Search Results (16)

The heat shock protein 60 (Hsp60) is a highly conserved molecular chaperonin belonging to the chaperone system, a complex network that maintains proteostasis and regulates numerous cellular processes beyond protein folding. Initially described as a mitochondrial protein essential for the folding of newly imported polypeptides, Hsp60 is now recognized as a multifunctional molecule. Its expression, localization, and post-translational modifications dynamically influence cell fate and tissue homeostasis. Alterations in Hsp60 quantity, structure, or distribution underlie a heterogeneous group of disorders known as chaperonopathies, which may occur “by defect,” “by excess,” or “by mistake” (also called “by collaborationism”). Genetic Hsp60’s chaperonopathies are associated with rare neurodegenerative and cardiovascular diseases, whereas acquired forms contribute to widespread conditions, including autoimmune, inflammatory, and malignant pathologies. This review provides a comprehensive overview of Hsp60 biology across human systems, emphasizing its structural plasticity, context-dependent functions, and dual role in health as both a biomarker and a therapeutic target. The emerging paradigm of chaperonotherapy, encompassing positive strategies to restore protective chaperones and negative strategies to inhibit pathogenic ones, highlights the translational potential of targeting Hsp60. Understanding the molecular mechanisms governing its activity will be essential for developing precision medicine approaches aimed at modulating the chaperone system in human disease. Full article

Molecular chaperones, especially Heat Shock Proteins (HSPs), play complex, context-dependent roles in cancer, particularly in nervous system (NS) tumors like glioblastoma (GBM) and neuroblastoma (NB). They are often upregulated, promoting tumor growth, poor prognosis, and resistance to therapy and immune responses. This supports the potential of negative chaperonotherapy, aimed at inhibiting them. However, some studies suggest chaperones can also act as tumor suppressors in certain cancers, indicating that positive chaperonotherapy—enhancing or restoring their function—may be beneficial. For NS tumors, this latter area is still understudied. With emphasis on GBM and NB, in this review we address the potential of molecular chaperones, particularly HSPs, as therapeutic targets or agents. We discuss strategies to inhibit pro-tumorigenic chaperones as well as the underexplored potential of chaperone induction and immunomodulation. Ultimately, we examine the emerging use of pharmacological and chemical chaperones to improve treatment outcomes in these NS tumors. These strategies, whether applied alone or in combination, may offer significant benefits for GBM and NB, which are presently among the most aggressive and challenging tumors to manage. Full article

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by self-immune tolerance breakdown and the production of autoantibodies, causing the deposition of immune complexes and triggering inflammation and immune-mediated damage. SLE pathogenesis involves genetic predisposition and a combination of environmental factors. Clinical manifestations are variable, making an early diagnosis challenging. Heat shock proteins (Hsps), belonging to the chaperone system, interact with the immune system, acting as pro-inflammatory factors, autoantigens, as well as immune tolerance promoters. Increased levels of some Hsps and the production of autoantibodies against them are correlated with SLE onset and progression. The production of these autoantibodies has been attributed to molecular mimicry, occurring upon viral and bacterial infections, since they are evolutionary highly conserved. Gut microbiota dysbiosis has been associated with the occurrence and severity of SLE. Numerous findings suggest that proteins and metabolites of commensal bacteria can mimic autoantigens, inducing autoimmunity, because of molecular mimicry. Here, we propose that shared epitopes between human Hsps and those of gut commensal bacteria cause the production of anti-Hsp autoantibodies that cross-react with human molecules, contributing to SLE pathogenesis. Thus, the involvement of the chaperone system, gut microbiota dysbiosis, and molecular mimicry in SLE ought to be coordinately studied. Full article

The putative pathogenic roles and therapeutic potential of the chaperone system (CS) in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are reviewed to provide a bibliographic and conceptual platform for launching research on the diagnostic and therapeutic applications of CS components. Various studies suggest that dysfunction of the CS contributes to the pathogenesis of ALS and MS, and here, we identify some of the implicated CS members. The physiology and pathophysiology of the CS members can be properly understood if they are studied or experimentally or clinically manipulated for diagnostic or therapeutic purposes, bearing in mind that they belong to a physiological system with multiple interacting and dynamic components, widespread throughout the body, intra- and extracellularly. Molecular chaperones, some called heat shock protein (Hsp), are the chief components of the CS, whose canonical functions are cytoprotective. However, abnormal chaperones can be etiopathogenic factors in a wide range of disorders, chaperonopathies, including ALS and MS, according to the data reviewed. Chaperones typically form teams, and these build functional networks to maintain protein homeostasis, the canonical role of the CS. However, members of the CS also display non-canonical functions unrelated to protein homeostasis. Therefore, chaperones and other members of the CS, if abnormal, may disturb not only protein synthesis, maturation, and migration but also other physiological processes. Thus, in elucidating the role of CS components in ALS and MS, one must look at protein homeostasis abnormalities and beyond, following the clues emerging from the works discussed here. Full article

