CRS type 3 and 4) or both (CRS type 5). In all types of CRS, the immune system, redox balance, mitochondrial dysfunction, and tissue remodeling have been the subject of numerous studies in the literature in order to elucidate mechanisms and propose new therapeutic strategies. In this sense, HSPs have been targeted by researchers as important connectors between kidney and heart. Thus, the present review has a focus to present the state of the art regarding the role of HSPs in the pathophysiology of cardiac and renal alterations, as well their role in the kidney–heart axis. Full article
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Review
Role of a Heat Shock Transcription Factor and the Major Heat Shock Protein Hsp70 in Memory Formation and Neuroprotection
Cells 2021, 10(7), 1638; https://doi.org/10.3390/cells10071638 - 29 Jun 2021
Cited by 2 | Viewed by 618
Abstract
Heat shock proteins (Hsps) represent the most evolutionarily ancient, conserved, and universal system for protecting cells and the whole body from various types of stress. Among Hsps, the group of proteins with a molecular weight of 70 kDa (Hsp70) plays a particularly important [...] Read more.
Heat shock proteins (Hsps) represent the most evolutionarily ancient, conserved, and universal system for protecting cells and the whole body from various types of stress. Among Hsps, the group of proteins with a molecular weight of 70 kDa (Hsp70) plays a particularly important role. These proteins are molecular chaperones that restore the native conformation of partially denatured proteins after exposure to proteotoxic forms of stress and are critical for the folding and intracellular trafficking of de novo synthesized proteins under normal conditions. Hsp70s are expressed at high levels in the central nervous system (CNS) of various animals and protect neurons from various types of stress, including heat shock, hypoxia, and toxins. Numerous molecular and behavioral studies have indicated that Hsp70s expressed in the CNS are important for memory formation. These proteins contribute to the folding and transport of synaptic proteins, modulate signaling cascades associated with synaptic activation, and participate in mechanisms of neurotransmitter release. In addition, HSF1, a transcription factor that is activated under stress conditions and mediates Hsps transcription, is also involved in the transcription of genes encoding many synaptic proteins, whose levels are increased in neurons under stress and during memory formation. Thus, stress activates the molecular mechanisms of memory formation, thereby allowing animals to better remember and later avoid potentially dangerous stimuli. Finally, Hsp70 has significant protective potential in neurodegenerative diseases. Increasing the level of endogenous Hsp70 synthesis or injecting exogenous Hsp70 reduces neurodegeneration, stimulates neurogenesis, and restores memory in animal models of ischemia and Alzheimer’s disease. These findings allow us to consider recombinant Hsp70 and/or Hsp70 pharmacological inducers as potential drugs for use in the treatment of ischemic injury and neurodegenerative disorders. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: CDK1-mediated Phosphorylation of BAG3 Promotes Mitotic Cell Shape Remodeling and the Molecular Assembly of Mitotic p62 bodies
Authors: Josée N. Lavoie
Affiliation: Département de biologie moléculaire, de biochimie médicale et de pathologie, Faculté de médecine, Université Laval,Canada
Abstract: The co-chaperone BAG3, in complex with the heat shock protein HSPB8, facilitates mitotic rounding, spindle orientation and proper abscission of daughter cells. The mitotic function of BAG3-HSPB8 implicates the sequestosome p62/SQSTM1, suggesting a role for protein quality control. However, the interplay between this chaperone-assisted pathway and the mitotic machinery is largely unknown. Here we show that phosphorylation of BAG3 at a conserved motif is regulated by CDK1 and activates its function in mitotic cell shape remodeling. BAG3 phosphorylation exhibited a high dynamic at mitotic entry. Remarkably, neither the non-phosphorylatable nor phosphomimetic BAG3 variant were able to correct the mitotic defects in BAG3-depleted cells, suggesting that BAG3 dynamic phosphorylation state is essential. We also demonstrate that BAG3 phosphorylation, HSPB8, and CDK1 modulate the molecular assembly of p62/SQSTM1 into mitotic bodies containing K63 polyubiquitinated chains. These findings suggest the existence of a mitotically regulated system of spatial quality control for the fidelity of cell shape remodeling in highly dividing cells.

