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Special Issue "The Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutics"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 September 2019.

Special Issue Editor

Guest Editor
Prof. Dr. Gregory Blatch E-Mail
The University of Notre Dame Australia, Fremantle, Western Australia, Australia
Interests: cell stress and chaperones; heat shock proteins; cancer; malaria

Special Issue Information

Dear Colleagues,

Many heat shock proteins (HSPs) are essential to survival, and play a critical role as molecular chaperones in maintaining cellular proteostasis through the integration of protein folding and degradation pathways. There have been extensive advances in our understanding of the mechanism by which co-chaperones regulate molecular chaperones. However, it is becoming generally accepted that HSPs have additional cellular functions beyond their role in proteostasis, and we are only just beginning to understand their biological function from a whole-of-organism perspective. HSPs are also linked to a range of different human disorders (e.g., cancer, diabetes, autoimmune disease, neurodegeneration, muscular dystrophies, and chronic heart failure) and infectious diseases (e.g., viral, microbial, and parasitic infections including malaria and trypanosomiasis), with changes in their expression and localisation linked to disease pathology. Contributions to this Special Issue will provide new insights into the mechanism of action of HSPs, deepen our understanding of their biological role in health and disease, and reveal novel HSP-based therapeutic opportunities.

Prof. Dr. Gregory Blatch
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • heat shock proteins
  • molecular chaperones
  • co-chaperones
  • protein folding
  • chronic diseases
  • infectious diseases

Published Papers (4 papers)

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Research

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Open AccessArticle
Stress-Induced, p53-Mediated Tumor Growth Inhibition of Melanoma by Modulated Electrohyperthermia in Mouse Models without Major Immunogenic Effects
Int. J. Mol. Sci. 2019, 20(16), 4019; https://doi.org/10.3390/ijms20164019 - 17 Aug 2019
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 p21waf1 and p27kip. 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
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Open AccessArticle
Unveiling the Interplay between the TLR4/MD2 Complex and HSP70 in the Human Cardiovascular System: A Computational Approach
Int. J. Mol. Sci. 2019, 20(13), 3121; https://doi.org/10.3390/ijms20133121 - 26 Jun 2019
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
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Review

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Open AccessReview
Heat Shock Proteins and Inflammasomes
Int. J. Mol. Sci. 2019, 20(18), 4508; https://doi.org/10.3390/ijms20184508 - 12 Sep 2019
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
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Open AccessReview
Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond
Int. J. Mol. Sci. 2019, 20(18), 4507; https://doi.org/10.3390/ijms20184507 - 11 Sep 2019
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
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