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Special Issue "Molecular Chaperones 2.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 31 December 2019.

Special Issue Editor

Guest Editor
Prof. Dr. Hideaki Itoh

Department of Life Science, Graduate School and Faculty of Engineering and Resource Science, Akita University, Akita 010-8502, Japan
Website | E-Mail

Special Issue Information

Dear Colleagues,

Homeostasis is essential for maintaining cell function. For that purpose, proteins must fold to their native state in order to achieve functionality. Many heat shock proteins (HSPs) perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by cell stress. Molecular chaperones belong to the family of conservative proteins with a high homology of the primary structure in both the prokaryote and eukaryote. HSPs are often classified according to their molecular weight and members include HSP90, HSP70, HSP60, and the small HSPs. Molecular chaperones have a large functional diversity. Their fundamental roles include de novo folding and the refolding of misfolded protein. Chaperones also regulate critical cellular processes, such as protein trafficking, protein degradation, protein complex assembly, and regulate functional proteins, such as steroid hormone receptors. The uniqueness of molecular chaperones results from their ability to interact with a very large number of different proteins, called clients. HSPs provide protection from cellular and environmental stress factors as molecular chaperones to maintain protein homeostasis. This Special Issue will include original research papers and outstanding reviews that show the role of molecular chaperones in the functionality of homeostasis in the cell.

Prof. Dr. Hideaki Itoh
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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • molecular chaperone
  • Heat shock protein (HSPs)
  • HSP90, HSP70, HSP60
  • de novo folding
  • misfolded protein
  • protein trafficking
  • protein degradation
  • protein complex assembly
  • homeostasis

Published Papers (7 papers)