The chaperone system (CS) is emerging as a key multistage participant in carcinogenesis. The CS chief components are the molecular chaperones (some of which are named heat shock proteins or Hsp), which are typically cytoprotective but if abnormal in structure, location, or quantity, can become etiopathogenic and cause diseases, known as chaperonopathies, including some cancers. For example, abnormal Hsp90 expression is associated with tumorigenesis and poor prognosis. Hsp90 is positioned at the center of several key oncogenic pathways by stabilizing and activating oncogenic kinases responsible for driving cell proliferation and survival. Consequently, inhibition of Hsp90 is being investigated as a possible anti-cancer strategy and some results are encouraging. However, the 5-year survival rate for patients suffering from salivary gland carcinomas is still unsatisfactory. Because of the rarity of these malignancies, they may have been overlooked and understudied and, thus, novel therapies (e.g., inhibition of CS components like Hsp90 and others) are urgently needed. In this review, we also summarize the histopathological quantitative patterns and the intra- and extra-cellular location characteristics of Hsp90 in tumors of salivary glands, pointing to their potential for differential diagnosis, prognostication, and patient monitoring. Full article

Genetic chaperonopathies are rare but, because of misdiagnosis, there are probably more cases than those that are recorded in the literature and databases. This occurs because practitioners are generally unaware of the existence and/or the symptoms and signs of chaperonopathies. It is necessary to educate the medical community about these diseases and, with research, to unveil their mechanisms. The structure and functions of various chaperones in vitro have been studied, but information on the impact of mutant chaperones in humans, in vivo, is scarce. Here, we present a succinct review of the most salient abnormalities of skeletal muscle, based on our earlier report of a patient who carried a mutation in the chaperonin CCT5 subunit and suffered from a distal motor neuropathy of early onset. We discuss our results in relation to the very few other published pertinent reports we were able to find. A complex picture of multiple muscle-tissue abnormalities was evident, with signs of atrophy, apoptosis, and abnormally low levels and atypical distribution patterns of some components of muscle and the chaperone system. In-silico analysis predicts that the mutation affects CCT5 in a way that could interfere with the recognition and handling of substrate. Thus, it is possible that some of the abnormalities are the direct consequence of defective chaperoning, but others may be indirectly related to defective chaperoning or caused by other different pathogenic pathways. Biochemical, and molecular biologic and genetic analyses should now help in understanding the mechanisms underpinning the histologic abnormalities and, thus, provide clues to facilitate diagnosis and guide the development of therapeutic tools. Full article

Mutations in genes encoding molecular chaperones, for instance the genes encoding the subunits of the chaperonin CCT (chaperonin containing TCP-1, also known as TRiC), are associated with rare neurodegenerative disorders. Using a classical molecular dynamics approach, we investigated the occurrence of conformational changes and differences in physicochemical properties of the CCT5 mutations His147Arg and Leu224Val associated with a sensory and a motor distal neuropathy, respectively. The apical domain of both variants was substantially but differently affected by the mutations, although these were in other domains. The distribution of hydrogen bonds and electrostatic potentials on the surface of the mutant subunits differed from the wild-type molecule. Structural and dynamic analyses, together with our previous experimental data, suggest that genetic mutations may cause different changes in the protein-binding capacity of CCT5 variants, presumably within both hetero- and/or homo-oligomeric complexes. Further investigations are necessary to elucidate the molecular pathogenic pathways of the two variants that produce the two distinct phenotypes. The data and clinical observations by us and others indicate that CCT chaperonopathies are more frequent than currently believed and should be investigated in patients with neuropathies. Full article

