scholarly journals Intercellular chaperone transmission via exosomes contributes to maintenance of protein homeostasis at the organismal level

2015 ◽  
Vol 112 (19) ◽  
pp. E2497-E2506 ◽  
Author(s):  
Toshihide Takeuchi ◽  
Mari Suzuki ◽  
Nobuhiro Fujikake ◽  
H. Akiko Popiel ◽  
Hisae Kikuchi ◽  
...  
Keyword(s):  
Heat Shock ◽  
Molecular Chaperones ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Physiological Role ◽  
Transcriptional Response ◽  
Cell Types ◽  
Protein Homeostasis ◽  
Stressful Environment ◽  
Elevated Expression

The heat shock response (HSR), a transcriptional response that up-regulates molecular chaperones upon heat shock, is necessary for cell survival in a stressful environment to maintain protein homeostasis (proteostasis). However, there is accumulating evidence that the HSR does not ubiquitously occur under stress conditions, but largely depends on the cell types. Despite such imbalanced HSR among different cells and tissues, molecular mechanisms by which multicellular organisms maintain their global proteostasis have remained poorly understood. Here, we report that proteostasis can be maintained by molecular chaperones not only in a cell-autonomous manner but also in a non–cell-autonomous manner. We found that elevated expression of molecular chaperones, such as Hsp40 and Hsp70, in a group of cells improves proteostasis in other groups of cells, both in cultured cells and in Drosophila expressing aggregation-prone polyglutamine proteins. We also found that Hsp40, as well as Hsp70 and Hsp90, is physiologically secreted from cells via exosomes, and that the J domain at the N terminus is responsible for its exosome-mediated secretion. Addition of Hsp40/Hsp70-containing exosomes to the culture medium of the polyglutamine-expressing cells results in efficient suppression of inclusion body formation, indicating that molecular chaperones non-cell autonomously improve the protein-folding environment via exosome-mediated transmission. Our study reveals that intercellular chaperone transmission mediated by exosomes is a novel molecular mechanism for non–cell-autonomous maintenance of organismal proteostasis that could functionally compensate for the imbalanced state of the HSR among different cells, and also provides a novel physiological role of exosomes that contributes to maintenance of organismal proteostasis.

scholarly journals Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Xu Zheng ◽  
Joanna Krakowiak ◽  
Nikit Patel ◽  
Ali Beyzavi ◽  
Jideofor Ezike ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Heat Shock ◽  
Signaling Pathways ◽  
Molecular Chaperones ◽  
Stress Resistance ◽  
Dynamic Control ◽  
Protein Homeostasis ◽  
Unfolded Proteins ◽  
Cell Signaling Pathways ◽  
Chaperone Hsp70

Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. Here we show that in budding yeast, Hsf1 basally associates with the chaperone Hsp70 and this association is transiently disrupted by heat shock, providing the first evidence that a chaperone repressor directly regulates Hsf1 activity. We develop and experimentally validate a mathematical model of Hsf1 activation by heat shock in which unfolded proteins compete with Hsf1 for binding to Hsp70. Surprisingly, we find that Hsf1 phosphorylation, previously thought to be required for activation, in fact only positively tunes Hsf1 and does so without affecting Hsp70 binding. Our work reveals two uncoupled forms of regulation - an ON/OFF chaperone switch and a tunable phosphorylation gain - that allow Hsf1 to flexibly integrate signals from the proteostasis network and cell signaling pathways.

scholarly journals Comparison of the RpoH-Dependent Regulon and General Stress Response in Neisseria gonorrhoeae

2006 ◽  
Vol 188 (13) ◽  
pp. 4769-4776 ◽  
Author(s):  
Ishara C. Gunesekere ◽  
Charlene M. Kahler ◽  
David R. Powell ◽  
Lori A. S. Snyder ◽  
Nigel J. Saunders ◽  
...  
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Neisseria Gonorrhoeae ◽  
Transcriptional Profiling ◽  
Transcriptional Response ◽  
Protein Homeostasis ◽  
Promoter Regions ◽  
General Stress Response ◽  
Genome Wide ◽  
Shock Proteins