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Research

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Open AccessArticle
GRP94 Is Involved in the Lipid Phenotype of Brain Metastatic Cells
Int. J. Mol. Sci. 2019, 20(16), 3883; https://doi.org/10.3390/ijms20163883
Received: 23 July 2019 / Revised: 6 August 2019 / Accepted: 6 August 2019 / Published: 9 August 2019
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Abstract
Metabolic adaptation may happen in response to the pressure exerted by the microenvironment and is a key step in survival of metastatic cells. Brain metastasis occurs as a consequence of the systemic dissemination of tumor cells, a fact that correlates with poor prognosis [...] Read more.
Metabolic adaptation may happen in response to the pressure exerted by the microenvironment and is a key step in survival of metastatic cells. Brain metastasis occurs as a consequence of the systemic dissemination of tumor cells, a fact that correlates with poor prognosis and high morbidity due to the difficulty in identifying biomarkers that allow a more targeted therapy. Previously, we performed transcriptomic analysis of human breast cancer patient samples and evaluated the differential expression of genes in brain metastasis (BrM) compared to lung, bone and liver metastasis. Our network approach identified upregulation of glucose-regulated protein 94 (GRP94) as well as proteins related to synthesis of fatty acids (FA) in BrM. Here we report that BrM cells show an increase in FA content and decreased saturation with regard to parental cells measured by Raman spectroscopy that differentiate BrM from other metastases. Moreover, BrM cells exerted a high ability to oxidize FA and compensate hypoglycemic stress due to an overexpression of proteins involved in FA synthesis and degradation (SREBP-1, LXRα, ACOT7). GRP94 ablation restored glucose dependence, down-regulated ACOT7 and SREBP-1 and decreased tumorigenicity in vivo. In conclusion, GRP94 is required for the metabolic stress survival of BrM cells, and it might act as a modulator of lipid metabolism to favor BrM progression. Full article
(This article belongs to the Special Issue Molecular Chaperones 2.0)
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Open AccessArticle
mRNA Engineering for the Efficient Chaperone-Mediated Co-Translational Folding of Recombinant Proteins in Escherichia coli
Int. J. Mol. Sci. 2019, 20(13), 3163; https://doi.org/10.3390/ijms20133163
Received: 6 June 2019 / Revised: 18 June 2019 / Accepted: 21 June 2019 / Published: 28 June 2019
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Abstract
The production of soluble, functional recombinant proteins by engineered bacterial hosts is challenging. Natural molecular chaperone systems have been used to solubilize various recombinant proteins with limited success. Here, we attempted to facilitate chaperone-mediated folding by directing the molecular chaperones to their protein [...] Read more.
The production of soluble, functional recombinant proteins by engineered bacterial hosts is challenging. Natural molecular chaperone systems have been used to solubilize various recombinant proteins with limited success. Here, we attempted to facilitate chaperone-mediated folding by directing the molecular chaperones to their protein substrates before the co-translational folding process completed. To achieve this, we either anchored the bacterial chaperone DnaJ to the 3ʹ untranslated region of a target mRNA by fusing with an RNA-binding domain in the chaperone-recruiting mRNA scaffold (CRAS) system, or coupled the expression of DnaJ and a target recombinant protein using the overlapping stop-start codons 5ʹ-TAATG-3ʹ between the two genes in a chaperone-substrate co-localized expression (CLEX) system. By engineering the untranslated and intergenic sequences of the mRNA transcript, bacterial molecular chaperones are spatially constrained to the location of protein translation, expressing selected aggregation-prone proteins in their functionally active, soluble form. Our mRNA engineering methods surpassed the in-vivo solubilization efficiency of the simple DnaJ chaperone co-overexpression method, thus providing more effective tools for producing soluble therapeutic proteins and enzymes. Full article
(This article belongs to the Special Issue Molecular Chaperones 2.0)
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Open AccessArticle
The Biophysical Interaction of the Danger-Associated Molecular Pattern (DAMP) Calreticulin with the Pattern-Associated Molecular Pattern (PAMP) Lipopolysaccharide
Int. J. Mol. Sci. 2019, 20(2), 408; https://doi.org/10.3390/ijms20020408
Received: 21 November 2018 / Revised: 11 January 2019 / Accepted: 12 January 2019 / Published: 18 January 2019
Cited by 1 | PDF Full-text (3372 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The endoplasmic reticulum (ER) chaperone protein, calreticulin (CRT), is essential for proper glycoprotein folding and maintaining cellular calcium homeostasis. During ER stress, CRT is overexpressed as part of the unfolded protein response (UPR). In addition, CRT can be released as a damage-associated molecular [...] Read more.
The endoplasmic reticulum (ER) chaperone protein, calreticulin (CRT), is essential for proper glycoprotein folding and maintaining cellular calcium homeostasis. During ER stress, CRT is overexpressed as part of the unfolded protein response (UPR). In addition, CRT can be released as a damage-associated molecular pattern (DAMP) molecule that may interact with pathogen-associated molecular patterns (PAMPs) during the innate immune response. One such PAMP is lipopolysaccharide (LPS), a component of the gram-negative bacterial cell wall. In this report, we show that recombinant and native human placental CRT strongly interacts with LPS in solution, solid phase, and the surface of gram-negative and gram-positive bacteria. Furthermore, LPS induces oilgomerization of CRT with a disappearance of the monomeric form. The application of recombinant CRT (rCRT) to size exclusion and anion exchange chromatography shows an atypical heterogeneous elution profile, indicating that LPS affects the conformation and ionic charge of CRT. Interestingly, LPS bound to CRT is detected in sera of bronchiectasis patients with chronic bacterial infections. By ELISA, rCRT dose-dependently bound to solid phase LPS via the N- and C-domain globular head region of CRT and the C-domain alone. The specific interaction of CRT with LPS may be important in PAMP innate immunity. Full article
(This article belongs to the Special Issue Molecular Chaperones 2.0)
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Open AccessArticle
Novel DnaJ Protein Facilitates Thermotolerance of Transgenic Tomatoes
Int. J. Mol. Sci. 2019, 20(2), 367; https://doi.org/10.3390/ijms20020367
Received: 18 December 2018 / Revised: 9 January 2019 / Accepted: 13 January 2019 / Published: 16 January 2019
Cited by 1 | PDF Full-text (5799 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
DnaJ proteins, which are molecular chaperones that are widely present in plants, can respond to various environmental stresses. At present, the function of DnaJ proteins was studied in many plant species, but only a few studies were conducted in tomato. Here, we examined [...] Read more.
DnaJ proteins, which are molecular chaperones that are widely present in plants, can respond to various environmental stresses. At present, the function of DnaJ proteins was studied in many plant species, but only a few studies were conducted in tomato. Here, we examined the functions of a novel tomato (Solanum lycopersicum) DnaJ protein (SlDnaJ20) in heat tolerance using sense and antisense transgenic tomatoes. Transient conversion assays of Arabidopsis protoplasts showed that SlDnaJ20 was targeted to chloroplasts. Expression analysis showed that SlDnaJ20 expression was induced by chilling, NaCl, polyethylene glycol, and H2O2, especially via heat stress. Under heat stress, sense plants showed higher fresh weights, chlorophyll content, fluorescence (Fv/Fm), and D1 protein levels, and a lower accumulation of reactive oxygen species (ROS) than antisense plants. These results suggest that SlDnaJ20 overexpression can reduce the photoinhibition of photosystem II (PSII) by relieving ROS accumulation. Moreover, higher expression levels of HsfA1 and HsfB1 were observed under heat stress in sense plants, indicating that SlDnaJ20 overexpression contributes to HSF expression. The yeast two-hybrid system proved that SlDnaJ20 can interact with the chloroplast heat-shock protein 70. Our results indicate that SlDnaJ20 overexpression enhances the thermotolerance of transgenic tomatoes, whereas suppression of SlDnaJ20 increases the heat sensitivity of transgenic tomatoes. Full article
(This article belongs to the Special Issue Molecular Chaperones 2.0)
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Review

