Research

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18 pages, 5656 KiB

Open AccessArticle

STIP1/HOP Regulates the Actin Cytoskeleton through Interactions with Actin and Changes in Actin-Binding Proteins Cofilin and Profilin

by Samantha Joy Beckley, Morgan Campbell Hunter, Sarah Naulikha Kituyi, Ianthe Wingate, Abantika Chakraborty, Kelly Schwarz, Matodzi Portia Makhubu, Robert Pierre Rousseau, Duncan Kyle Ruck, Jo-Anne de la Mare, Gregory Lloyd Blatch and Adrienne Lesley Edkins

Int. J. Mol. Sci. 2020, 21(9), 3152; https://doi.org/10.3390/ijms21093152 - 30 Apr 2020

Cited by 8 | Viewed by 5180

Abstract

Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and [...] Read more.

Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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15 pages, 1810 KiB

Open AccessCommunication

Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells

by Celeste Caruso Bavisotto, Antonella Marino Gammazza, Filippa Lo Cascio, Emanuele Mocciaro, Alessandra Maria Vitale, Giuseppe Vergilio, Andrea Pace, Francesco Cappello, Claudia Campanella and Antonio Palumbo Piccionello

Int. J. Mol. Sci. 2020, 21(2), 661; https://doi.org/10.3390/ijms21020661 - 19 Jan 2020

Cited by 16 | Viewed by 3637

Abstract

The fundamental challenge in fighting cancer is the development of protective agents able to interfere with the classical pathways of malignant transformation, such as extracellular matrix remodeling, epithelial–mesenchymal transition and, alteration of protein homeostasis. In the tumors of the brain, proteotoxic stress represents [...] Read more.

The fundamental challenge in fighting cancer is the development of protective agents able to interfere with the classical pathways of malignant transformation, such as extracellular matrix remodeling, epithelial–mesenchymal transition and, alteration of protein homeostasis. In the tumors of the brain, proteotoxic stress represents one of the main triggering agents for cell transformation. Curcumin is a natural compound with anti-inflammatory and anti-cancer properties with promising potential for the development of therapeutic drugs for the treatment of cancer as well as neurodegenerative diseases. Among the mediators of cancer development, HSP60 is a key factor for the maintenance of protein homeostasis and cell survival. High HSP60 levels were correlated, in particular, with cancer development and progression, and for this reason, we investigated the ability of curcumin to affect HSP60 expression, localization, and post-translational modifications using a neuroblastoma cell line. We have also looked at the ability of curcumin to interfere with the HSP60/HSP10 folding machinery. The cells were treated with 6, 12.5, and 25 µM of curcumin for 24 h, and the flow cytometry analysis showed that the compound induced apoptosis in a dose-dependent manner with a higher percentage of apoptotic cells at 25 µM. This dose of curcumin-induced a decrease in HSP60 protein levels and an upregulation of HSP60 mRNA expression. Moreover, 25 µM of curcumin reduced HSP60 ubiquitination and nitration, and the chaperonin levels were higher in the culture media compared with the untreated cells. Furthermore, curcumin at the same dose was able to favor HSP60 folding activity. The reduction of HSP60 levels, together with the increase in its folding activity and the secretion in the media led to the supposition that curcumin might interfere with cancer progression with a protective mechanism involving the chaperonin. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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18 pages, 4163 KiB

Open AccessArticle

Extracellular Hsp70 Reduces the Pro-Tumor Capacity of Monocytes/Macrophages Co-Cultivated with Cancer Cells

by Elena Y. Komarova, Larisa V. Marchenko, Alexander V. Zhakhov, Alina D. Nikotina, Nikolay D. Aksenov, Roman V. Suezov, Alexander M. Ischenko, Boris A. Margulis and Irina V. Guzhova

Int. J. Mol. Sci. 2020, 21(1), 59; https://doi.org/10.3390/ijms21010059 - 20 Dec 2019

Cited by 15 | Viewed by 3760

Abstract

Cancer cells are known to contain high levels of the heat shock protein 70 kDa (Hsp70), which mediates increased cell proliferation, escape from programmed cell death, enhanced invasion, and metastasis. A part of Hsp70 molecules may release from cancer cells and affect the [...] Read more.

