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International Journal of Molecular... Apr 2021Thyroid cancers are the most common of the endocrine system malignancies and progress must be made in the areas of differential diagnosis and treatment to improve... (Review)
Review
Thyroid cancers are the most common of the endocrine system malignancies and progress must be made in the areas of differential diagnosis and treatment to improve patient management. Advances in the understanding of carcinogenic mechanisms have occurred in various fronts, including studies of the chaperone system (CS). Components of the CS are found to be quantitatively increased or decreased, and some correlations have been established between the quantitative changes and tumor type, prognosis, and response to treatment. These correlations provide the basis for identifying distinctive patterns useful in differential diagnosis and for planning experiments aiming at elucidating the role of the CS in tumorigenesis. Here, we discuss studies of the CS components in various thyroid cancers (TC). The chaperones belonging to the families of the small heat-shock proteins Hsp70 and Hsp90 and the chaperonin of Group I, Hsp60, have been quantified mostly by immunohistochemistry and Western blot in tumor and normal control tissues and in extracellular vesicles. Distinctive differences were revealed between the various thyroid tumor types. The most frequent finding was an increase in the chaperones, which can be attributed to the augmented need for chaperones the tumor cells have because of their accelerated metabolism, growth, and division rate. Thus, chaperones help the tumor cell rather than protect the patient, exemplifying chaperonopathies by mistake or collaborationism. This highlights the need for research on chaperonotherapy, namely the development of means to eliminate/inhibit pathogenic chaperones.
Topics: Animals; Chaperonin 60; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Thyroid Neoplasms
PubMed: 33919591
DOI: 10.3390/ijms22084196 -
Cold Spring Harbor Perspectives in... Nov 2019The continuous refreshment of the proteome is critical to maintain protein homeostasis and to adapt cells to changing conditions. Thus, de novo protein biogenesis by... (Review)
Review
The continuous refreshment of the proteome is critical to maintain protein homeostasis and to adapt cells to changing conditions. Thus, de novo protein biogenesis by ribosomes is vitally important to every cellular system. This process is delicate and error-prone and requires, besides cytosolic chaperones, the guidance by a specialized set of molecular chaperones that bind transiently to the translation machinery and the nascent protein to support early folding events and to regulate cotranslational protein transport. These chaperones include the bacterial trigger factor (TF), the archaeal and eukaryotic nascent polypeptide-associated complex (NAC), and the eukaryotic ribosome-associated complex (RAC). This review focuses on the structures, functions, and substrates of these ribosome-associated chaperones and highlights the most recent findings about their potential mechanisms of action.
Topics: Eukaryotic Cells; Molecular Chaperones; Protein Biosynthesis; Protein Transport; Ribosomes
PubMed: 30833456
DOI: 10.1101/cshperspect.a033977 -
Cold Spring Harbor Perspectives in... Oct 2019Maintenance of a healthy and functional proteome in all cellular compartments is critical to cell and organismal homeostasis. Yet, our understanding of the proteostasis... (Review)
Review
Maintenance of a healthy and functional proteome in all cellular compartments is critical to cell and organismal homeostasis. Yet, our understanding of the proteostasis process within the nucleus is limited. Here, we discuss the identified roles of the major molecular chaperones Hsp90, Hsp70, and Hsp60 with client proteins working in diverse DNA-associated pathways. The unique challenges facing proteins in the nucleus are considered as well as the conserved features of the molecular chaperone system in facilitating DNA-linked processes. As nuclear protein inclusions are a common feature of protein-aggregation diseases (e.g., neurodegeneration), a better understanding of nuclear proteostasis is warranted.
Topics: Cell Nucleus; DNA; Humans; Molecular Chaperones; Nuclear Proteins
PubMed: 30745291
DOI: 10.1101/cshperspect.a034009 -
Free Radical Biology & Medicine Feb 2022Molecular chaperones are a family of proteins that maintain cellular protein homeostasis through non-covalent peptide folding and quality control mechanisms. The... (Review)
Review
Molecular chaperones are a family of proteins that maintain cellular protein homeostasis through non-covalent peptide folding and quality control mechanisms. The chaperone proteins found within mitochondria play significant protective roles in mitochondrial biogenesis, quality control, and stress response mechanisms. Defective mitochondrial chaperones have been implicated in aging, neurodegeneration, and cancer. In this review, we focus on the two most prominent mitochondrial chaperones: mtHsp60 and mtHsp70. These proteins demonstrate different cellular localization patterns, interact with different targets, and have different functional activities. We discuss the structure and function of these prominent mitochondrial chaperone proteins and give an update on newly discovered regulatory mechanisms and disease implications.
