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Cell Stress & Chaperones Feb 2024Preserving and regulating cellular homeostasis in the light of changing environmental conditions or developmental processes is of pivotal importance for single cellular...
Preserving and regulating cellular homeostasis in the light of changing environmental conditions or developmental processes is of pivotal importance for single cellular and multicellular organisms alike. To counteract an imbalance in cellular homeostasis transcriptional programs evolved, called the heat shock response, unfolded protein response, and integrated stress response, that act cell-autonomously in most cells but in multicellular organisms are subjected to cell-nonautonomous regulation. These transcriptional programs downregulate the expression of most genes but increase the expression of heat shock genes, including genes encoding molecular chaperones and proteases, proteins involved in the repair of stress-induced damage to macromolecules and cellular structures. Sixty-one years after the discovery of the heat shock response by Ferruccio Ritossa, many aspects of stress biology are still enigmatic. Recent progress in the understanding of stress responses and molecular chaperones was reported at the 12th International Symposium on Heat Shock Proteins in Biology, Medicine and the Environment in the Old Town Alexandria, VA, USA from 28th to 31st of October 2023.
Topics: Heat-Shock Proteins; Molecular Chaperones; Heat-Shock Response; Medicine; Biology
PubMed: 38311120
DOI: 10.1016/j.cstres.2024.01.006 -
Biomolecules Dec 2023Alzheimer's disease (AD) is an extremely devastating neurodegenerative disease, and there is no cure for it. AD is specified as the misfolding and aggregation of... (Review)
Review
Alzheimer's disease (AD) is an extremely devastating neurodegenerative disease, and there is no cure for it. AD is specified as the misfolding and aggregation of amyloid-β protein (Aβ) and abnormalities in hyperphosphorylated tau protein. Current approaches to treat Alzheimer's disease have had some success in slowing down the disease's progression. However, attempts to find a cure have been largely unsuccessful, most likely due to the complexity associated with AD pathogenesis. Hence, a shift in focus to better understand the molecular mechanism of Aβ processing and to consider alternative options such as chaperone proteins seems promising. Chaperone proteins act as molecular caretakers to facilitate cellular homeostasis under standard conditions. Chaperone proteins like heat shock proteins (Hsps) serve a pivotal role in correctly folding amyloid peptides, inhibiting mitochondrial dysfunction, and peptide aggregation. For instance, Hsp90 plays a significant role in maintaining cellular homeostasis through its protein folding mechanisms. In this review, we analyze the most recent studies from 2020 to 2023 and provide updates on Aβ regulation by Hsp90, BRICHOS domain chaperone, and distinctive newly reported chaperones.
Topics: Humans; Alzheimer Disease; Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Molecular Chaperones; Neurodegenerative Diseases; Amyloid beta-Peptides
PubMed: 38254616
DOI: 10.3390/biom14010016 -
Annual Review of Biophysics May 2022Molecular chaperones are the guardians of the proteome inside the cell. Chaperones recognize and bind unfolded or misfolded substrates, thereby preventing further... (Review)
Review
Molecular chaperones are the guardians of the proteome inside the cell. Chaperones recognize and bind unfolded or misfolded substrates, thereby preventing further aggregation; promoting correct protein folding; and, in some instances, even disaggregating already formed aggregates. Chaperones perform their function by means of an array of weak protein-protein interactions that take place over a wide range of timescales and are therefore invisible to structural techniques dependent upon the availability of highly homogeneous samples. Nuclear magnetic resonance (NMR) spectroscopy, however, is ideally suited to study dynamic, rapidly interconverting conformational states and protein-protein interactions in solution, even if these involve a high-molecular-weight component. In this review, we give a brief overview of the principles used by chaperones to bind their client proteins and describe NMR methods that have emerged as valuable tools to probe chaperone-substrate and chaperone-chaperone interactions. We then focus on a few systems for which the application of these methods has greatly increased our understanding of the mechanisms underlying chaperone functions.