Cancer cells are known to contain high levels of the heat shock protein 70 kDa (Hsp70), which mediates increased cell proliferation, escape from programmed cell death, enhanced invasion, and metastasis. A part of Hsp70 molecules may release from cancer cells and affect the behavior of adjacent stromal cells. To explore the effects of Hsp70 on the status of monocytes/macrophages in the tumor locale, we incubated human carcinoma cells of three distinct lines with normal and reduced content of Hsp70 with THP1 monocytes. Using two methods, we showed that the cells with knock-down of Hsp70 released a lower amount of protein in the extracellular medium. Three cycles of the co-cultivation of cancer and monocytic cells led to the secretion of several cytokines typical of the tumor microenvironment (TME) and to pro-cancer activation of the monocytes/macrophages as established by elevation of F4/80 and arginase-1 markers. Unexpectedly, the efficacy of epithelial–mesenchymal transition and resistance of carcinoma cells to anticancer drugs after incubation with monocytic cells were more pronounced in cells with lower Hsp70, e.g., releasing less Hsp70 into the extracellular milieu. These data suggest that Hsp70 released from tumor cells into the TME is able, together with the development of an anti-cancer immune response, to limit the conversion of a considerable part of monocytic cells to the pro-tumor phenotype. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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15 pages, 1780 KiB

Open AccessArticle

Trypanosoma brucei J-Protein 2 Functionally Co-Operates with the Cytosolic Hsp70 and Hsp70.4 Proteins

by Stephen John Bentley and Aileen Boshoff

Int. J. Mol. Sci. 2019, 20(23), 5843; https://doi.org/10.3390/ijms20235843 - 21 Nov 2019

Cited by 5 | Viewed by 2745

Abstract

The etiological agent of African trypanosomiasis, Trypanosoma brucei (Tb), has been identified to possess an expanded and diverse group of heat shock proteins, which have been implicated in cytoprotection, differentiation, and subsequently progression and transmission of the disease. Heat shock protein 70 (Hsp70) [...] Read more.

The etiological agent of African trypanosomiasis, Trypanosoma brucei (Tb), has been identified to possess an expanded and diverse group of heat shock proteins, which have been implicated in cytoprotection, differentiation, and subsequently progression and transmission of the disease. Heat shock protein 70 (Hsp70) is a highly conserved and ubiquitous molecular chaperone that is important in maintaining protein homeostasis in the cell. Its function is regulated by a wide range of co-chaperones, and inhibition of these functions and interactions with co-chaperones are emerging as potential therapeutic targets for numerous diseases. This study sought to biochemically characterize the cytosolic TbHsp70 and TbHsp70.4 proteins and to investigate if they functionally co-operate with the Type I J-protein, Tbj2. Expression of TbHsp70 was shown to be heat inducible, while TbHsp70.4 was constitutively expressed. The basal ATPase activities of TbHsp70.4 and TbHsp70 were stimulated by Tbj2. It was further determined that Tbj2 functionally co-operated with TbHsp70 and TbHsp70.4 as the J-protein was shown to stimulate the ability of both proteins to mediate the refolding of chemically denatured β-galactosidase. This study provides further insight into this important class of proteins, which may contribute to the development of new therapeutic strategies to combat African Trypanosomiasis. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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24 pages, 4189 KiB

Open AccessArticle

HSF1Base: A Comprehensive Database of HSF1 (Heat Shock Factor 1) Target Genes

by Dániel Kovács, Tímea Sigmond, Bernadette Hotzi, Balázs Bohár, Dávid Fazekas, Veronika Deák, Tibor Vellai and János Barna

Int. J. Mol. Sci. 2019, 20(22), 5815; https://doi.org/10.3390/ijms20225815 - 19 Nov 2019

Cited by 55 | Viewed by 6075

Abstract

HSF1 (heat shock factor 1) is an evolutionarily conserved master transcriptional regulator of the heat shock response (HSR) in eukaryotic cells. In response to high temperatures, HSF1 upregulates genes encoding molecular chaperones, also called heat shock proteins, which assist the refolding or degradation [...] Read more.