Title: CDK1-mediated Phosphorylation of BAG3 Promotes Mitotic Cell Shape Remodeling and the Molecular Assembly of Mitotic p62 bodies
Authors: Carole Luthold1,2, Herman Lambert1,2, Margit Fuchs1,2‡, Solenn M. Guilbert1,2‡, Marc-Antoine Rodrigue1,2, Alice Anaïs Varlet1,2, Amélie Fradet-Turcotte1,2 and Josée N. Lavoie1,2 *
Affiliation: 1 Université Laval Cancer Research Center & Department of Molecular Biology, Medical Biochemistry and Pathology, Medicine Faculty, Université Laval, Qc, Canada, G1V OA6; 2 CHU de Québec-Université Laval Research Center, Oncology division; ‡ Authors contributes equally to this work
Abstract: The co-chaperone BAG3, in complex with the heat shock protein HSPB8, facilitates mitotic rounding, spindle orientation and proper abscission of daughter cells. The mitotic function of BAG3-HSPB8 implicates the sequestosome p62/SQSTM1, suggesting a role for protein quality control. However, the interplay between this chaperone-assisted pathway and the mitotic machinery is largely unknown. Here we show that phosphorylation of BAG3 at a conserved motif is regulated by CDK1 and activates its function in mitotic cell shape remodeling. BAG3 phosphorylation exhibited a high dynamic at mitotic entry. Remarkably, neither the non-phosphorylatable nor phosphomimetic BAG3 variant were able to correct the mitotic defects in BAG3-depleted cells, suggesting that BAG3 dynamic phosphorylation state is essential. We also demonstrate that BAG3 phosphorylation, HSPB8, and CDK1 modulate the molecular assembly of p62/SQSTM1 into mitotic bodies containing K63 polyubiquitinated chains. These findings suggest the existence of a mitotically regulated system of spatial quality control for the fidelity of cell shape remodeling in highly dividing cells.

Title: Heat shock proteins in cancer: functions, mechanisms, and cancer therapy
Authors: Jixian Xiong
Affiliation: Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Health Science Center, Shenzhen 518060, China

Title: Activation of the Heat Shock signaling as a marker of cells that cause problems in later life
Authors: Shisui Torii; Pasko Rakic
Affiliation: Department of Neuroscience, School of Medicine, Yale University
Abstract: Heat Shock signaling is activated by various types of cellular stress. By the activation, cells are protected from immediate threats in the surrounding environment. However, the activation happens in a random manner among the cell population. It is also known to change the epigenetic status of the cells, thereby leading to abnormal functions in the body. This review summarizes recent progress of the molecular and genetic tools that allow us to monitor such cells. Then focusing on recent findings using those reporter tools of the heat shock signaling activation, we will discuss the potential usage and expansion of those tools as well as the limitation and cautions in the interpretation of the data obtained with them.

Title: Regional differences in heat shock protein 25 expression in brain and spinal cord astrocytes of wildtype and SOD1G93A mice
Authors: R. San Gil1,2*; B. Clarke3,4*; H. Ecroyd1, B. Kalmar3#; L. Greensmith3#.
Affiliation: 1 Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2519 Australia; Illawarra Health and Medical Research Institute, Wollongong, NSW 2519 Australia 2 Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia 3 Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, Queen Square London WC1N 3BG, UK 4 The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
Abstract: Heterogeneity of glia in different brain regions may contribute to the selective vulnerability of neuronal populations in neurodegenerative conditions such as Amyotrophic Lateral Sclerosis (ALS). Here, we explored regional variations in the expression of Heat shock protein 25 in glia under conditions of acute and chronic stress. Hsp27 (Hsp27; murine orthologue: Hsp25) fulfils a number of cytoprotective functions and may therefore be a possible therapeutic target in ALS. We identified a subpopulation of astrocytes in primary murine mixed glial cultures that expressed Hsp25. Under basal conditions, the proportion of Hsp25-positive astrocytes was twice as high in spinal cord cultures than in cortical cultures. To explore the physiological role of the elevated Hsp25 expression in spinal cord astrocytes, we exposed cortical and spinal cord glia to acute stress, using heat stress and proinflammatory stimuli. Surprisingly, we observed no stress-induced increase in Hsp25 expression in either cortical or spinal cord astrocytes. Similarly, exposure to endogenous stress, as modelled in glial cultures from SOD1G93A-ALS mice, did not increase Hsp25 expression above that observed in astrocytes from wildtype mice. In vivo, Hsp25 expression was greater under conditions of chronic stress present in the spinal cord of SOD1G93A mice than in wildtype mice, although this increase in expression is likely to be due to the extensive gliosis that occurs in this model. Together, these results show that there are differences in the expression of Hsp25 in astrocytes in different regions of the central nervous system, but Hsp25 expression is not upregulated under acute or chronic stress conditions.