Topics: Humans; Lenses; Magnetic Resonance Spectroscopy; Molecular Chaperones; Protein Folding; Proteome
PubMed: 35044800
DOI: 10.1146/annurev-biophys-090921-120150 -
Cells Oct 2019Chaperone-mediated autophagy (CMA) ensures the selective degradation of cellular proteins endowed with a KFERQ-like motif by lysosomes. It is estimated that 30% of all... (Review)
Review
Chaperone-mediated autophagy (CMA) ensures the selective degradation of cellular proteins endowed with a KFERQ-like motif by lysosomes. It is estimated that 30% of all cellular proteins can be directed to the lysosome for CMA degradation, but only a few substrates have been formally identified so far. Mechanistically, the KFERQ-like motifs present in substrate proteins are recognized by the molecular chaperone Hsc70c (Heat shock cognate 71 kDa protein cytosolic), also known as HSPA8, and directed to LAMP2A, which acts as the CMA receptor at the lysosomal surface. Following linearization, the protein substrate is next transported to the lumen of the lysosomes, where it is degraded by resident proteases, mainly cathepsins and eventually recycled to sustain cellular homeostasis. CMA is induced by different stress conditions, including energy deprivation that also activates macro-autophagy (MA), that may make it difficult to decipher the relative impact of both pathways on cellular homeostasis. Besides common inducing triggers, CMA and MA might be induced as compensatory mechanisms when either mechanism is altered, as it is the often the case in different pathological settings. Therefore, CMA activation can compensate for alterations of MA and vice versa. In this context, these compensatory mechanisms, when occurring, may be targeted for therapeutic purposes. Both processes have received particular attention from scientists and clinicians, since modulation of MA and CMA may have a profound impact on cellular proteostasis, metabolism, death, differentiation, and survival and, as such, could be targeted for therapeutic intervention in degenerative and immune diseases, as well as in cancer, including hematopoietic malignancies. The role of MA in cancer initiation and progression is now well established, but whether and how CMA is involved in tumorigenesis has been only sparsely explored. In the present review, we encompass the description of the mechanisms involved in CMA, its function in the physiology and pathogenesis of hematopoietic cells, its emerging role in cancer initiation and development, and, finally, the potential therapeutic opportunity to target CMA or CMA-mediated compensatory mechanisms in hematological malignancies.
Topics: Autophagy; Chaperone-Mediated Autophagy; HSC70 Heat-Shock Proteins; Hematologic Neoplasms; Humans; Lysosomal-Associated Membrane Protein 2; Lysosomes; Molecular Chaperones; Neoplasms
PubMed: 31623164
DOI: 10.3390/cells8101260 -
Cell Stress & Chaperones Jul 2022Heat shock protein 70 (Hsp70) is a molecular chaperone and central regulator of protein homeostasis (proteostasis). Paramount to this role is Hsp70's binding to client... (Review)
Review
Heat shock protein 70 (Hsp70) is a molecular chaperone and central regulator of protein homeostasis (proteostasis). Paramount to this role is Hsp70's binding to client proteins and co-chaperones to produce distinct complexes, such that understanding the protein-protein interactions (PPIs) of Hsp70 is foundational to describing its function and dysfunction in disease. Mounting evidence suggests that these PPIs include both "canonical" interactions, which are universally conserved, and "non-canonical" (or "secondary") contacts that seem to have emerged in eukaryotes. These two categories of interactions involve discrete binding surfaces, such that some clients and co-chaperones engage Hsp70 with at least two points of contact. While the contributions of canonical interactions to chaperone function are becoming increasingly clear, it can be challenging to deconvolute the roles of secondary interactions. Here, we review what is known about non-canonical contacts and highlight examples where their contributions have been parsed, giving rise to a model in which Hsp70's secondary contacts are not simply sites of additional avidity but are necessary and sufficient to impart unique functions. From this perspective, we propose that further exploration of non-canonical contacts will generate important insights into the evolution of Hsp70 systems and inspire new approaches for developing small molecules that tune Hsp70-mediated proteostasis.
Topics: Eukaryota; HSP110 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Molecular Chaperones; Protein Binding; Protein Folding
PubMed: 35670950
DOI: 10.1007/s12192-022-01281-1 -
Biomolecules Jul 2022Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is... (Review)
Review
Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and Tsc1 has broadened the spectrum of Hsp90 regulators. These new co-chaperones mediate the stability of critical tumor suppressors FLCN and Tsc2 as well as the various classes of Hsp90 kinase and non-kinase clients. Many early observations of the roles of FNIP1, FNIP2, and Tsc1 suggested functions independent of FLCN and Tsc2 but have not been fully delineated. Given the broad cellular impact of Hsp90-dependent signaling, it is possible to explain the cellular activities of these new co-chaperones by their influence on Hsp90 function. Here, we review the literature on FNIP1, FNIP2, and Tsc1 as co-chaperones and discuss the potential downstream impact of this regulation on normal cellular function and in human diseases.
Topics: HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins
PubMed: 35883484
DOI: 10.3390/biom12070928 -
Chaperoning Endoplasmic Reticulum-Associated Degradation (ERAD) and Protein Conformational Diseases.Cold Spring Harbor Perspectives in... Aug 2019Misfolded proteins compromise cellular homeostasis. This is especially problematic in the endoplasmic reticulum (ER), which is a high-capacity protein-folding... (Review)
Review
Misfolded proteins compromise cellular homeostasis. This is especially problematic in the endoplasmic reticulum (ER), which is a high-capacity protein-folding compartment and whose function requires stringent protein quality-control systems. Multiprotein complexes in the ER are able to identify, remove, ubiquitinate, and deliver misfolded proteins to the 26S proteasome for degradation in the cytosol, and these events are collectively termed ER-associated degradation, or ERAD. Several steps in the ERAD pathway are facilitated by molecular chaperone networks, and the importance of ERAD is highlighted by the fact that this pathway is linked to numerous protein conformational diseases. In this review, we discuss the factors that constitute the ERAD machinery and detail how each step in the pathway occurs. We then highlight the underlying pathophysiology of protein conformational diseases associated with ERAD.