HSF1 (heat shock factor 1) is an evolutionarily conserved master transcriptional regulator of the heat shock response (HSR) in eukaryotic cells. In response to high temperatures, HSF1 upregulates genes encoding molecular chaperones, also called heat shock proteins, which assist the refolding or degradation of damaged intracellular proteins. Accumulating evidence reveals however that HSF1 participates in several other physiological and pathological processes such as differentiation, immune response, and multidrug resistance, as well as in ageing, neurodegenerative demise, and cancer. To address how HSF1 controls these processes one should systematically analyze its target genes. Here we present a novel database called HSF1Base (hsf1base.org) that contains a nearly comprehensive list of HSF1 target genes identified so far. The list was obtained by manually curating publications on individual HSF1 targets and analyzing relevant high throughput transcriptomic and chromatin immunoprecipitation data derived from the literature and the Yeastract database. To support the biological relevance of HSF1 targets identified by high throughput methods, we performed an enrichment analysis of (potential) HSF1 targets across different tissues/cell types and organisms. We found that general HSF1 functions (targets are expressed in all tissues/cell types) are mostly related to cellular proteostasis. Furthermore, HSF1 targets that are conserved across various animal taxa operate mostly in cellular stress pathways (e.g., autophagy), chromatin remodeling, ribosome biogenesis, and ageing. Together, these data highlight diverse roles for HSF1, expanding far beyond the HSR. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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26 pages, 4663 KiB

Open AccessArticle

Establishing Computational Approaches Towards Identifying Malarial Allosteric Modulators: A Case Study of Plasmodium falciparum Hsp70s

by Arnold Amusengeri, Lindy Astl, Kevin Lobb, Gennady M. Verkhivker and Özlem Tastan Bishop

Int. J. Mol. Sci. 2019, 20(22), 5574; https://doi.org/10.3390/ijms20225574 - 08 Nov 2019

Cited by 13 | Viewed by 3573

Abstract

Combating malaria is almost a never-ending battle, as Plasmodium parasites develop resistance to the drugs used against them, as observed recently in artemisinin-based combination therapies. The main concern now is if the resistant parasite strains spread from Southeast Asia to Africa, the continent [...] Read more.

Combating malaria is almost a never-ending battle, as Plasmodium parasites develop resistance to the drugs used against them, as observed recently in artemisinin-based combination therapies. The main concern now is if the resistant parasite strains spread from Southeast Asia to Africa, the continent hosting most malaria cases. To prevent catastrophic results, we need to find non-conventional approaches. Allosteric drug targeting sites and modulators might be a new hope for malarial treatments. Heat shock proteins (HSPs) are potential malarial drug targets and have complex allosteric control mechanisms. Yet, studies on designing allosteric modulators against them are limited. Here, we identified allosteric modulators (SANC190 and SANC651) against P. falciparum Hsp70-1 and Hsp70-x, affecting the conformational dynamics of the proteins, delicately balanced by the endogenous ligands. Previously, we established a pipeline to identify allosteric sites and modulators. This study also further investigated alternative approaches to speed up the process by comparing all atom molecular dynamics simulations and dynamic residue network analysis with the coarse-grained (CG) versions of the calculations. Betweenness centrality (BC) profiles for PfHsp70-1 and PfHsp70-x derived from CG simulations not only revealed similar trends but also pointed to the same functional regions and specific residues corresponding to BC profile peaks. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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14 pages, 1897 KiB

Open AccessArticle

Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity

by Diondra C. Harris, Yenni A. Garcia, Cheryl Storer Samaniego, Veronica W. Rowlett, Nina R. Ortiz, Ashley N. Payan, Tatsuya Maehigashi and Marc B. Cox

Int. J. Mol. Sci. 2019, 20(21), 5346; https://doi.org/10.3390/ijms20215346 - 28 Oct 2019

Cited by 5 | Viewed by 2683

Abstract

Previous studies demonstrated that the 52-kDa FK506-binding protein (FKBP52) proline-rich loop is functionally relevant in the regulation of steroid hormone receptor activity. While zebra fish (Danio rerio; Dr) FKBP52 contains all of the analogous domains and residues previously identified as critical [...] Read more.