Title: Ins and Outs of Heat Shock Proteins in Hepatocellular Carcinoma: Its role in carcinogenesis and therapeutic perspectives
Authors: Jibran Sualeh Muhammad1*
Affiliation: Department of Basic Medical Sciences, College of Medicine, University of Sharjah
Abstract: Cancer cells can reprogram their metabolic activities and undergo uncontrolled proliferation by utilizing the power of heat shock proteins (HSPs). HSPs are a highly conserved chaperone, functions to facilitate the correct folding of intracellular proteins under stressful conditions. Constitutively, HSPs are expressed at low levels, but their expression is significantly upregulated in response to a wide variety of insults including the effects of anti-cancer therapies. Thus, allowing the cancer cell to develop chemoresistance. In recent years, several researchers have reported that HSPs could be an important therapeutic target in difficult-to-treat cancers such as Hepatocellular carcinoma (HCC). HCC is the most common type of primary liver cancer, the third leading cause of cancer-related death in both sexes, and worldwide it is the sixth most common cancer. Most of those patients present at an advanced stage with a poor prognosis. The molecular complexity and the coexisting cirrhosis present a major obstacle towards the development of an effective treatment. Over the past several years, significant progress has been made in our understanding regarding the role of HSPs in the pathogenesis of HCC. Moreover, novel therapeutic strategies that target HSPs alone or combined with other anticancer agents are widely investigated. Herein, we present an overview of the functional mechanism and diagnostic or prognostic potentials of HSPs in HCC. Also, the emerging anti-HCC strategies based on targeting HSPs will be discussed.

Title: DNA methylation of heat shock proteins as an epigenetic regulator of carcinogenesis: A pan-cancer-wide in silico analysis
Authors: Jibran Sualeh Muhammad1*
Affiliation: Department of Basic Medical Sciences, College of Medicine, University of Sharjah
Abstract: Cancer is a major global health challenge and a leading cause of death, which accounted for over 9 million deaths worldwide in the year 2018. Given the complexity of carcinogenesis, it is important to conduct a pan-cancer expression analysis of any gene of interest and assess its correlation with clinical prognosis and potential molecular mechanisms. Heat shock proteins (HSPs) are powerful chaperones required for the maintenance of the normal structure and protein folding during stressful conditions. Besides that, HSPs play important roles in carcinogenesis via the regulation of angiogenesis, cell proliferation, migration, invasion, metastasis and mediates resistance to some anticancer drugs. The mechanisms behind the modulation of HSPs expression could identify strategies to pinpoint therapeutic targets. Among other gene regulatory processes, DNA methylation-mediated epigenetic regulation has a key role in regulating HSPs functions in cancer. DNA methylation of CpG islands (CGI), regions with a high frequency of cytosine just before guanine, in the promoter of a gene could directly affect the binding of transcription factors essential for expression, thus rendering loss- or gain-of-function. In this study, we investigate pan-cancer-wide DNA methylation, mRNA expression patterns, and survival status of all the HSPs having GCI in their promoter regions. For the first time, using in silico analysis of large-scale data provided by The Cancer Genome Atlas, we provide a comprehensive understanding of the mechanistic oncogenic roles of HSPs across many different cancer types.