Topics: HSP70 Heat-Shock Proteins; Humans; Mitochondria; Mitochondrial Proteins; Molecular Chaperones; Protein Folding
PubMed: 34780988
DOI: 10.1016/j.freeradbiomed.2021.11.015 -
Biomolecules Aug 2022The heat shock protein 90 (Hsp90) is a molecular chaperone and a key regulator of proteostasis under both physiological and stress conditions. In mammals, there are two... (Review)
Review
The heat shock protein 90 (Hsp90) is a molecular chaperone and a key regulator of proteostasis under both physiological and stress conditions. In mammals, there are two cytosolic Hsp90 isoforms: Hsp90α and Hsp90β. These two isoforms are 85% identical and encoded by two different genes. Hsp90β is constitutively expressed and essential for early mouse development, while Hsp90α is stress-inducible and not necessary for survivability. These two isoforms are known to have largely overlapping functions and to interact with a large fraction of the proteome. To what extent there are isoform-specific functions at the protein level has only relatively recently begun to emerge. There are studies indicating that one isoform is more involved in the functionality of a specific tissue or cell type. Moreover, in many diseases, functionally altered cells appear to be more dependent on one particular isoform. This leaves space for designing therapeutic strategies in an isoform-specific way, which may overcome the unfavorable outcome of pan-Hsp90 inhibition encountered in previous clinical trials. For this to succeed, isoform-specific functions must be understood in more detail. In this review, we summarize the available information on isoform-specific functions of mammalian Hsp90 and connect it to possible clinical applications.
Topics: Animals; HSP90 Heat-Shock Proteins; Mice; Molecular Chaperones; Protein Isoforms; Proteome
PubMed: 36139005
DOI: 10.3390/biom12091166 -
Molecular Cell Jun 2021From biosynthesis to assembly into nucleosomes, histones are handed through a cascade of histone chaperones, which shield histones from non-specific interactions....
From biosynthesis to assembly into nucleosomes, histones are handed through a cascade of histone chaperones, which shield histones from non-specific interactions. Whether mechanisms exist to safeguard the histone fold during histone chaperone handover events or to release trapped intermediates is unclear. Using structure-guided and functional proteomics, we identify and characterize a histone chaperone function of DNAJC9, a heat shock co-chaperone that promotes HSP70-mediated catalysis. We elucidate the structure of DNAJC9, in a histone H3-H4 co-chaperone complex with MCM2, revealing how this dual histone and heat shock co-chaperone binds histone substrates. We show that DNAJC9 recruits HSP70-type enzymes via its J domain to fold histone H3-H4 substrates: upstream in the histone supply chain, during replication- and transcription-coupled nucleosome assembly, and to clean up spurious interactions. With its dual functionality, DNAJC9 integrates ATP-resourced protein folding into the histone supply pathway to resolve aberrant intermediates throughout the dynamic lives of histones.
Topics: Cell Line, Tumor; Chromatin; Chromatin Assembly and Disassembly; DNA Replication; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HeLa Cells; Histone Chaperones; Histones; Humans; Minichromosome Maintenance Complex Component 2; Models, Molecular; Molecular Chaperones; Nucleosomes; Protein Binding; Proteomics
PubMed: 33857403
DOI: 10.1016/j.molcel.2021.03.041 -
Journal of Molecular Histology Apr 2023The chaperone system (CS) of an organism is composed of molecular chaperones, chaperone co-factors, co-chaperones, and chaperone receptors and interactors. It is present... (Review)
Review
The chaperone system (CS) of an organism is composed of molecular chaperones, chaperone co-factors, co-chaperones, and chaperone receptors and interactors. It is present throughout the body but with distinctive features for each cell and tissue type. Previous studies pertaining to the CS of the salivary glands have determined the quantitative and distribution patterns for several members, the chaperones, in normal and diseased glands, focusing on tumors. Chaperones are cytoprotective, but can also be etiopathogenic agents causing diseases, the chaperonopathies. Some chaperones such as Hsp90 potentiate tumor growth, proliferation, and metastasization. Quantitative data available on this chaperone in salivary gland tissue with inflammation, and benign and malignant tumors suggest that assessing tissue Hsp90 levels and distribution patterns is useful for differential diagnosis-prognostication, and patient follow up. This, in turn, will reveal clues for developing specific treatment centered on the chaperone, for instance by inhibiting its pro-carcinogenic functions (negative chaperonotherapy). Here, we review data on the carcinogenic mechanisms of Hsp90 and their inhibitors. Hsp90 is the master regulator of the PI3K-Akt-NF-kB axis that promotes tumor cell proliferation and metastasization. We discuss pathways and interactions involving these molecular complexes in tumorigenesis and review Hsp90 inhibitors that have been tested in search of an efficacious anti-cancer agent. This targeted therapy deserves extensive investigation in view of its theoretical potential and some positive practical results and considering the need of novel treatments for tumors of the salivary glands as well as other tissues.