Previous studies demonstrated that the 52-kDa FK506-binding protein (FKBP52) proline-rich loop is functionally relevant in the regulation of steroid hormone receptor activity. While zebra fish (Danio rerio; Dr) FKBP52 contains all of the analogous domains and residues previously identified as critical for FKBP52 potentiation of receptor activity, it fails to potentiate activity. Thus, we used a cross-species comparative approach to assess the residues that are functionally critical for FKBP52 function. Random selection of gain-of-function DrFKBP52 mutants in Saccharomyces cerevisiae identified two critical residues, alanine 111 (A111) and threonine 157 (T157), for activation of receptor potentiation by DrFKBP52. In silico homology modeling suggests that alanine to valine substitution at position 111 in DrFKBP52 induces an open conformation of the proline-rich loop surface similar to that observed on human FKBP52, which may allow for sufficient surface area and increased hydrophobicity for interactions within the receptor–chaperone complex. A second mutation in the FKBP12-like domain 2 (FK2), threonine 157 to arginine (T157R), also enhanced potentiation, and the DrFKBP52-A111V/T157R double mutant potentiated receptor activity similar to human FKBP52. Collectively, these results confirm the functional importance of the FKBP52 proline-rich loop, suggest that an open conformation on the proline-rich loop surface is a predictor of activity, and highlight the importance of an additional residue within the FK2 domain. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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16 pages, 2969 KiB

Open AccessArticle

Stress-Induced, p53-Mediated Tumor Growth Inhibition of Melanoma by Modulated Electrohyperthermia in Mouse Models without Major Immunogenic Effects

by Balázs Besztercei, Tamás Vancsik, Anett Benedek, Enikő Major, Mbuotidem J. Thomas, Csaba A. Schvarcz, Tibor Krenács, Zoltán Benyó and Andrea Balogh

Int. J. Mol. Sci. 2019, 20(16), 4019; https://doi.org/10.3390/ijms20164019 - 17 Aug 2019

Cited by 15 | Viewed by 4130

Abstract

Modulated electrohyperthermia (mEHT), an innovative complementary technique of radio-, chemo-, and targeted oncotherapy modalities, can induce tumor apoptosis and contribute to a secondary immune-mediated cancer death. Here, we tested the efficiency of high-fever range (~42 °C) mEHT on B16F10 melanoma both in cell [...] Read more.

Modulated electrohyperthermia (mEHT), an innovative complementary technique of radio-, chemo-, and targeted oncotherapy modalities, can induce tumor apoptosis and contribute to a secondary immune-mediated cancer death. Here, we tested the efficiency of high-fever range (~42 °C) mEHT on B16F10 melanoma both in cell culture and allograft models. In vivo, mEHT treatment resulted in significant tumor size reduction when repeated three times, and induced major stress response as indicated by upregulated cytoplasmic and cell membrane hsp70 levels. Despite the increased PUMA and apoptosis-inducing factor 1, and moderate rise in activated-caspase-3, apoptosis was not significant. However, phospho-H2AX indicated DNA double-strand breaks, which upregulated p53 protein and its downstream cyclin-dependent kinase inhibitors p21^waf1 and p27^kip. Combined in vitro treatment with mEHT and the p53 activator nutlin-3a additively reduced cell viability compared to monotherapies. Though mEHT promoted the release of damage-associated molecular pattern (DAMP) damage signaling molecules hsp70, HMGB1 and ATP to potentiate the tumor immunogenicity of melanoma allografts, it reduced MHC-I and melan-A levels in tumor cells. This might explain why the number of cytotoxic T cells was moderately reduced, while the amount of natural killer (NK) cells was mainly unchanged and only macrophages increased significantly. Our results suggest that mEHT-treatment-related tumor growth control was primarily mediated by cell-stress-induced p53, which upregulated cyclin-dependent kinase inhibitors. The downregulated tumor antigen-presenting machinery may explain the reduced cytotoxic T-cell response despite increased DAMP signaling. Decreased tumor antigen and MHC-I levels suggest that natural killer (NK) cells and macrophages were the major contributors to tumor eradication. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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16 pages, 33638 KiB