Jump to: Research

Open AccessReview
The Complex Phosphorylation Patterns that Regulate the Activity of Hsp70 and Its Cochaperones
Int. J. Mol. Sci. 2019, 20(17), 4122; https://doi.org/10.3390/ijms20174122 (registering DOI)
Received: 8 August 2019 / Revised: 21 August 2019 / Accepted: 22 August 2019 / Published: 23 August 2019
PDF Full-text (1340 KB)
Abstract
Proteins must fold into their native structure and maintain it during their lifespan to display the desired activity. To ensure proper folding and stability, and avoid generation of misfolded conformations that can be potentially cytotoxic, cells synthesize a wide variety of molecular chaperones [...] Read more.
Proteins must fold into their native structure and maintain it during their lifespan to display the desired activity. To ensure proper folding and stability, and avoid generation of misfolded conformations that can be potentially cytotoxic, cells synthesize a wide variety of molecular chaperones that assist folding of other proteins and avoid their aggregation, which unfortunately is unavoidable under acute stress conditions. A protein machinery in metazoa, composed of representatives of the Hsp70, Hsp40, and Hsp110 chaperone families, can reactivate protein aggregates. We revised herein the phosphorylation sites found so far in members of these chaperone families and the functional consequences associated with some of them. We also discuss how phosphorylation might regulate the chaperone activity and the interaction of human Hsp70 with its accessory and client proteins. Finally, we present the information that would be necessary to decrypt the effect that post-translational modifications, and especially phosphorylation, could have on the biological activity of the Hsp70 system, known as the “chaperone code”. Full article
(This article belongs to the Special Issue Molecular Chaperones 2.0)
Open AccessReview
14-3-3 Proteins Are on the Crossroads of Cancer, Aging, and Age-Related Neurodegenerative Disease
Int. J. Mol. Sci. 2019, 20(14), 3518; https://doi.org/10.3390/ijms20143518
Received: 18 June 2019 / Revised: 15 July 2019 / Accepted: 16 July 2019 / Published: 18 July 2019
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Abstract
14-3-3 proteins are a family of conserved regulatory adaptor molecules which are expressed in all eukaryotic cells. These proteins participate in a variety of intracellular processes by recognizing specific phosphorylation motifs and interacting with hundreds of target proteins. Also, 14-3-3 proteins act as [...] Read more.
14-3-3 proteins are a family of conserved regulatory adaptor molecules which are expressed in all eukaryotic cells. These proteins participate in a variety of intracellular processes by recognizing specific phosphorylation motifs and interacting with hundreds of target proteins. Also, 14-3-3 proteins act as molecular chaperones, preventing the aggregation of unfolded proteins under conditions of cellular stress. Furthermore, 14-3-3 proteins have been shown to have similar expression patterns in tumors, aging, and neurodegenerative diseases. Therefore, we put forward the idea that the adaptor activity and chaperone-like activity of 14-3-3 proteins might play a substantial role in the above-mentioned conditions. Interestingly, 14-3-3 proteins are considered to be standing at the crossroads of cancer, aging, and age-related neurodegenerative diseases. There are great possibilities to improve the above-mentioned diseases and conditions through intervention in the activity of the 14-3-3 protein family. Full article
(This article belongs to the Special Issue Molecular Chaperones 2.0)
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Open AccessReview
The Physics of Entropic Pulling: A Novel Model for the Hsp70 Motor Mechanism
Int. J. Mol. Sci. 2019, 20(9), 2334; https://doi.org/10.3390/ijms20092334
Received: 5 April 2019 / Revised: 6 May 2019 / Accepted: 8 May 2019 / Published: 11 May 2019
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Abstract
Hsp70s use ATP to generate forces that disassemble protein complexes and aggregates, and that translocate proteins into organelles. Entropic pulling has been proposed as a novel mechanism, distinct from the more familiar power-stroke and Brownian ratchet models, for how Hsp70s generate these forces. [...] Read more.
Hsp70s use ATP to generate forces that disassemble protein complexes and aggregates, and that translocate proteins into organelles. Entropic pulling has been proposed as a novel mechanism, distinct from the more familiar power-stroke and Brownian ratchet models, for how Hsp70s generate these forces. Experimental evidence supports entropic pulling, but this model may not be well understood among scientists studying these systems. In this review we address persistent misconceptions regarding the dynamics of proteins in solution that contribute to this lack of understanding, and we clarify the basic physics of entropic pulling with some simple analogies. We hope that increased understanding of the entropic pulling mechanism will inform future efforts to characterize how Hsp70s function as motors, and how they coordinate with their regulatory cochaperones in mechanochemical cycles that transduce the energy of ATP hydrolysis into physical changes in their protein substrates. Full article
(This article belongs to the Special Issue Molecular Chaperones 2.0)
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Graphical abstract

