Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

While cells from multicellular organisms are dependent upon exogenous signals for their survival, growth, and proliferation, commitment to a specific cell fate requires the correct folding and maturation of proteins, as well as the degradation of misfolded or aggregated proteins within the cell. This general control of protein quality involves the expression and the activity of molecular chaperones such as heat shock proteins (HSPs). HSPs, through their interaction with the STAT3/STAT5 transcription factor pathway, can be crucial both for the tumorigenic properties of cancer cells (cell proliferation, survival) and for the microenvironmental immune cell compartment (differentiation, activation, cytokine secretion) that contributes to immunosuppression, which, in turn, potentially promotes tumor progression. Understanding the contribution of chaperones such as HSP27, HSP70, HSP90, and HSP110 to the STAT3/5 signaling pathway has raised the possibility of targeting such HSPs to specifically restrain STAT3/5 oncogenic functions. In this review, we present how HSPs control STAT3 and STAT5 activation, and vice versa, how the STAT signaling pathways modulate HSP expression. We also discuss whether targeting HSPs is a valid therapeutic option and which HSP would be the best candidate for such a strategy.

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Alzheimer Cells on Their Way to Derailment Show Selective Changes in Protein Quality Control Network

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.00214 ◽

2020 ◽

Vol 7 ◽

Author(s):

Margreet B. Koopman ◽

Stefan G. D. Rüdiger

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Quality Control ◽

Heat Shock ◽

Heat Shock Proteins ◽

Protein Quality ◽

Protein Quality Control ◽

Brain Regions ◽

Control Network ◽

Shock Proteins

Alzheimer’s Disease is driven by protein aggregation and is characterized by accumulation of Tau protein into neurofibrillary tangles. In healthy neurons the cellular protein quality control is successfully in charge of protein folding, which raises the question to which extent this control is disturbed in disease. Here, we describe that brain cells in Alzheimer’s Disease show very specific derailment of the protein quality control network. We performed a meta-analysis on the Alzheimer’s Disease Proteome database, which provides a quantitative assessment of disease-related proteome changes in six brain regions in comparison to age-matched controls. We noted that levels of all paralogs of the conserved Hsp90 chaperone family are reduced, while most other chaperones – or their regulatory co-chaperones - do not change in disease. The notable exception is a select group consisting of the stress inducible HSP70, its nucleotide exchange factor BAG3 – which links the Hsp70 system to autophagy - and neuronal small heat shock proteins, which are upregulated in disease. They are all members of a cascade controlled in the stress response, channeling proteins towards a pathway of chaperone assisted selective autophagy. Together, our analysis reveals that in an Alzheimer’s brain, with exception of Hsp90, the players of the protein quality control are still present in full strength, even in brain regions most severely affected in disease. The specific upregulation of small heat shock proteins and HSP70:BAG3, ubiquitous in all brain areas analyzed, may represent a last, unsuccessful attempt to advert cell death.

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Heat Shock Proteins and Protein Quality Control in Alzheimer’s Disease

The Molecular and Cellular Basis of Neurodegenerative Diseases ◽

10.1016/b978-0-12-811304-2.00010-9 ◽

2018 ◽

pp. 269-298 ◽

Cited By ~ 3

Author(s):

Fred W. van Leeuwen ◽

Harm H. Kampinga

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Quality Control ◽

Heat Shock ◽

Heat Shock Proteins ◽

Protein Quality ◽

Protein Quality Control ◽

Shock Proteins

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α-Crystallin-Type Heat Shock Proteins: Socializing Minichaperones in the Context of a Multichaperone Network

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.66.1.64-93.2002 ◽

2002 ◽

Vol 66 (1) ◽

pp. 64-93 ◽

Cited By ~ 379

Author(s):