Open AccessArticle

Unveiling the Interplay between the TLR4/MD2 Complex and HSP70 in the Human Cardiovascular System: A Computational Approach

by Amanda Almeida de Oliveira, Josemar Faustino, Maria Elena de Lima, Ronaldo Menezes and Kenia Pedrosa Nunes

Int. J. Mol. Sci. 2019, 20(13), 3121; https://doi.org/10.3390/ijms20133121 - 26 Jun 2019

Cited by 19 | Viewed by 4507

Abstract

While precise mechanisms underlying cardiovascular diseases (CVDs) are still not fully understood, previous studies suggest that the innate immune system, through Toll-like receptor 4 (TLR4), plays a crucial part in the pathways leading to these diseases, mainly because of its interplay with endogenous [...] Read more.

While precise mechanisms underlying cardiovascular diseases (CVDs) are still not fully understood, previous studies suggest that the innate immune system, through Toll-like receptor 4 (TLR4), plays a crucial part in the pathways leading to these diseases, mainly because of its interplay with endogenous molecules. The Heat-shock protein 70 family (HSP70-70kDa) is of particular interest in cardiovascular tissues as it may have dual effects when interacting with TLR4 pathways. Although the hypothesis of the HSP70 family members acting as TLR4 ligands is becoming widely accepted, to date no co-crystal structure of this complex is available and it is still unknown whether this process requires the co-adaptor MD2. In this study, we aimed at investigating the interplay between the TLR4/MD2 complex and HSP70 family members in the human cardiovascular system through transcriptomic data analysis and at proposing a putative interaction model between these proteins. We report compelling evidence of correlated expression levels between TLR4 and MD2 with HSP70 cognate family members, especially in heart tissue. In our molecular docking simulations, we found that HSP70 in the ATP-bound state presents a better docking score towards the TLR4/MD2 complex compared to the ADP-bound state (−22.60 vs. −10.29 kcal/mol, respectively). Additionally, we show via a proximity ligation assay for HSP70 and TLR4, that cells stimulated with ATP have higher formation of fluorescent spots and that MD2 might be required for the complexation of these proteins. The insights provided by our computational approach are potential scaffolds for future in vivo studies investigating the interplay between the TLR4/MD2 complex and HSP70 family members in the cardiovascular system. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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Review

Jump to: Research

12 pages, 1272 KiB

Open AccessReview

Cardiac Protective Role of Heat Shock Protein 27 in the Stress Induced by Drugs of Abuse

by Elena Martínez-Laorden, Javier Navarro-Zaragoza, María Victoria Milanés, María Luisa Laorden and Pilar Almela

Int. J. Mol. Sci. 2020, 21(10), 3623; https://doi.org/10.3390/ijms21103623 - 21 May 2020

Cited by 5 | Viewed by 2974

Abstract

Heat shock proteins (HSP) are induced after different stress situations. Some of these proteins, particularly HSP-27, function as markers to indicate cellular stress or damage and protect the heart during addictive processes. Morphine withdrawal induces an enhancement of sympathetic activity in parallel with [...] Read more.