ABSTRACT In the gammaproteobacteria the RpoH regulon is often equated with the stress response, as the regulon contains many of the genes that encode what have been termed heat shock proteins that deal with the presence of damaged proteins. However, the betaproteobacteria primarily utilize the HrcA repressor protein to control genes involved in the stress response. We used genome-wide transcriptional profiling to compare the RpoH regulon and stress response of Neisseria gonorrhoeae, a member of the betaproteobacteria. To identify the members of the RpoH regulon, a plasmid-borne copy of the rpoH gene was overexpressed during exponential-phase growth at 37°C. This resulted in increased expression of 12 genes, many of which encode proteins that are involved in the stress response in other species. The putative promoter regions of many of these up-regulated genes contain a consensus RpoH binding site similar to that of Escherichia coli. Thus, it appears that unlike other members of the betaproteobacteria, N. gonorrhoeae utilizes RpoH, and not an HrcA homolog, to regulate the stress response. In N. gonorrhoeae exposed to 42°C for 10 min, we observed a much broader transcriptional response involving 37 differentially expressed genes. Genes that are apparently not part of the RpoH regulon showed increased transcription during heat shock. A total of 13 genes were also down-regulated. From these results we concluded that although RpoH acts as the major regulator of protein homeostasis, N. gonorrhoeae has additional means of responding to temperature stress.

scholarly journals Functions and Therapeutic Potential of Extracellular Hsp60, Hsp70, and Hsp90 in Neuroinflammatory Disorders

2021 ◽  
Vol 11 (2) ◽  
pp. 736
Author(s):  
Giusi Alberti ◽  
Letizia Paladino ◽  
Alessandra Maria Vitale ◽  
Celeste Caruso Bavisotto ◽  
Everly Conway de Macario ◽  
...  
Keyword(s):  
Molecular Chaperones ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Protein Homeostasis ◽  
Canonical Function ◽  
Cytoprotective Activity ◽  
Ubiquitin Proteasome ◽  
Chaperone Mediated Autophagy

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.

scholarly journals Roles of the nucleotide exchange factor and chaperone Hsp110 in cellular proteostasis and diseases of protein misfolding

2018 ◽  
Vol 399 (10) ◽  
pp. 1215-1221 ◽  
Author(s):  
Unekwu M. Yakubu ◽  
Kevin A. Morano
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Recent Progress ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Nucleotide Exchange Factor

Abstract Cellular protein homeostasis (proteostasis) is maintained by a broad network of proteins involved in synthesis, folding, triage, repair and degradation. Chief among these are molecular chaperones and their cofactors that act as powerful protein remodelers. The growing realization that many human pathologies are fundamentally diseases of protein misfolding (proteopathies) has generated interest in understanding how the proteostasis network impacts onset and progression of these diseases. In this minireview, we highlight recent progress in understanding the enigmatic Hsp110 class of heat shock protein that acts as both a potent nucleotide exchange factor to regulate activity of the foldase Hsp70, and as a passive chaperone capable of recognizing and binding cellular substrates on its own, and its integration into the proteostasis network.

scholarly journals Comparative docking studies of rosmarinic acid and sinesitin to inhibit HSP70

2019 ◽  
Vol 6 (1) ◽  
pp. 115-119
Author(s):  
Mansoureh Nazari V. ◽  
Syed Mahmood ◽  
Subashini Raman
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Molecular Chaperones ◽  
Rosmarinic Acid ◽  
Poor Prognosis ◽  
Docking Studies ◽  
Protein Homeostasis ◽  
Hsp70 Family ◽  
Adenosine Triphosphatases ◽  
Shock Proteins

The HSP70 family of heat shock proteins consists of molecular chaperones of approximately 70kDa in size that serve critical roles in protein homeostasis. These adenosine triphosphatases unfold misfolded or denatured proteins and can keep these proteins in an unfolded, folding-competent state. They also protect nascently translating proteins, promote the cellular or organellar transport of proteins, reduce proteotoxic protein aggregates and serve general housekeeping roles in maintaining protein homeostasis. The HSP70 family is the most conserved in evolution, and all eukaryotes contain multiple members.  the HSP70 family of proteins can be thought of as a potent buffering system for cellular stress either from extrinsic (physiological, viral and environmental) or intrinsic (replicative or oncogenic) stimuli. Not surprisingly, cancer cells rely heavily on this buffering system for survival. The overwhelming majority of human tumours overexpress HSP70 family members, and expression of these proteins is typically a marker for poor prognosis.

Heat Shock Factor (HSF): The Promoter of Chaperone Genes. A Mini Review

2018 ◽  
Vol 16 (1) ◽  
pp. 22-30 ◽  
Author(s):  
Natália Galdi Quel ◽  
Carlos H.I. Ramos
Keyword(s):  
Heat Shock ◽  
Molecular Chaperones ◽  
Protein Quality ◽  
Cell Function ◽  
Heat Shock Factor ◽  
Protein Homeostasis ◽  
General Knowledge ◽  
Protein Quality Control System ◽  
Shock Proteins ◽  
And Function

Protein homeostasis, or proteostasis, is required for proper cell function and thus must be under tight maintenance in all circumstances. In crowded cell conditions, protein folding is sometimes unfavorable, and this condition is worsened during stress situations. Cells cope with such stress through the use of a Protein Quality Control system, which uses molecular chaperones and heat shock proteins as its major players. This system aids with folding, avoiding misfolding and/or reversing aggregation. A pivotal regulator of the response to heat stress is Heat Shock Factor, which is recruited to the promoters of the chaperone genes, inducting their expression. This mini review aims to cover our general knowledge on the structure and function of this factor.