Franz Narberhaus

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Protein Quality ◽

Chaperone Activity ◽

Close Cooperation ◽

Irreversible Aggregation ◽

Functional Features ◽

Shock Proteins ◽

And Function ◽

Temperature Upshift

SUMMARY α-Crystallins were originally recognized as proteins contributing to the transparency of the mammalian eye lens. Subsequently, they have been found in many, but not all, members of the Archaea, Bacteria, and Eucarya. Most members of the diverse α-crystallin family have four common structural and functional features: (i) a small monomeric molecular mass between 12 and 43 kDa; (ii) the formation of large oligomeric complexes; (iii) the presence of a moderately conserved central region, the so-called α-crystallin domain; and (iv) molecular chaperone activity. Since α-crystallins are induced by a temperature upshift in many organisms, they are often referred to as small heat shock proteins (sHsps) or, more accurately, α-Hsps. α-Crystallins are integrated into a highly flexible and synergistic multichaperone network evolved to secure protein quality control in the cell. Their chaperone activity is limited to the binding of unfolding intermediates in order to protect them from irreversible aggregation. Productive release and refolding of captured proteins into the native state requires close cooperation with other cellular chaperones. In addition, α-Hsps seem to play an important role in membrane stabilization. The review compiles information on the abundance, sequence conservation, regulation, structure, and function of α-Hsps with an emphasis on the microbial members of this chaperone family.

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Partners in Mischief: Functional Networks of Heat Shock Proteins of Plasmodium falciparum and Their Influence on Parasite Virulence

Biomolecules ◽

10.3390/biom9070295 ◽

2019 ◽

Vol 9 (7) ◽

pp. 295 ◽

Cited By ~ 12

Author(s):

Michael O. Daniyan ◽

Jude M. Przyborski ◽

Addmore Shonhai

Keyword(s):

Plasmodium Falciparum ◽

Heat Shock ◽

Heat Shock Proteins ◽

Protein Quality ◽

A Genome ◽

Parasite Plasmodium ◽

Parasite Plasmodium Falciparum ◽

Human Proteins ◽

Protein Quality Control System ◽

Shock Proteins

The survival of the human malaria parasite Plasmodium falciparum under the physiologically distinct environments associated with their development in the cold-blooded invertebrate mosquito vectors and the warm-blooded vertebrate human host requires a genome that caters to adaptability. To this end, a robust stress response system coupled to an efficient protein quality control system are essential features of the parasite. Heat shock proteins constitute the main molecular chaperone system of the cell, accounting for approximately two percent of the malaria genome. Some heat shock proteins of parasites constitute a large part (5%) of the ‘exportome’ (parasite proteins that are exported to the infected host erythrocyte) that modify the host cell, promoting its cyto-adherence. In light of their importance in protein folding and refolding, and thus the survival of the parasite, heat shock proteins of P. falciparum have been a major subject of study. Emerging evidence points to their role not only being cyto-protection of the parasite, as they are also implicated in regulating parasite virulence. In undertaking their roles, heat shock proteins operate in networks that involve not only partners of parasite origin, but also potentially functionally associate with human proteins to facilitate parasite survival and pathogenicity. This review seeks to highlight these interplays and their roles in parasite pathogenicity. We further discuss the prospects of targeting the parasite heat shock protein network towards the developments of alternative antimalarial chemotherapies.

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Alzheimer cells on their way to derailment show selective changes in protein quality control network

10.1101/2020.05.17.099465 ◽

2020 ◽

Cited By ~ 1

Author(s):

Margreet B. Koopman ◽

Stefan G.D Rüdiger

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Quality Control ◽

Heat Shock ◽

Heat Shock Proteins ◽

Protein Quality ◽

Protein Quality Control ◽

Brain Regions ◽

Control Network ◽

Shock Proteins

Alzheimer’s Disease is driven by protein aggregation and is characterised by accumulation of Tau protein into neurofibrillary tangles. In healthy neurons the cellular protein quality control is successfully in charge of protein folding, which raises the question to which extent this control is disturbed in disease. Here we describe that brain cells in Alzheimer’s Disease show very specific derailment of the protein quality control network. We performed a meta-analysis on the Alzheimer’s Disease Proteasome database, which provides a quantitative assessment of disease-related proteome changes in six brain regions in comparison with age-matched controls. We noted that levels of all paralogues of the conserved Hsp90 chaperone family are reduced, while most other chaperones – or their regulatory co-chaperones – do not change in disease. The notable exception is a select group consisting of the stress inducible HSP70, its nucleotide exchange factor BAG3 – which links the Hsp70 system to autophagy – and neuronal small heat shock proteins, which are upregulated in disease. They are all members of a cascade controlled in the stress response, channelling proteins towards a pathway of chaperone assisted selective autophagy. Together, our analysis reveals that in an Alzheimer’s brain, with exception of Hsp90, the players of the protein quality control are still present in full strength, even in brain regions most severely affected in disease. The specific upregulation of small heat shock proteins and HSP70:BAG3, ubiquitous in all brain areas analysed, may represent a last, unsuccessful attempt to advert neuronal cell death.