Title: The pathophysiological role of heat shock response in autoimmunity
Authors: Ariadni Androvitsanea 1, Kostas Stylianou 2, Ioannis Petrakis 3
Affiliation: 1. Department of internal medicine and Nephrology, Erlangen University Hospital, Germany; 2. Department of Nephrology, University of Crete; 3. Renal physician, Erlangen, Germany.

Title: Heat Shock Proteins: connectors between heart and kidney
Authors: Carolina Victoria da Cruz Junho1, Carolina Amaral Bueno Azevedo2, Regiane Stafim da Cunha2, Ainhoa Rodriguez de Yurre3, Emiliano Medei3, Andréa Emilia Marques Stinghen2, Marcela Sorelli Carneiro-Ramos
Affiliation: 1 Laboratory of Cardiovascular Immunology, Center of Natural and Human Sciences (CCNH), Federal University of ABC, Santo André, SP, Brazil. 2 Experimental Nephrology Laboratory, Basic Pathology Department, Universidade Federal do Paraná, Curitiba, PR, Brazil 3Laboratory of Cardioimmunology. Federal University of Rio de Janeiro. Institute of Biophysics Carlos Chagas Filho. Rio de Janeiro. Brazil
Abstract: Over the development of eukaryotic cells, intrinsic mechanisms have been developed to provide the ability to survive under several stress conditions. In this sense, a group of proteins play a crucial role in controlling the cellular process, production of several proteins, guaranteeing cell survival. Since 1962, when it was first reported in Drosophila salivary glands, Heat Shock Proteins (HSPs), have been linked to different cellular functions, being activated under conditions of cellular stress, not only imposed by thermal variation. In pathological situations as observed in cardiovascular and renal diseases, HSPs have been shown to be important mediators involved in the control of gene transcription and intracellular signaling, in addition to be an important connector with the immune system. Thus, the present review has as focus to present the role of HSPs in the pathophysiology of cardiac and renal diseases, as well their role in the kidneyheart connection. Key words: Heat Shock Proteins, renal diseases, cardiac diseases, immune system, cardiorenal syndrome.

Title: Transgenic overexpression of Heat shock protein 70 alleviates cardiac remodeling and survival rate in a protein phosphatase 2A transgenic mice with chronic heart failure
Authors: Somy Yoon 1 and Gwang Hyeon Eom 1,*
Affiliation: 1. Department of Pharmacology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea
Abstract: Abstract: Heat shock protein (HSP) 70 is a member of molecular chaperone that regulates protein structure in response to thermal stress in the cell. Beside the basic role, HSP70 involves in posttranslational modifications process and disease severity. We tested the functional relevance of long lasting expression of HSP70 in non-ischemic heart failure model by use of protein phosphatase 2 catalytic subunit A (PP2CA) transgenic mice. Cardiac specific transgenic mice expressing Pp2ca abruptly died after 12 weeks postnatal. Serial echocardiogram to determine cardiac function revealed that ejection fraction (EF) was gradually deteriorated in Pp2ca. Besides, TgPp2ca expression exacer-bated systolic dysfunction, LV dilatation with free wall thinning, which indicates fatal dilated cardiomyopathy. Interestingly, simultaneous expression of HSP70 (double transgenic mice, dTg) significantly improved devastative dilated cardiomyopathy phenotype of TgPp2ca. We observed better survival, preserved ejection fraction, attenuated chamber enlargement, and suppressed free wall thinning. Notable changes in the real-time quantitative PCR were not determined. For mo-lecular mechanism, HSP70 might preferentially regulate phosphorylation of AKT and STAT5. Phosphorylation of those genes were significantly reduced in TgPp2ca mice but restored in dTg mice. Signal crosstalk between AKT and STAT5 in association with HSP70 might be noteworthy for intervention of non-ischemic heart failure patients to improve survival rate and to suppress cardiac remodeling. Keywords: Post Translational Modification; Phosphorylation; Dilated cardiomyopathy; Heart failure; HSP70