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. Full article

Brain tumors have a poor prognosis and progress must be made for developing efficacious treatments, but for this to occur their biology and interaction with the host must be elucidated beyond current knowledge. What has been learned from other tumors may be applied to study brain tumors, for example, the role of Hsp60, miRNAs, and extracellular vesicles (EVs) in the mechanisms of cell proliferation and dissemination, and resistance to immune attack and anticancer drugs. It has been established that Hsp60 increases in cancer cells, in which it occurs not only in the mitochondria but also in the cytosol and plasma-cell membrane and it is released in EVs into the extracellular space and in circulation. There is evidence suggesting that these EVs interact with cells near and far from their original cell and that this interaction has an impact on the functions of the target cell. It is assumed that this crosstalk between cancer and host cells favors carcinogenesis in various ways. We, therefore, propose to study the triad Hsp60-related miRNAs-EVs in brain tumors and have standardized methods for the purpose. These revealed that EVs with Hsp60 and related miRNAs increase in patients’ blood in a manner that reflects disease status. The means are now available to monitor brain tumor patients by measuring the triad and to dissect its effects on target cells in vitro, and in experimental models in vivo. Full article

Hsp60 is one of the most ancient and evolutionarily conserved members of the chaperoning system. It typically resides within mitochondria, in which it contributes to maintaining the organelle’s proteome integrity and homeostasis. In the last few years, it has been shown that Hsp60 also occurs in other locations, intracellularly and extracellularly, including cytosol, plasma-cell membrane, and extracellular vesicles (EVs). Consequently, non-canonical functions and interacting partners of Hsp60 have been identified and it has been realized that it is a hub molecule in diverse networks and pathways and that it is implicated, directly or indirectly, in the development of various pathological conditions, the Hsp60 chaperonopathies. In this review, we will focus on the multi-faceted role of this chaperonin in human cancers, showing the contribution of intra- and extracellular Hsp60 in cancer development and progression, as well as the impact of miRNA-mediated regulation of Hsp60 in carcinogenesis. There are still various aspects of this intricate biological scenario that are poorly understood but ongoing research is steadily providing new insights and we will direct attention to them. For instance, we will highlight the possible applications of the Hsp60 involvement in carcinogenesis not only in diagnosis, but also in the development of specific anti-cancer therapies centered on the use of the chaperonin as therapeutic target or agent and depending on its role, pro- or anti-tumor. Full article

The chaperone (or chaperoning) system (CS) constitutes molecular chaperones, co-chaperones, and chaperone co-factors, interactors and receptors, and its canonical role is protein quality control. A malfunction of the CS may cause diseases, known as the chaperonopathies. These are caused by qualitatively and/or quantitatively abnormal molecular chaperones. Since the CS is ubiquitous, chaperonopathies are systemic, affecting various tissues and organs, playing an etiologic-pathogenic role in diverse conditions. In this review, we focus on chaperonopathies involved in the pathogenic mechanisms of diseases of the central and peripheral nervous systems: the neurochaperonopathies (NCPs). Genetic NCPs are linked to pathogenic variants of chaperone genes encoding, for example, the small Hsp, Hsp10, Hsp40, Hsp60, and CCT-BBS (chaperonin-containing TCP-1- Bardet–Biedl syndrome) chaperones. Instead, the acquired NCPs are associated with malfunctional chaperones, such as Hsp70, Hsp90, and VCP/p97 with aberrant post-translational modifications. Awareness of the chaperonopathies as the underlying primary or secondary causes of disease will improve diagnosis and patient management and open the possibility of investigating and developing chaperonotherapy, namely treatment with the abnormal chaperone as the main target. Positive chaperonotherapy would apply in chaperonopathies by defect, i.e., chaperone insufficiency, and consist of chaperone replacement or boosting, whereas negative chaperonotherapy would be pertinent when a chaperone actively participates in the initiation and progression of the disease and must be blocked and eliminated. Full article

