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Life Sciences Jun 2019Glucose-Regulated Protein 78 (GRP78) is a chaperone heat shock protein that has been intensely studied in the last two decades. GRP78 is the master of the unfolded... (Review)
Review
BACKGROUND
Glucose-Regulated Protein 78 (GRP78) is a chaperone heat shock protein that has been intensely studied in the last two decades. GRP78 is the master of the unfolded protein response (UBR) in the Endoplasmic Reticulum (ER) in normal cells. GRP78 force the unfolded proteins to refold or degrade using cellular degradation mechanisms.
SCOPE
Under stress, the overexpression of GRP78 on the cell membrane mediates the vast amount of disordered proteins. Unfortunately, this makes it a tool for pathogens (bacterial, fungal and viral) to enter the cell and to start different pathways leading to pathogenesis. Additionally, GRP78 is overexpressed on the membranes of various cancer cells and increase the aggressiveness of the disease.
MAJOR CONCLUSIONS
The current review summarizes structure, function, and different mechanisms GRP78 mediate in response to normal or stress conditions.
GENERAL SIGNIFICANCE
GRP78 targeting and possible inhibition mechanisms are also covered in the present review aiming to prevent the virulence of pathogens and cancer.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; HSP70 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Molecular Chaperones; Unfolded Protein Response
PubMed: 30978349
DOI: 10.1016/j.lfs.2019.04.022 -
Molecules (Basel, Switzerland) Nov 2018Heat shock proteins (Hsps) are conserved molecules whose main role is to facilitate folding of other proteins. Most Hsps are generally stress-inducible as they play a... (Review)
Review
Heat shock proteins (Hsps) are conserved molecules whose main role is to facilitate folding of other proteins. Most Hsps are generally stress-inducible as they play a particularly important cytoprotective role in cells exposed to stressful conditions. Initially, Hsps were generally thought to occur intracellulary. However, recent work has shown that some Hsps are secreted to the cell exterior particularly in response to stress. For this reason, they are generally regarded as danger signaling biomarkers. In this way, they prompt the immune system to react to prevailing adverse cellular conditions. For example, their enhanced secretion by cancer cells facilitate targeting of these cells by natural killer cells. Notably, Hsps are implicated in both pro-inflammatory and anti-inflammatory responses. Their effects on immune cells depends on a number of aspects such as concentration of the respective Hsp species. In addition, various Hsp species exert unique effects on immune cells. Because of their conservation, Hsps are implicated in auto-immune diseases. Here we discuss the various metabolic pathways in which various Hsps manifest immune modulation. In addition, we discuss possible experimental variations that may account for contradictory reports on the immunomodulatory function of some Hsps.
Topics: Animals; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Immunologic Factors; Immunomodulation
PubMed: 30388847
DOI: 10.3390/molecules23112846 -
Philosophical Transactions of the Royal... Jan 2018The molecular chaperone heat shock protein 90 (Hsp90) facilitates metastable protein maturation, stabilization of aggregation-prone proteins, quality control of... (Review)
Review
The molecular chaperone heat shock protein 90 (Hsp90) facilitates metastable protein maturation, stabilization of aggregation-prone proteins, quality control of misfolded proteins and assists in keeping proteins in activation-competent conformations. Proteins that rely on Hsp90 for function are delivered to Hsp90 utilizing a co-chaperone-assisted cycle. Co-chaperones play a role in client transfer to Hsp90, Hsp90 ATPase regulation and stabilization of various Hsp90 conformational states. Many of the proteins chaperoned by Hsp90 (Hsp90 clients) are essential for the progression of various diseases, including cancer, Alzheimer's disease and other neurodegenerative diseases, as well as viral and bacterial infections. Given the importance of these clients in different diseases and their dynamic interplay with the chaperone machinery, it has been suggested that targeting Hsp90 and its respective co-chaperones may be an effective method for combating a large range of illnesses.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.
Topics: Animals; HSP90 Heat-Shock Proteins; Humans; Mammals
PubMed: 29203712
DOI: 10.1098/rstb.2016.0527 -
Journal of Molecular Biology Jul 2023Small heat shock proteins (sHSPs) are essential ATP-independent chaperones that protect the cellular proteome. These proteins assemble into polydisperse oligomeric...