Title: Phosphorylation in the Charged Linker Modulates Interactions and Secretion of Hsp90β
Authors: Lorenz Weidenauer; Manfredo Quadroni
Affiliation: University of Lausanne
Abstract: Hsp90β is a major chaperone involved in numerous cellular processes. Hundreds of client proteins depend on Hsp90β for proper folding and/or activity. Regulation of Hsp90β is critical to coordinate its tasks and is mediated by several post-translational modifications. Here, we focus on two phosphorylation sites located in the charged linker region of human Hsp90β, Ser226 and Ser255, which have been frequently reported but whose function remains poorly understood. Targeted measurements by mass spectrometry indicated that intracellular Hsp90β is highly phosphorylated on both sites (>90%). The level of phosphorylation was unaffected by various stresses (e.g. heat shock, inhibition with drugs) that impact Hsp90β activity. Mutating the two serines to alanines increased the amount of proteins interacting with Hsp90β globally and increased the sensitivity to tryptic cleavage in the C-terminal domain. Further investigation revealed that phosphorylation on Ser255 and to a lesser extent on Ser226 is decreased in the conditioned medium of cultured K562 cells, and that a non-phosphorylatable double alanine mutant was found in greater amounts in the conditioned medium of transfected cells relative to the wild type. We thus hypothesize that dynamic phosphorylation of S226 and S255 can regulate global Hsp90β conformation by adding or removing constraints at the charged linker, with implications for both its chaperoning activity and its secretion.

Title: Forcing the antitumoural effects of HSPs using an electric field
Authors: Carrie Anne Minnaar1; Andras Szasz2
Affiliation: 1. Wits Donald Gordon Academic Hospital, Johannesburg, South Africa; University of the Witwatersrand, Department of Radiation Sciences, Gauteng, South Africa; 2. Biotechnics Department, Hungarian University of Agriculture and Life Sciences, Godollo, Hungary
Abstract: (1) Background: The role of Heat Shock Proteins (HSPs) are a double-edged sword in tumours. Their location and interactions determine their pro- or antitumour activity. Our objective is to promote the antitumoral properties of HSPs by manipulating the electromagnetic interactions. (2) Methods: An amplitude-modulated radiofrequency is applied with 13.56 MHz carrier frequency. The field uses the electric heterogeneity of the tumour tissue and the tumorous cells to select and affect the cancer cells. (3) Results: The treatment promotes expression of HSP70 on the plasma membrane triggering the innate immune reactions. In further steps, HSP70 is exported to the extracellular matrix and stimulates immunogenic cell death. The extracellular HSP70 signals the promotion of a damage-associated molecular pattern. The liberated HSP70s, together with HMGB1 and Calreticulin, maturate the dendritic cells for antigen-presentation, and the process releases CD8+ killer T-cells. The process has solid preclinical proof, and the associated abscopal effect has been validated clinically. (4) Conclusion: When properly applied, the electric field promotes the antitumoural HSP activity, and in-situ it promotes the tumour-specific immune effects which act locally and also systemically for disseminated cells and metastatic lesions.