Topics: Humans; Phosphatidylinositol 3-Kinases; Molecular Chaperones; HSP90 Heat-Shock Proteins; Neoplasms
PubMed: 36933095
DOI: 10.1007/s10735-023-10119-8 -
FEBS Letters Jul 2023Fluctuations in nutrient and biomass availability, often as a result of disease, impart metabolic challenges that must be overcome in order to sustain cell survival and... (Review)
Review
Fluctuations in nutrient and biomass availability, often as a result of disease, impart metabolic challenges that must be overcome in order to sustain cell survival and promote proliferation. Cells adapt to these environmental changes and stresses by adjusting their metabolic networks through a series of regulatory mechanisms. Our understanding of these rewiring events has largely been focused on those genetic transformations that alter protein expression and the biochemical mechanisms that change protein behavior, such as post-translational modifications and metabolite-based allosteric modulators. Mounting evidence suggests that a class of proteome surveillance proteins called molecular chaperones also can influence metabolic processes. Here, we summarize several ways the Hsp90 and Hsp70 chaperone families act on human metabolic enzymes and their supramolecular assemblies to change enzymatic activities and metabolite flux. We further highlight how these chaperones can assist in the translocation and degradation of metabolic enzymes. Collectively, these studies provide a new view for how metabolic processes are regulated to meet cellular demand and inspire new avenues for therapeutic intervention.
Topics: Humans; Protein Folding; Molecular Chaperones; HSP90 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Protein Processing, Post-Translational
PubMed: 37287189
DOI: 10.1002/1873-3468.14682 -
Biomedicine & Pharmacotherapy =... Mar 2022Protein misfolding causes aggregation and build-up in a variety of brain diseases. There are numeral molecules that are linked with the protein homeostasis mechanism.... (Review)
Review
Protein misfolding causes aggregation and build-up in a variety of brain diseases. There are numeral molecules that are linked with the protein homeostasis mechanism. Molecular chaperones are one of such molecules that are responsible for protection against protein misfolded and aggregation-induced neurotoxicity. Many studies have explored the participation of molecular chaperones in Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, and Huntington's diseases. In this review, we highlighted the constructive role of molecular chaperones in neurological diseases characterized by protein misfolding and aggregation and their capability to control aberrant protein interactions at an early stage thus successfully suppressing pathogenic cascades. A comprehensive understanding of the protein misfolding associated with brain diseases and the molecular basis of involvement of chaperone against aggregation-induced cellular stress might lead to the progress of new therapeutic intrusion-related to protein misfolding and aggregation.
Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Autophagy; Brain; Huntington Disease; Molecular Chaperones; Parkinson Disease; Proteasome Endopeptidase Complex; Proteostasis; Proteostasis Deficiencies; Ubiquitin; Humans
PubMed: 35149361
DOI: 10.1016/j.biopha.2022.112647 -
Medicinal Research Reviews Nov 2022The 94 kDa molecular chaperone, glucose-regulated protein 94 (Grp94), has garnered interest during the last decade due to its direct association with endoplasmic... (Review)
Review
The 94 kDa molecular chaperone, glucose-regulated protein 94 (Grp94), has garnered interest during the last decade due to its direct association with endoplasmic reticulum (ER) stress and disease. Grp94 belongs to the Hsp90 family of molecular chaperones and is a master regulator of ER homeostasis due to its ability to fold and stabilize proteins/receptors, and to chaperone misfolded proteins for degradation. Multiple studies have demonstrated that Grp94 knockdown or inhibition leads to the degradation of client protein substrates, which leads to disruption of disease-dependent signaling pathways. As a result, small molecule inhibitors of Grp94 have become a promising therapeutic approach to target a variety of disease states. Specifically, Grp94 has proven to be a promising target for cancer, glaucoma, immune-mediated inflammation, and viral infection. Moreover, Grp94-peptide complexes have been utilized effectively as adjuvants for vaccines against a variety of disease states. This work highlights the significance of Grp94 biology and the development of therapeutics that target this molecular chaperone in multiple disease states.
Topics: Biology; HSP70 Heat-Shock Proteins; Humans; Membrane Glycoproteins; Membrane Proteins; Molecular Chaperones
PubMed: 35861260
DOI: 10.1002/med.21915