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.

Review: Calnexin/calreticulin cycle: a structural perspective
Authors: Kalle Gehring, Guennadi Kozlov

 

Review: Molecular chaperones in cancer stem cells: determinants of stemness and targets for therapy
Authors: Alexander Kabakov, et al.

 

Review on the chaperone network in human cells is responsible for aggregate reactivation and the potential effects that post-translational modifications might have on its biological activity
Authors: ARTURO MUGA , Fernando Moro, et al.

 

Review on Fine tuning: Effects of post-translational modification on chaperone proteins.
Authors: Holmes, William M.

 

Review on the Role of heat shock proteins in glaucoma
Authors: Teresa Tsai, Pia Grotegut, Sabrina Reinehr, Stephanie C. Joachim

 

Review Inhibitors of  molecular chaperones in recipes of anti-cancer therapeutics
Authors: Maxim Shevtsov, et al.


Title:  Role of the bacterial chaperone DnaK in cellular transformation, by
Authors: Davide Zella, et al.

 

Title:  HSP90 plays a chaperone function using GTPase energy source
Authors: Hideaki Itoh

 

Title: Development of new HSP90 M-domain inhibitors
Authors: Ivanhoe Leung, Oi Wei Mak

 

Title: Immunomorphology and biomolecular evaluation of Heat Shock Proteins in thyroid diseases
Authors: Francesca Rappa, et al.

Title: Neuromuscular diseases due to chaperone dysfunction – a review and some new results
Authors: 
Jaakko Sarparanta, Per-Harald Jonson,   Bjarne Udd, et al.

 

Title: HSP90 inhibition and drug transporter activities in cancer cells
Authors: Vincent E Sollars, et al.