Heat shock proteins (HSP) are induced after different stress situations. Some of these proteins, particularly HSP-27, function as markers to indicate cellular stress or damage and protect the heart during addictive processes. Morphine withdrawal induces an enhancement of sympathetic activity in parallel with an increased HSP-27 expression and phosphorylation, indicating a severe situation of stress. HSP-27 can interact with different intracellular signaling pathways. Propranolol and SL-327 were able to antagonize the activation of hypothalamic-pituitary adrenal (HPA) axis and the phosphorylation of HSP-27 observed during morphine withdrawal. Therefore, β-adrenergic receptors and the extracellular signal-regulated kinase (ERK) pathway would be involved in HPA axis activity, and consequently, in HSP-27 activation. Finally, selective blockade of corticotrophin releasing factor (CRF)-1 receptor and the genetic deletion of CRF1 receptors antagonize cardiac adaptive changes. These changes are increased noradrenaline (NA) turnover, HPA axis activation and decreased HSP-27 expression and phosphorylation. This suggests a link between the HPA axis and HSP-27. On the other hand, morphine withdrawal increases µ-calpain expression, which in turn degrades cardiac troponin T (cTnT). This fact, together with a co-localization between cTnT and HSP-27, suggests that this chaperone avoids the degradation of cTnT by µ-calpain, correcting the cardiac contractility abnormalities observed during addictive processes. The aim of our research is to review the possible role of HSP-27 in the cardiac changes observed during morphine withdrawal and to understand the mechanisms implicated in its cardiac protective functions. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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15 pages, 1590 KiB

Open AccessReview

Role of the Novel Hsp90 Co-Chaperones in Dynein Arms’ Preassembly

by Hanna Fabczak and Anna Osinka

Int. J. Mol. Sci. 2019, 20(24), 6174; https://doi.org/10.3390/ijms20246174 - 07 Dec 2019

Cited by 21 | Viewed by 5334

Abstract

The outer and inner dynein arms (ODAs and IDAs) are composed of multiple subunits including dynein heavy chains possessing a motor domain. These complex structures are preassembled in the cytoplasm before being transported to the cilia. The molecular mechanism(s) controlling dynein arms’ preassembly [...] Read more.

The outer and inner dynein arms (ODAs and IDAs) are composed of multiple subunits including dynein heavy chains possessing a motor domain. These complex structures are preassembled in the cytoplasm before being transported to the cilia. The molecular mechanism(s) controlling dynein arms’ preassembly is poorly understood. Recent evidence suggests that canonical R2TP complex, an Hsp-90 co-chaperone, in cooperation with dynein axonemal assembly factors (DNAAFs), plays a crucial role in the preassembly of ODAs and IDAs. Here, we have summarized recent data concerning the identification of novel chaperone complexes and their role in dynein arms’ preassembly and their association with primary cilia dyskinesia (PCD), a human genetic disorder. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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29 pages, 10230 KiB

Open AccessReview

Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites

by Tawanda Zininga and Addmore Shonhai

Int. J. Mol. Sci. 2019, 20(23), 5930; https://doi.org/10.3390/ijms20235930 - 25 Nov 2019

Cited by 28 | Viewed by 6645

Abstract

Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological [...] Read more.

Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological conditions associated with the human host and in the arthropod vectors requires the parasites to modulate their metabolic complement in order to meet the prevailing conditions. One of the key features of these parasites essential for their survival and host infectivity is timely expression of various proteins. Even more importantly is the need to keep their proteome functional by maintaining its functional capabilities in the wake of physiological changes and host immune responses. For this reason, molecular chaperones (also called heat shock proteins)—whose role is to facilitate proteostasis—play an important role in the survival of these parasites. Heat shock protein 90 (Hsp90) and Hsp70 are prominent molecular chaperones that are generally induced in response to physiological stress. Both Hsp90 and Hsp70 members are functionally regulated by nucleotides. In addition, Hsp70 and Hsp90 cooperate to facilitate folding of some key proteins implicated in cellular development. In addition, Hsp90 and Hsp70 individually interact with other accessory proteins (co-chaperones) that regulate their functions. The dependency of these proteins on nucleotide for their chaperone function presents an Achille’s heel, as inhibitors that mimic ATP are amongst potential therapeutic agents targeting their function in obligate intracellular human parasites. Most of the promising small molecule inhibitors of parasitic heat shock proteins are either antibiotics or anticancer agents, whose repurposing against parasitic infections holds prospects. Both cancer cells and obligate human parasites depend upon a robust protein quality control system to ensure their survival, and hence, both employ a competent heat shock machinery to this end. Furthermore, some inhibitors that target chaperone and co-chaperone networks also offer promising prospects as antiparasitic agents. The current review highlights the progress made so far in design and application of small molecule inhibitors against obligate intracellular human parasites of the kinetoplastida and apicomplexan kingdoms. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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24 pages, 2296 KiB