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The role of heat shock proteins and co-chaperones in heart failure

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0530 ◽

2017 ◽

Vol 373 (1738) ◽

pp. 20160530 ◽

Cited By ~ 27

Author(s):

Mark J. Ranek ◽

Marisa J. Stachowski ◽

Jonathan A. Kirk ◽

Monte S. Willis

Keyword(s):

Heart Failure ◽

Quality Control ◽

Heat Shock ◽

Heat Shock Proteins ◽

Structural Integrity ◽

Protein Quality ◽

Protein Quality Control ◽

Experimental Models ◽

Human Heart Failure ◽

Shock Proteins

The ongoing contractile and metabolic demands of the heart require a tight control over protein quality control, including the maintenance of protein folding, turnover and synthesis. In heart disease, increases in mechanical and oxidative stresses, post-translational modifications (e.g., phosphorylation), for example, decrease protein stability to favour misfolding in myocardial infarction, heart failure or ageing. These misfolded proteins are toxic to cardiomyocytes, directly contributing to the common accumulation found in human heart failure. One of the critical class of proteins involved in protecting the heart against these threats are molecular chaperones, including the heat shock protein70 (HSP70), HSP90 and co-chaperones CHIP (carboxy terminus of Hsp70-interacting protein, encoded by the Stub1 gene) and BAG-3 (BCL2-associated athanogene 3). Here, we review their emerging roles in the maintenance of cardiomyocytes in human and experimental models of heart failure, including their roles in facilitating the removal of misfolded and degraded proteins, inhibiting apoptosis and maintaining the structural integrity of the sarcomere and regulation of nuclear receptors. Furthermore, we discuss emerging evidence of increased expression of extracellular HSP70, HSP90 and BAG-3 in heart failure, with complementary independent roles from intracellular functions with important therapeutic and diagnostic considerations. While our understanding of these major HSPs in heart failure is incomplete, there is a clear potential role for therapeutic modulation of HSPs in heart failure with important contextual considerations to counteract the imbalance of protein damage and endogenous protein quality control systems. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

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Heat Shock Proteins: Cell Protection through Protein Triage

The Scientific World JOURNAL ◽

10.1100/tsw.2010.152 ◽

2010 ◽

Vol 10 ◽

pp. 1543-1552 ◽

Cited By ~ 119

Author(s):

David Lanneau ◽

Guillaume Wettstein ◽

Philippe Bonniaud ◽

Carmen Garrido

Keyword(s):

Quality Control ◽

Heat Shock ◽

Heat Shock Proteins ◽

Protein Quality ◽

Ubiquitin Proteasome System ◽

Control Mechanisms ◽

Cell Protection ◽

Ubiquitin Proteasome ◽

Folded Proteins ◽

Shock Proteins

Heat shock proteins (HSPs) are chaperones that catalyze the proper folding of nascent proteins and the refolding of denatured proteins. The ubiquitin-proteasome system is an error-checking system that directs improperly folded proteins for destruction. A coordinated interaction between the HSPs (renaturation) and the proteasome (degradation) must exist to assure protein quality control mechanisms. Although it still remains unknown how the decision of folding vs. degradation is taken, many pieces of evidence demonstrate that HSPs interact directly or indirectly with the proteasome, assuring quite selectively the proteasomal degradation of certain proteins under stress conditions. In this review, we will describe the different data that demonstrate a role for HSP90, HSP70, HSP27, and alpha-B-crystallin in the partitioning of proteins to either one of these pathways, referred as protein triage.

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