Small heat shock proteins (sHSPs) are essential ATP-independent chaperones that protect the cellular proteome. These proteins assemble into polydisperse oligomeric structures, the composition of which dramatically affects their chaperone activity. The biomolecular consequences of variations in sHSP ratios, especially inside living cells, remain elusive. Here, we study the consequences of altering the relative expression levels of HspB2 and HspB3 in HEK293T cells. These chaperones are partners in a hetero-oligomeric complex, and genetic mutations that abolish their mutual interaction are associated with myopathic disorders. HspB2 displays three distinct phenotypes when co-expressed with HspB3 at varying ratios. Expression of HspB2 alone leads to formation of liquid nuclear condensates, while shifting the stoichiometry towards HspB3 resulted in the formation of large solid-like aggregates. Only cells co-expressing HspB2 with a limited amount of HspB3 formed fully soluble complexes that were distributed homogeneously throughout the nucleus. Strikingly, both condensates and aggregates were reversible, as shifting the HspB2:HspB3 balance in situ resulted in dissolution of these structures. To uncover the molecular composition of HspB2 condensates and aggregates, we used APEX-mediated proximity labelling. Most proteins interact transiently with the condensates and were neither enriched nor depleted in these cells. In contrast, we found that HspB2:HspB3 aggregates sequestered several disordered proteins and autophagy factors, suggesting that the cell is actively attempting to clear these aggregates. This study presents a striking example of how changes in the relative expression levels of interacting proteins affects their phase behavior. Our approach could be applied to study the role of protein stoichiometry and the influence of client binding on phase behavior in other biomolecular condensates and aggregates.
Topics: Humans; Heat-Shock Proteins; Heat-Shock Proteins, Small; HEK293 Cells; HSP27 Heat-Shock Proteins; Cell Nucleus; Protein Aggregates
PubMed: 37146746
DOI: 10.1016/j.jmb.2023.168139 -
Biomolecules Aug 2022Over a hundred different autoimmune diseases have been described to date, which can affect every organ in the body, including the largest one, the skin. In fact, up to... (Review)
Review
Over a hundred different autoimmune diseases have been described to date, which can affect every organ in the body, including the largest one, the skin. In fact, up to one-fifth of the world's population suffers from chronic, noninfectious inflammatory skin diseases, the development of which is significantly influenced by an autoimmune response. One of the hallmarks of autoimmune diseases is the loss of immune tolerance, which leads to the formation of autoreactive lymphocytes or autoantibodies and, consequently, to chronic inflammation and tissue damage. The treatment of autoimmune skin diseases mainly focuses on immunosuppression (using, e.g., corticosteroids) but almost never leads to the development of permanent mechanisms of immune tolerance. In addition, current therapies and their long-term administration may cause serious adverse effects. Hence, safer and more effective therapies that bring sustained balance between pro- and anti-inflammatory responses are still desired. Both intra- and extracellular heat shock proteins (Hsps), specifically well-characterized inducible Hsp90 and Hsp70 chaperones, have been highlighted as therapeutic targets for autoimmune diseases. This review presents preclinical data on the involvement of Hsp90 and Hsp70 in modulating the immune response, specifically in the context of the treatment of selected autoimmune skin diseases with emphasis on autoimmune bullous skin diseases and psoriasis.
Topics: Autoimmune Diseases; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Skin Diseases
PubMed: 36009046
DOI: 10.3390/biom12081153 -
Frontiers in Immunology 2022Heat shock proteins (HSPs) are a kind of proteins which mostly found in bacterial, plant and animal cells, in which they are involved in the monitoring and regulation of... (Review)
Review
Heat shock proteins (HSPs) are a kind of proteins which mostly found in bacterial, plant and animal cells, in which they are involved in the monitoring and regulation of cellular life activities. HSPs protect other proteins under environmental and cellular stress by regulating protein folding and supporting the correctly folded structure of proteins as chaperones. During viral infection, some HSPs can have an antiviral effect by inhibiting viral proliferation through interaction and activating immune pathways to protect the host cell. However, although the biological function of HSPs is to maintain the homeostasis of cells, some HSPs will also be hijacked by viruses to help their invasion, replication, and maturation, thereby increasing the chances of viral survival in unfavorable conditions inside the host cell. In this review, we summarize the roles of the heat shock protein family in various stages of viral infection and the potential uses of these proteins in antiviral therapy.
Topics: Animals; Heat-Shock Proteins; Homeostasis; Molecular Chaperones; Protein Folding; Virus Diseases
PubMed: 35990630
DOI: 10.3389/fimmu.2022.947789 -
Current Pharmaceutical Design 2022Colorectal cancer (CRC) is the third most common cancer worldwide. Despite the enormous amount of effort in the diagnosis and treatment of CRC, the overall survival rate... (Review)
Review
Colorectal cancer (CRC) is the third most common cancer worldwide. Despite the enormous amount of effort in the diagnosis and treatment of CRC, the overall survival rate of patients remains low. The precise molecular and cellular basis underlying CRC has not been completely understood yet. Over time, new genes and molecular pathways involved in the pathogenesis of the disease are being identified. The accurate discovery of these genes and signaling pathways are important and urgent missions for the next generation of anticancer therapy research. Chaperone DnaJ, also known as Hsp40 (heat shock protein 40), has been of particular interest in CRC pathogenesis, as it is involved in the fundamental cell activities for maintaining cellular homeostasis. Evidence shows that protein family members of DnaJ/Hsp40 play both roles, enhancing and reducing the growth of CRC cells. In the present review, we focus on the current knowledge of the molecular mechanisms responsible for DnaJ/Hsp40 in CRC carcinogenesis and biology.