Open AccessReview

Heat Shock Proteins in Glioblastoma Biology: Where Do We Stand?

by Rebeca Piatniczka Iglesia, Camila Felix de Lima Fernandes, Bárbara Paranhos Coelho, Mariana Brandão Prado, Maria Isabel Melo Escobar, Gustavo Henrique Doná Rodrigues Almeida and Marilene Hohmuth Lopes

Int. J. Mol. Sci. 2019, 20(22), 5794; https://doi.org/10.3390/ijms20225794 - 18 Nov 2019

Cited by 25 | Viewed by 4524

Abstract

Heat shock proteins (HSPs) are evolutionary conserved proteins that work as molecular chaperones and perform broad and crucial roles in proteostasis, an important process to preserve the integrity of proteins in different cell types, in health and disease. Their function in cancer is [...] Read more.

Heat shock proteins (HSPs) are evolutionary conserved proteins that work as molecular chaperones and perform broad and crucial roles in proteostasis, an important process to preserve the integrity of proteins in different cell types, in health and disease. Their function in cancer is an important aspect to be considered for a better understanding of disease development and progression. Glioblastoma (GBM) is the most frequent and lethal brain cancer, with no effective therapies. In recent years, HSPs have been considered as possible targets for GBM therapy due their importance in different mechanisms that govern GBM malignance. In this review, we address current evidence on the role of several HSPs in the biology of GBMs, and how these molecules have been considered in different treatments in the context of this disease, including their activities in glioblastoma stem-like cells (GSCs), a small subpopulation able to drive GBM growth. Additionally, we highlight recent works that approach other classes of chaperones, such as histone and mitochondrial chaperones, as important molecules for GBM aggressiveness. Herein, we provide new insights into how HSPs and their partners play pivotal roles in GBM biology and may open new therapeutic avenues for GBM based on proteostasis machinery. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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15 pages, 854 KiB

Open AccessReview

The Functions and Therapeutic Potential of Heat Shock Proteins in Inflammatory Bowel Disease—An Update

by Abdullah Hoter and Hassan Y. Naim

Int. J. Mol. Sci. 2019, 20(21), 5331; https://doi.org/10.3390/ijms20215331 - 26 Oct 2019

Cited by 21 | Viewed by 14818

Abstract

Inflammatory bowel disease (IBD) is a multifactorial human intestinal disease that arises from numerous, yet incompletely defined, factors. Two main forms, Crohn’s disease (CD) and ulcerative colitis (UC), lead to a chronic pathological form. Heat shock proteins (HSPs) are stress-responsive molecules involved in [...] Read more.

Inflammatory bowel disease (IBD) is a multifactorial human intestinal disease that arises from numerous, yet incompletely defined, factors. Two main forms, Crohn’s disease (CD) and ulcerative colitis (UC), lead to a chronic pathological form. Heat shock proteins (HSPs) are stress-responsive molecules involved in various pathophysiological processes. Several lines of evidence link the expression of HSPs to the development and prognosis of IBD. HSP90, HSP70 and HSP60 have been reported to contribute to IBD in different aspects. Moreover, induction and/or targeted inhibition of specific HSPs have been suggested to ameliorate the disease consequences. In the present review, we shed the light on the role of HSPs in IBD and their targeting to prevent further disease progression. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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15 pages, 252 KiB

Open AccessReview

Hsp90 and Its Co-Chaperones in Neurodegenerative Diseases

by Anastasiia Bohush, Paweł Bieganowski and Anna Filipek

Int. J. Mol. Sci. 2019, 20(20), 4976; https://doi.org/10.3390/ijms20204976 - 09 Oct 2019

Cited by 61 | Viewed by 5601

Abstract

Proper folding is crucial for proteins to achieve functional activity in the cell. However, it often occurs that proteins are improperly folded (misfolded) and form aggregates, which are the main hallmark of many diseases including cancers, neurodegenerative diseases and many others. Proteins that [...] Read more.