Strain and Substrate Stiffness Affect Calcium Accumulation in Aortic Valve Interstitial Cells

2011 ◽  
Author(s):  
Joshua D. Hutcheson ◽  
M. K. Sewell-Loftin ◽  
W. David Merryman
Keyword(s):  
Aortic Valve ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Mechanical Strain ◽  
Cell Types ◽  
Interstitial Cells ◽  
Nodule Formation ◽  
Native Tissue

The progression of aortic valve (AV) disease is often characterized by the formation of calcific nodules on thickened AV leaflets, limiting the biomechanical function of the valve. Calcification is a major problem that often leads to the failure of bioprosthetic replacement valves [1]. In these cases, the association of extracellular Ca2+ with phosphates remaining in cellular debris within the decellularized scaffolds has been proposed to lead to the nucleation and growth of Ca3(PO4)2 nodules. In native tissue, calcification is thought to be a more active process involving AV interstitial cells (AVICs). The exact molecular mechanisms that lead to the formation of these calcific nodules in native tissue remain unclear; however, AVICs have been shown to form nodule-like structures in vitro through differentiation to a phenotype with osteogenic character [2]. Additionally, in vitro nodules are characterized by activated smooth muscle α-actin positive AVICs and high levels of apoptosis [2–3]. Mechanical strain has also been shown to influence nodule formation in excised AV leaflets [4]. Intracellular Ca2+ exhibits mechanodependency in cultured cells [5], and heightened levels of intracellular Ca2+ have been shown to be associated with apoptosis in many cell types [6] In this study, we assess the role of mechanically-induced changes in intracellular calcium and its function in modulating AVIC behavior. We hypothesized that intracellular Ca2+ will increase in strained AVICs and that over time, this will lead to apoptosis. We believe that the results from this study will help illustrate the mechanotransductive role of Ca2+ in AVICs and may elucidate early cellular changes that lead to AV calcification.

Neuroprotective Mechanisms of Heat Shock Gene Expression

1998 ◽  
Vol 4 (4) ◽  
pp. 236-239
Author(s):  
B. Joy Snider
Keyword(s):  
Heat Shock ◽  
Molecular Chaperones ◽  
Cell Types ◽  
Heat Shock Gene ◽  
Cellular Injury ◽  
Genetic Manipulations ◽  
Enhanced Expression ◽  
Shock Gene ◽  
Heat Shock Gene Expression ◽  
Shock Proteins

Heat shock proteins were initially described as the predominant proteins expressed immediately after a thermal stress. These ubiquitously expressed proteins function as molecular chaperones; they aid in the folding, subcellular translocation, and assembly of other proteins. Although most of these proteins are expressed constitutively, enhanced expression, induced by stress or genetic manipulations, can reduce subsequent cellular injury in many cell types, including neurons and glia. Further understanding of how the expression of these proteins is controlled in the nervous system, and how they can be manipulated to attenuate injury, could provide therapeutic targets for cerebral ischemia and neurodegenerative disorders.

The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting

2021 ◽  
Vol 61 (1) ◽  
pp. 541-563 ◽  
Author(s):  
Martine J. Smit ◽  
Géraldine Schlecht-Louf ◽  
Maria Neves ◽  
Jelle van den Bor ◽  
Petronila Penela ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Chemokine Receptors ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cancer Therapies ◽  
Signaling Crosstalk ◽  
Wide Range ◽  
Elevated Expression

Elevated expression of the chemokine receptors CXCR4 and ACKR3 and of their cognate ligand CXCL12 is detected in a wide range of tumors and the tumor microenvironment (TME). Yet, the molecular mechanisms by which the CXCL12/CXCR4/ACKR3 axis contributes to the pathogenesis are complex and not fully understood. To dissect the role of this axis in cancer, we discuss its ability to impinge on canonical and less conventional signaling networks in different cancer cell types; its bidirectional crosstalk, notably with receptor tyrosine kinase (RTK) and other factors present in the TME; and the infiltration of immune cells that supporttumor progression. We discuss current and emerging avenues that target the CXCL12/CXCR4/ACKR3 axis. Coordinately targeting both RTKs and CXCR4/ACKR3 and/or CXCL12 is an attractive approach to consider in multitargeted cancer therapies. In addition, inhibiting infiltrating immune cells or reactivating the immune system along with modulating the CXCL12/CXCR4/ACKR3 axis in the TME has therapeutic promise.

Sign in / Sign up

Export Citation Format

Share Document