 

Title: Epigenetic alterations for Heat shock protein (HSPs) in Cancer
Authors: Cho Hyun-Soo, et al.

 

Title: The endoplasmic reticulum chaperone GRP94 is involved in the lipidic phenotype of brain metastatic cells
Authors: Naiara Santana-Codina1,2,, Anna Marcé1, Laia Muixí1,, Claudia Nieva1,3, Mónica Marro3, David Sebastián4, Juan Pablo Muñoz4, Antonio Zorzano4, Angels Sierra5, *
1 Biological Clues of the Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona E-08908, Spain.
2 Universitat Autònoma de Barcelona (UAB), Campus Bellaterra, Cerdanyola del Vallés, Barcelona E-08193, Spain.
3 ICFO - Institut de Ciències Fotòniques, Av. Carl Friedrich Gauss, 3. Castelldefels, Barcelona E-08860, Spain
4 Institute for Research in Biomedicine (IRB Barcelona), Universitat de Barcelona, and CIBERDEM, Barcelona, 08028, Catalonia, Spain
5 Laboratory of Molecular and Translational Oncology, Centre de Recerca Biomèdica CELLEX-CRBC- Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Barcelona E-08036, Spain.
ABSTRACT
Background: Metabolic alterations in cancer cells mechanistically underpin many aspects of malignant transformation and therapy resistance. Metabolic rewiring can happen as a consequence of the pressure exerted by the microenvironment, a key step in adaptation and survival of tumor metastatic cells. This phenomenon is even more important in the pathogenesis of brain metastasis, which happens in 40% of all diagnosed cancer cases as a consequence of the systemic dissemination of tumour cells and which correlates with poor prognosis and high morbidity (1). One of the main reasons for this poor prognosis is the difficulty in the identification of biomarkers that allow a more targeted therapy. In order to obtain a list of brain metastatic organ-specific genes, we performed transcriptomic analysis of breast cancer metastasis from patients and evaluated the differential expression of genes in brain metastasis in comparison to lung, bone and liver metastasis (2). To determine organ-specific de-regulated functions, we used a network approach to identify network parameters based on the whole human interactome (topology information) and internal connections between genes (functional
interpretation) (3,4). Over-expression of glucose regulated protein-94 (GRP94) predicted brain metastasis in breast carcinoma patients, either triple negative or ErbB2 positive tumors. Moreover, we identified a differential over-expression of proteins related to synthesis of Total Unsaturated Fatty Acids (TUSFA) in brain metastasis. Here, we investigated the role of GRP94 as a chaperone that mediates adaptation and survival of brain metastatic cells (BRM) to low glucose conditions.
Methods: To analyse the effects of GRP94 expression on progression and on the lipogenic phenotype of BrM, we used metastatic variants from human breast cancer cell lines (MDA-MB-435, MDA-MB-361 and SA52) and the highly brain metastatic cell line BRV5, which was obtained after five in vitro/in vivo rounds. We used Raman spectroscopy as a non-invasive technique to quantify Total Fatty Acids (TFA) and Total Unsaturated Fatty Acids (TUFA). Finally, we assessed fatty acid oxidation by 14C-palmitate oxidation assays and we identified by Western Blot some of the proteins involved in this lipidic phenotype.
Results: BrM cells present an increase in fatty acid content measured by Raman spectroscopy, which correlates with increased expression of proteins involved in fatty acid synthesis like SREBP-1 and LXRα. Furthermore, BrM cells presented a higher ability to oxidize fatty acids in basal and in glucose deprivation conditions, together with increased levels of ACOT-7. This phenotype correlated with increased mitochondrial mass and fusion in BrM cells which may promote higher mitochondrial efficiency. GRP94 knockdown increased glucose dependence and decreased etomoxir sensitivity which correlated with a down regulation ACOT7 in addition to reduce in vivo tumorigenicity.
Conclusions: Here, we show that GRP94 is directly implicated in lipid metabolism of brain metastatic cells. Overall, our data suggest that fatty acid oxidation may be a metabolic strategy to favor BrM growth and overcome stress induced by glucose starvation.

Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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