Proper folding is crucial for proteins to achieve functional activity in the cell. However, it often occurs that proteins are improperly folded (misfolded) and form aggregates, which are the main hallmark of many diseases including cancers, neurodegenerative diseases and many others. Proteins that assist other proteins in proper folding into three-dimensional structures are chaperones and co-chaperones. The key role of chaperones/co-chaperones is to prevent protein aggregation, especially under stress. An imbalance between chaperone/co-chaperone levels has been documented in neurons, and suggested to contribute to protein misfolding. An essential protein and a major regulator of protein folding in all eukaryotic cells is the heat shock protein 90 (Hsp90). The function of Hsp90 is tightly regulated by many factors, including co-chaperones. In this review we summarize results regarding the role of Hsp90 and its co-chaperones in neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and prionopathies. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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13 pages, 578 KiB

Open AccessReview

Heat Shock Proteins and Inflammasomes

by Pierre Martine and Cédric Rébé

Int. J. Mol. Sci. 2019, 20(18), 4508; https://doi.org/10.3390/ijms20184508 - 12 Sep 2019

Cited by 39 | Viewed by 4201

Abstract

Heat shock proteins (HSP) regulate inflammation in many physiological contexts. However, inflammation is a broad process, involving numerous cytokines produced by different molecular pathways with multiple functions. In this review, we focused on the particular role of HSP on the inflammasomes intracellular platforms [...] Read more.

Heat shock proteins (HSP) regulate inflammation in many physiological contexts. However, inflammation is a broad process, involving numerous cytokines produced by different molecular pathways with multiple functions. In this review, we focused on the particular role of HSP on the inflammasomes intracellular platforms activated by danger signals and that enable activation of inflammatory caspases, mainly caspase-1, leading to the production of the pro-inflammatory cytokine IL-1β. Interestingly, some members of the HSP family favor inflammasomes activation whereas others inhibit it, suggesting that HSP modulators for therapeutic purposes, must be carefully chosen. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond

by Benjamin J. Lang, Martín Eduardo Guerrero-Giménez, Thomas L. Prince, Andrew Ackerman, Cristina Bonorino and Stuart K. Calderwood

Int. J. Mol. Sci. 2019, 20(18), 4507; https://doi.org/10.3390/ijms20184507 - 11 Sep 2019

Cited by 54 | Viewed by 5921

Abstract

Heat shock protein (HSP) synthesis is switched on in a remarkably wide range of tumor cells, in both experimental animal systems and in human cancer, in which these proteins accumulate in high levels. In each case, elevated HSP concentrations bode ill for the [...] Read more.

Heat shock protein (HSP) synthesis is switched on in a remarkably wide range of tumor cells, in both experimental animal systems and in human cancer, in which these proteins accumulate in high levels. In each case, elevated HSP concentrations bode ill for the patient, and are associated with a poor outlook in terms of survival in most cancer types. The significance of elevated HSPs is underpinned by their essential roles in mediating tumor cell intrinsic traits such as unscheduled cell division, escape from programmed cell death and senescence, de novo angiogenesis, and increased invasion and metastasis. An increased HSP expression thus seems essential for tumorigenesis. Perhaps of equal significance is the pronounced interplay between cancer cells and the tumor milieu, with essential roles for intracellular HSPs in the properties of the stromal cells, and their roles in programming malignant cells and in the release of HSPs from cancer cells to influence the behavior of the adjacent tumor and infiltrating the normal cells. These findings of a triple role for elevated HSP expression in tumorigenesis strongly support the targeting of HSPs in cancer, especially given the role of such stress proteins in resistance to conventional therapies. Full article

(This article belongs to the Special Issue The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics)

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