Neuroinflammation is implicated in central nervous system (CNS) diseases, but the molecular mechanisms involved are poorly understood. Progress may be accelerated by developing a comprehensive view of the pathogenesis of CNS disorders, including the immune and the chaperone systems (IS and CS). The latter consists of the molecular chaperones; cochaperones; and chaperone cofactors, interactors, and receptors of an organism and its main collaborators in maintaining protein homeostasis (canonical function) are the ubiquitin–proteasome system and chaperone-mediated autophagy. The CS has also noncanonical functions, for instance, modulation of the IS with induction of proinflammatory cytokines. This deserves investigation because it may be at the core of neuroinflammation, and elucidation of its mechanism will open roads toward developing efficacious treatments centered on molecular chaperones (i.e., chaperonotherapy). Here, we discuss information available on the role of three members of the CS—heat shock protein (Hsp)60, Hsp70, and Hsp90—in IS modulation and neuroinflammation. These three chaperones occur intra- and extracellularly, with the latter being the most likely involved in neuroinflammation because they can interact with the IS. We discuss some of the interactions, their consequences, and the molecules involved but many aspects are still incompletely elucidated, and we hope that this review will encourage research based on the data presented to pave the way for the development of chaperonotherapy. This may consist of blocking a chaperone that promotes destructive neuroinflammation or replacing or boosting a defective chaperone with cytoprotective activity against neurodegeneration. Full article

The COVID-19 pandemic made imperative the search for means to end it, which requires a knowledge of the mechanisms underpinning the multiplication and spread of its cause, the coronavirus SARS-CoV-2. Many viruses use members of the hosts’ chaperoning system to infect the target cells, replicate, and spread, and here we present illustrative examples. Unfortunately, the role of chaperones in the SARS-CoV-2 cycle is still poorly understood. In this review, we examine the interactions of various coronaviruses during their infectious cycle with chaperones in search of information useful for future research on SARS-CoV-2. We also call attention to the possible role of molecular mimicry in the development of autoimmunity and its widespread pathogenic impact in COVID-19 patients. Viral proteins share highly antigenic epitopes with human chaperones, eliciting anti-viral antibodies that crossreact with the chaperones. Both, the critical functions of chaperones in the infectious cycle of viruses and the possible role of these molecules in COVID-19 autoimmune phenomena, make clear that molecular chaperones are promising candidates for the development of antiviral strategies. These could consist of inhibiting-blocking those chaperones that are necessary for the infectious viral cycle, or those that act as autoantigens in the autoimmune reactions causing generalized destructive effects on human tissues. Full article

Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, Hsp60) and II (e.g., Chaperonin Containing T-Complex polypeptide 1, CCT). Examples of the former are hypomyelinating leukodystrophy 4 (HLD4 or MitCHAP60) and hereditary spastic paraplegia (SPG13). A distal sensory mutilating neuropathy has been linked to a mutation [p.(His147Arg)] in subunit 5 of the CCT5 gene. Here, we describe a new possibly pathogenic variant [p.(Leu224Val)] of the same subunit but with a different phenotype. This yet undescribed disease affects a girl with early onset demyelinating neuropathy and a severe motor disability. By whole exome sequencing (WES), we identified a homozygous CCT5 c.670C>G p.(Leu224Val) variant in the CCT5 gene. In silico 3D-structure analysis and bioinformatics indicated that this variant could undergo abnormal conformation and could be pathogenic. We compared the patient’s clinical, neurophysiological and laboratory data with those from patients carrying p.(His147Arg) in the equatorial domain. Our patient presented signs and symptoms absent in the p.(His147Arg) cases. Molecular dynamics simulation and modelling showed that the Leu224Val mutation that occurs in the CCT5 intermediate domain near the apical domain induces a conformational change in the latter. Noteworthy is the striking difference between the phenotypes putatively linked to mutations in the same CCT subunit but located in different structural domains, offering a unique opportunity for elucidating their distinctive roles in health and disease Full article

The process of axon myelination involves various proteins including molecular chaperones. Myelin alteration is a common feature in neurological diseases due to structural and functional abnormalities of one or more myelin proteins. Genetic proteinopathies may occur either in the presence of a normal chaperoning system, which is unable to assist the defective myelin protein in its folding and migration, or due to mutations in chaperone genes, leading to functional defects in assisting myelin maturation/migration. The latter are a subgroup of genetic chaperonopathies causing demyelination. In this brief review, we describe some paradigmatic examples pertaining to the chaperonins Hsp60 (HSPD1, or HSP60, or Cpn60) and CCT (chaperonin-containing TCP-1). Our aim is to make scientists and physicians aware of the possibility and advantages of classifying patients depending on the presence or absence of a chaperonopathy. In turn, this subclassification will allow the development of novel therapeutic strategies (chaperonotherapy) by using molecular chaperones as agents or targets for treatment. Full article