Small heat shock proteins in ageing and age-related diseases

Charmpilas, Nikolaos; Kyriakakis, Emmanouil; Tavernarakis, Nektarios

doi:10.1007/s12192-016-0761-x

Cited by 38 publications

(19 citation statements)

References 135 publications

(122 reference statements)

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“…Heat shock protein 27 kDa (HSP27) is a member of the small heat shock protein family that is known to promote cellular homeostasis as an ATP-independent molecular chaperone, antiapoptotic molecule, and regulator of signaling pathways (1,2). Through a multiplicity of functional activities, HSP27 was originally considered to be exclusively localized within cells; however, increasing evidence points to its presence and functional role(s) in the extracellular space (3).…”

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confidence: 99%

Characterization of heat shock protein 27 in extracellular vesicles: a potential anti‐inflammatory therapy

et al. 2018

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Previously, we reported that elevated serum levels of heat shock protein 27 (HSP27) are predictive of a lower risk of having a heart attack, stroke, or death from cardiovascular disease. Moreover, augmenting HSP27 (or the murine ortholog, HSP25) attenuated experimental atherogenesis, reduced inflammation, and lowered cholesterol levels. Recently, we noted that HSP27 activates NF-κB via TLR-4, resulting in attenuation of plaque inflammation; however, the precise anti-atherosclerosis mechanisms mediated by extracellular HSP27 are incompletely understood. Our purpose in this study was to investigate the existence of HSP27 in extracellular vesicles (EVs) and whether HSP27 elicited atheroprotective effects on target cells. Here, we provide evidence that HSP27 localizes to EVs derived from THP-1 cells using transmission electron microscopy (TEM) and immunogold labeling, Western blotting, ELISA, and fluorescence-activated cell sorting. TEM imaging indicated that HSP27 is found at the exosomal membrane. Multiple reactor monitor-mass spectrometric analysis of large vesicles, which included microparticles and exosomes, isolated from human plasma, also led to detection of HSP27 using the unique signature peptide, R.LFDQAFGLPR.L. Studies using THP-1 and human embryonic kidney cells show that HSP27-laden exosomes significantly stimulated NF-κB activation ( P < 0.001) and release of IL-10 ( P < 0.0001), suggesting that HSP27 may be important exosomal cargo with beneficial anti-inflammatory effects.-Shi, C., Ulke-Lemée, A., Deng, J., Batulan, Z., O'Brien, E. R. Characterization of heat shock protein 27 in extracellular vesicles: a potential anti-inflammatory therapy.

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Characterization of heat shock protein 27 in extracellular vesicles: a potential anti‐inflammatory therapy

et al. 2018

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“…Chaperones of the Hsp70 class are also known to suppress neurodegeneration 16 , 23 , 35 , are upregulated in the brains of E(z) mutant animals and may contribute to the protective effects of PRC2 inhibition. In humans, mutations in various sHSPs are associated with age-associated neuropathies, making these proteins of interest for their role in the brain with age 41 , 42 .…”

Section: Discussionmentioning

confidence: 99%

MiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging

2018

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Aging is a prominent risk factor for neurodegenerative disease. Defining gene expression mechanisms affecting healthy brain aging should lead to insight into genes that modulate susceptibility to disease. To define such mechanisms, we have pursued analysis of miR-34 mutants in Drosophila. The miR-34 mutant brain displays a gene expression profile of accelerated aging, and miR-34 upregulation is a potent suppressor of polyglutamine-induced neurodegeneration. We demonstrate that Pcl and Su(z)12, two components of polycomb repressive complex 2, (PRC2), are targets of miR-34, with implications for age-associated processes. Because PRC2 confers the repressive H3K27me3 mark, we hypothesize that miR-34 modulates PRC2 activity to relieve silencing of genes promoting healthful aging. Gene expression profiling of the brains of hypomorphic mutants in Enhancer of zeste (E(z)), the enzymatic methyltransferase component of PRC2, revealed a younger brain transcriptome profile and identified the small heat shock proteins as key genes reduced in expression with age.

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“…Small heat-shock proteins (sHsps) 5 are a class of ATP-independent chaperones, expressed across all kingdoms of life, that are proposed to act as a cell's "first-responders" under stress conditions (1)(2)(3)(4)(5)(6). Mutations or misexpression of specific human sHsps are associated with myopathies, neuropathies, and cancers (1,(7)(8)(9). The canonical function of sHsps is that they capture substrate proteins that are partially denatured by heat or other stresses in large soluble complexes, which are acted upon by ATP-dependent molecular machines to promote either substrate refolding or degradation (1,10).…”

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confidence: 99%

It takes a dimer to tango: Oligomeric small heat shock proteins dissociate to capture substrate

Santhanagopalan

Degiacomi

Shepherd

et al. 2018

Journal of Biological Chemistry

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Small heat-shock proteins (sHsps) are ubiquitous molecular chaperones, and sHsp mutations or altered expression are linked to multiple human disease states. sHsp monomers assemble into large oligomers with dimeric substructure, and the dynamics of sHsp oligomers has led to major questions about the form that captures substrate, a critical aspect of their mechanism of action. We show here that substructural dimers of two plant dodecameric sHsps, Ta16.9 and homologous Ps18.1, are functional units in the initial encounter with unfolding substrate. We introduced inter-polypeptide disulfide bonds at the two dodecameric interfaces, dimeric and nondimeric, to restrict how their assemblies can dissociate. When disulfide-bonded at the nondimeric interface, mutants of Ta16.9 and Ps18.1 (Ta CT-ACD and Ps CT-ACD) were inactive but, when reduced, had WT-like chaperone activity, demonstrating that dissociation at nondimeric interfaces is essential for sHsp activity. Moreover, the size of the Ta CT-ACD and Ps CT-ACD covalent unit defined a new tetrahedral geometry for these sHsps, different from that observed in the Ta16.9 X-ray structure. Importantly, oxidized Ta dimer (disulfide bonded at the dimeric interface) exhibited greatly enhanced ability to protect substrate, indicating that strengthening the dimeric interface increases chaperone efficiency. Temperature-induced size and secondary structure changes revealed that folded sHsp dimers interact with substrate and that dimer stability affects chaperone efficiency. These results yield a model in which sHsp dimers capture substrate before assembly into larger, heterogeneous sHspsubstrate complexes for substrate refolding or degradation, and suggest that tuning the strength of the dimer interface can be used to engineer sHsp chaperone efficiency.

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Small heat shock proteins in ageing and age-related diseases

Cited by 38 publications

References 135 publications

Characterization of heat shock protein 27 in extracellular vesicles: a potential anti‐inflammatory therapy

Characterization of heat shock protein 27 in extracellular vesicles: a potential anti‐inflammatory therapy

MiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging

It takes a dimer to tango: Oligomeric small heat shock proteins dissociate to capture substrate

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