Topics: Cytoplasm; Endoplasmic Reticulum; Endoplasmic Reticulum-Associated Degradation; Genome, Human; Homeostasis; Humans; Molecular Chaperones; Mutation; Peptides; Polysaccharides; Proteasome Endopeptidase Complex; Protein Conformation; Protein Folding; Proteostasis; Proteostasis Deficiencies; Quality Control
PubMed: 30670468
DOI: 10.1101/cshperspect.a033928 -
Journal of Molecular Biology Jul 2024The Heat Shock Protein 90 (Hsp90) molecular chaperone is a key driver of protein homeostasis (proteostasis) under physiologically normal and stress conditions. In... (Review)
Review
The Heat Shock Protein 90 (Hsp90) molecular chaperone is a key driver of protein homeostasis (proteostasis) under physiologically normal and stress conditions. In eukaryotes, Hsp90 is essential and is one of the most abundant proteins in a cell where the chaperone shuttles between the cytoplasm and nucleus to fold, stabilize, and regulate client proteins and protein complexes. Numerous high-throughput screens have mapped the Hsp90 interactome, building a vast network comprising ∼25% of the proteome in budding yeast. How Hsp90 is able to associate with this diverse and large cadre of targets is critical to comprehending how the proteostatic process works. Here, we review recent progress on our understanding of the molecular underpinnings driving Hsp90-client interactions from both the perspective of the targets and Hsp90. In addition to considering the available Hsp90-client structures, we also assessed recently identified Hsp90-client peptide complexes to build a model that justifies how Hsp90 might recognize a wide spectrum of target proteins. In brief, Hsp90 either directly recognizes a site within an intrinsically disordered region (IDR) of a client protein to transiently regulate that client or it associates with an unstructured polypeptide section created by the concerted efforts of multiple chaperones and cochaperones to stably associate with a client. Overall, Hsp90 exploits a common recognition property (i.e., IDR) within diverse clients to support chaperone-actionthereby enabling its central role in proteostasis.
Topics: HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Proteostasis; Protein Binding; Intrinsically Disordered Proteins; Protein Conformation
PubMed: 38301804
DOI: 10.1016/j.jmb.2024.168460 -
Cells Oct 2022Cardiovascular disease is the result of complicated pathophysiological processes in the tissues that make up the blood vessels and heart. Heat shock protein 90 (HSP90)... (Review)
Review
Cardiovascular disease is the result of complicated pathophysiological processes in the tissues that make up the blood vessels and heart. Heat shock protein 90 (HSP90) can interact with 10% of the proteome and is the most widely studied molecular chaperone in recent years. HSP90 is extensively involved in the regulation of protein folding and intracellular protein stability, making HSP90 a hopeful target for the treatment of multiple cardiovascular diseases. Numerous client proteins of HSP90 have been identified in known cardiac disease pathways, including MAPK signaling, PI3K/AKT (PKB)/mTOR, and TNF-α signaling. Therefore, these pathways can be controlled by regulating HSP90. Among them, the activity of HSP90 can be regulated via numerous inhibitors. In this review, first, we will discuss the function of HSP90 and its role in pathological pathways. In addition, HSP90 plays a significant role in most cardiovascular diseases, including hypertension, pulmonary venous hypertension, atherosclerosis, and heart failure; next we will focus on this part. Finally, we will summarize the currently known HSP90 inhibitors and their potential in the treatment of heart disease.
Topics: Humans; Antineoplastic Agents; Cardiovascular Diseases; HSP90 Heat-Shock Proteins; Molecular Chaperones; Phosphatidylinositol 3-Kinases
PubMed: 36359837
DOI: 10.3390/cells11213444 -
DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones.Nature Communications Nov 2023Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins. Mutations in...
Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins. Mutations in one such chaperone, DNAJB6, were identified in patients with LGMDD1, a dominant autosomal disorder characterized by myofibrillar degeneration and accumulations of aggregated protein within myocytes. The molecular mechanisms through which such mutations cause this dysfunction, however, are not well understood. Here we employ a combination of solution NMR and biochemical assays to investigate the structural and functional changes in LGMDD1 mutants of DNAJB6. Surprisingly, we find that DNAJB6 disease mutants show no reduction in their aggregation-prevention activity in vitro, and instead differ structurally from the WT protein, affecting their interaction with Hsp70 chaperones. While WT DNAJB6 contains a helical element regulating its ability to bind and activate Hsp70, in LGMDD1 disease mutants this regulation is disrupted. These variants can thus recruit and hyperactivate Hsp70 chaperones in an unregulated manner, depleting Hsp70 levels in myocytes, and resulting in the disruption of proteostasis. Interfering with DNAJB6-Hsp70 binding, however, reverses the disease phenotype, suggesting future therapeutic avenues for LGMDD1.
Topics: Humans; Gain of Function Mutation; Molecular Chaperones; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Protein Folding; Nerve Tissue Proteins
PubMed: 37923706
DOI: 10.1038/s41467-023-42735-z