Topics: Carcinogenesis; Colorectal Neoplasms; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans
PubMed: 35570564
DOI: 10.2174/1381612828666220513124603 -
Protein and Peptide Letters 2009The mechanism by which Hsp40 and other molecular chaperones recognize and interact with non-native polypeptides is a fundamental question, as is how Hsp40 co-operates... (Review)
Review
The mechanism by which Hsp40 and other molecular chaperones recognize and interact with non-native polypeptides is a fundamental question, as is how Hsp40 co-operates with Hsp70 to facilitate protein folding. Years of structural studies of Hsp40 from yeast and other species, conducted using X-ray protein crystallography, NMR and small-angle X-ray scattering, have shed light on the mechanisms how Hsp40 functions as a molecular chaperone and how Hsp40-Hsp70 pair promotes protein folding, protein transport and degradation. This review provides a discussion of recent structural studies of Hsp40s and their functional implications.
Topics: Crystallography, X-Ray; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Nuclear Magnetic Resonance, Biomolecular; Protein Folding; Protein Structure, Tertiary
PubMed: 19519518
DOI: 10.2174/092986609788490159 -
International Journal of Molecular... Jan 2024Heat shock proteins (Hsps) are a group of stress-induced proteins involved in protein folding and maturation. Based on their molecular weight, Hsps can be divided into... (Review)
Review
Heat shock proteins (Hsps) are a group of stress-induced proteins involved in protein folding and maturation. Based on their molecular weight, Hsps can be divided into six families: small Hsps, Hsp40, Hsp60, Hsp70, Hsp90, and large Hsps. In the process of breast cancer tumorigenesis, Hsps play a central role in regulating cell reactions and functions including proliferation, metastasis, and apoptosis. Moreover, some of the critical Hsps also regulate the fine balance between the protective and destructive immunological responses within the tumor microenvironment. In this review, we systematically summarize the roles of major Hsps in breast cancer biology and point out the potential uses of these proteins in breast cancer diagnosis and therapy. Understanding the roles of different families of Hsps in breast cancer pathogenesis will help in the development of more effective prevention and treatment measures for breast cancer.
Topics: Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Heat-Shock Proteins, Small; Apoptosis; Neoplasms
PubMed: 38255948
DOI: 10.3390/ijms25020876 -
Journal of Translational Medicine May 2022Molecular chaperones assist protein folding, facilitate degradation of misfolded polypeptides, and thereby maintain protein homeostasis. Impaired chaperone activity...
BACKGROUND
Molecular chaperones assist protein folding, facilitate degradation of misfolded polypeptides, and thereby maintain protein homeostasis. Impaired chaperone activity leads to defective protein quality control that is implicated in multiple skeletal muscle diseases. The heat shock protein A4 (HSPA4) acts as a co-chaperone for HSP70. Previously, we showed that Hspa4 deletion causes impaired protein homeostasis in the heart. However, its functional role in skeletal muscle has not been explored.
METHODS
We performed a comparative phenotypic and biochemical analyses of Hspa4 knockout (KO) mice with wild-type (WT) littermates.
RESULTS
HSPA4 is markedly upregulated in regenerating WT muscle in vivo, and in differentiated myoblasts in vitro. Hspa4-KO mice are marked by growth retardation and increased variability in body weight, accompanied by 35% mortality rates during the peri-weaning period. The surviving Hspa4-KO mice experienced progressive skeletal muscle myopathy, characterized by increased number of muscle fibers with centralized nuclei, heterogeneous myofiber size distribution, inflammatory cell infiltrates and upregulation of embryonic and perinatal myosin heavy chain transcripts. Hspa4-KO muscles demonstrated an accumulation of autophagosome-associated proteins including microtubule associated protein1 light chain 3-II (LC3-II) and p62/sequestosome accompanied by increased number of TUNEL-positive nuclei.
CONCLUSIONS
Our findings underscore the indispensable role of HSPA4 in maintenance of muscle integrity through contribution in skeletal muscle autophagy and apoptosis, which might provide a novel therapeutic strategy for skeletal muscle morbidities.
Topics: Animals; Apoptosis; Autophagy; HSP110 Heat-Shock Proteins; Heat-Shock Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Chaperones; Muscle, Skeletal; Muscular Diseases
PubMed: 35568953
DOI: 10.1186/s12967-022-03418-3