Title: The GRP94 inhibitor PU-WS13 decreases M2-like macrophages in murine TNBC tumors: a pharmaco-imaging study with 99mTc-Tilmanocept SPECT
Authors: Alexanne Bouchard1,2, Hugo Sikner1, Anaïs-Rachel Garnier1, Marie Monterrat1, Mathieu Moreau3, Emeric Limagne4, Carmen Garrido2,5, Evelyne Kohli2,6,7*, Bertrand Collin1,3,6*, Pierre-Simon Bellaye1,2*
Affiliation: 1Centre George-François Leclerc, Service de médecine nucléaire, Plateforme d’imagerie et de radiothérapie précliniques, labellisée équipement d’excellence (Equipex) IMAPPI, Dijon, France 2UMR INSERM/uB/AGROSUP 1231, Team 3 HSP-Pathies, labellisée Ligue Nationale contre le Cancer and Laboratoire d'Excellence LipSTIC, Université Bourgogne Franche-Comté Dijon, France 3Institut de Chimie Moléculaire de l’Université de Bourgogne, UMR CNRS/uB 6302, Université de Bourgogne Franche-Comté, labellisée équipement d’excellence (Equipex) IMAPPI, Dijon, France 4Centre George-François Leclerc, Plateforme de transfert en biologie cancérologique, Dijon, France 5Centre George-François Leclerc, labellisée équipement d’excellence (Equipex) IMAPPI, Dijon, France 6UFR des Sciences de Santé, Université de Bourgogne, Dijon, France 7CHU Dijon, France
Abstract: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancers and is not eligible for hormone and anti-HER2 therapies. Identifying therapeutic targets and associated biomarkers in TNBC is a clinical challenge to improve patients’ outcome and management. High infiltration of CD206+ M2-like macrophages in the tumor microenvironment (TME) indicates poor prognosis and survival in TNBC patients. As we previously showed that membrane expression of GRP94, an endoplasmic reticulum chaperone, was associated with the anti-inflammatory profile of human PBMC-derived M2 macrophages, we hypothesized that intra-tumoral CD206+ M2 macrophages expressing GRP94 may represent innovative targets in TNBC for theranostic purposes. We demonstrate in a preclinical model of TNBC (4T1 xenograft in Balb/c mice) that (i) CD206-expressing M2-like macrophages in the TME of TNBC can be specifically quantified using in vivo SPECT imaging with 99mTc-Tilmanocept, (ii) the inhibition of GRP94 with the chemical inhibitor PU-WS13 induces a decrease in CD206-expressing M2-like macrophages in the TME. This result correlated with reduced tumor growth and collagen content as well as an increase in CD8+ cells in the TME. 99mTc-Tilmanocept SPECT imaging might represent an innovative non-invasive strategy to quantify CD206+ tumor-associated macrophages as a biomarker of anti-GRP94 therapy efficacy and TNBC tumor aggressiveness.

Title: Unzipping the secrets of amyloid disassembly by the human disaggregase
Authors: Aitor Franco1,2, Lorea Velasco-Carneros1,2, Naiara Alvarez1,2, Natalia Orozco1,3, Fernando Moro1,2, Adelina Prado1,2, Arturo Muga1,2,*
Affiliation: 1. Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, 48080 Bilbao, Spain 2. Instituto Biofisika (UPV/EHU, CSIC), University of the Basque Country, Leioa, E-48940, Spain 3. Fundación Biofísica Bizkaia/Biofisika Bizkaia Fundazioa (FBB), Barrio Sarriena s/n, Leioa, E-48940, Spain
Abstract: Neurodegenerative diseases (NDs) are increasingly positioning as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a major global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), has been shown to disassemble α-synuclein amyloids, which are implicated in Parkinson´s disease, as well as of other disease-associated proteins such as tau and huntingtin. We highlight the recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregation activity. We also discuss the universality of the chaperone-mediated disassembly mechanism, analyzing the results obtained with different amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies. Keywords: neurodegeneration, amyloid, chaperone, disaggregase

Title: Heat Shock Proteins in Tumor Immunity
Authors: Zarema Albakova1
Affiliation: 1Department of Immunology, Lomonosov Moscow State University, Moscow, Russia
Abstract: Heat shock proteins are molecular chaperones which support tumor development by regulating various cellular processes including unfolded protein response, mitochondrial bioenergetics, apoptosis, autophagy, necroptosis, lipid metabolism, angiogenesis, cancer cell stemness, epithelial-mesenchymal transition and tumor immunity. Apart from their intracellular activities, HSPs have also distinct extracellular functions. However, the role that HSP chaperones play in the regulation of immune responses inside and outside the cell is not yet clear. Herein, we explore the immunologic functions of HSPs in cancer. A broader understanding of how HSPs modulate immune responses may provide critical insights for the development of effective immunotherapies. Keywords: heat shock proteins, tumor immunity, immunotherapy, cancer

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