Extracellular Chaperones and Proteostasis

Wyatt, Amy R.; Yerbury, Justin J.; Ecroyd, Heath; Wilson, Mark R.

doi:10.1146/annurev-biochem-072711-163904

Cited by 161 publications

(181 citation statements)

References 244 publications

(214 reference statements)

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“…It is well-established that molecular chaperones are vitally important for targeting misfolded proteins for repair or degradation within cells (12), and it is becoming increasingly apparent that extracellular chaperones, including α 2 M, also participate in essential proteostasis systems that function outside of cells (11). It has been shown that hypochlorite generated by stimulated neutrophils induces dissociation of α 2 M in vitro (26), and increased oxidation of α 2 M has been detected in rheumatoid ar- thritis and Alzheimer's disease (27,44), two protein misfolding conditions in which myeloperoxidase activity is known to be elevated (5, 45).…”

Section: Discussionmentioning

confidence: 99%

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Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Wyatt

Kumita

Mifsud

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hypochlorite, an oxidant generated in vivo by the innate immune system, kills invading pathogens largely by inducing the misfolding of microbial proteins. Concomitantly, the nonspecific activity of hypochlorite also damages host proteins, and the accumulation of damaged (misfolded) proteins is implicated in the pathology of a variety of debilitating human disorders (e.g., Alzheimer's disease, atherosclerosis, and arthritis). It is well-known that cells respond to oxidative stress by up-regulating proteostasis machinery, but the direct activation of mammalian chaperones by hypochlorite has not, to our knowledge, been previously reported. In this study, we show that hypochlorite-induced modifications of human α 2 -macroglobulin (α 2 M) markedly increase its chaperone activity by generating species, particularly dimers formed by dissociation of the native tetramer, which have enhanced surface hydrophobicity. Moreover, dimeric α 2 M is generated in whole-blood plasma in the presence of physiologically relevant amounts of hypochlorite. The chaperone activity of hypochlorite-modified α 2 M involves the formation of stable soluble complexes with misfolded client proteins, including heat-denatured enzymes, oxidized fibrinogen, oxidized LDL, and native or oxidized amyloid β-peptide (Aβ 1-42 ). Here, we show that hypochlorite-modified α 2 M delivers its misfolded cargo to lipoprotein receptors on macrophages and reduces Aβ 1-42 neurotoxicity. Our results support the conclusion that α 2 M is a specialized chaperone that prevents the extracellular accumulation of misfolded and potentially pathogenic proteins, particularly during innate immune system activity. molecular chaperone | inflammation | protein folding | clearance H ypochlorite, a potent oxidant produced by immune cells through the myeloperoxidase-H 2 O 2 -chloride system, kills invading microbes predominately by inducing the misfolding and aggregation of their proteins (1). The effects of hypochlorite, however, are nonspecific; therefore, when generated in vivo, the host organism suffers collateral damage (reviewed in refs. 2 and 3). During inflammation, hypochlorite production is accompanied by additional stresses, which are themselves capable of inducing protein misfolding (e.g., increased temperature and lowered pH); it is, therefore, not surprising that, in a large number of diseases [e.g., atherosclerosis (4), Alzheimer's disease (5, 6), age-related macular degeneration (7), and arthritis (8)], inflammatory pathology is associated with the accumulation of misfolded proteins.α 2 -Macroglobulin (α 2 M) is a highly abundant secreted protein that is best known for its ability to trap proteases (9); α 2 M can, however, interact with a broad range of molecules, and consequently, many other biological roles have been suggested, including targeting cytokines for clearance, sequestration of zinc, and opsonization of bacteria (reviewed in ref. 10). Furthermore, α 2 M has been identified as one of a small number of abundant extracellular chaperones (11). Although our un...

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Section: Discussionmentioning

confidence: 99%

“…10). Furthermore, α 2 M has been identified as one of a small number of abundant extracellular chaperones (11). Although our understanding of extracellular proteostasis has increased in recent years, it is still limited compared with our extensive knowledge of the mechanisms comprising intracellular proteostasis (12).…”

mentioning

confidence: 99%

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Wyatt

Kumita

Mifsud

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Molecules with chaperone activity are key components of the quality control processes used by living systems to maintain protein homeostasis in the highly crowded cellular environment. The majority of chaperones are located within cells Hartl et al, 2011;Bukau et al, 2006), but the presence of protective guardians in the extracellular environment collectively referred to as extracellular chaperones is now widely acknowledged (Wyatt et al 2012;Wyatt et al, 2013). Typically, chaperones prevent the aggregation of unfolded polypeptide chains ("holdase" activity) and/or promote their de novo protein folding or refolding, i.e.…”

Section: Introductionmentioning

confidence: 99%

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

Cappelli

Penco²,

Mannini³

et al. 2016

Biological Chemistry

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. (2016). Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations. Biological Chemistry: official scientific journal of the GBM, 397 (5), 401-415. Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations AbstractLiving systems protect themselves from aberrant proteins by a network of chaperones. We have tested in vitro the effects of different concentrations, ranging from 0 to 16 μm, of two molecular chaperones, namely αB-crystallin and clusterin, and an engineered monomeric variant of transthyretin (M-TTR), on the morphology and cytotoxicity of preformed toxic oligomers of HypF-N, which represent a useful model of misfolded protein aggregates. Using atomic force microscopy imaging and static light scattering analysis, all were found to bind HypF-N oligomers and increase the size of the aggregates, to an extent that correlates with chaperone concentration. SDS-PAGE profiles have shown that the large aggregates were predominantly composed of the HypF-N protein. ANS fluorescence measurements show that the chaperone-induced clustering of HypF-N oligomers does not change the overall solvent exposure of hydrophobic residues on the surface of the oligomers. αB-crystallin, clusterin and M-TTR can diminish the cytotoxic effects of the HypF-N oligomers at all chaperone concentration, as demonstrated by MTT reduction and Ca2+ influx measurements. The observation that the protective effect is primarily at all concentrations of chaperones, both when the increase in HypF-N aggregate size is minimal and large, emphasizes the efficiency and versatility of these protein molecules. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication DetailsCappelli, S., Penco, A., Mannini, B., Cascella, R., Wilson, M. R., Ecroyd, H., Li, X., Buxbaum, J. N., Dobson, C. M., Cecchi, C., Relini, A. & Chiti, F. (2016 measurements. The observation that the protective effect is primarily at all concentrations of chaperones, both when the increase in HypF-N aggregate size is minimal and large, emphasises the efficiency and versatility of these protein molecules.

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“…88,89 Another fascinating aspect of ECs and extracellular proteostasis is that of an extracellular protease machinery. Wyatt et al 90 in several of their review articles have discussed about the role of an extracellular protease machinery in protein quality control mechanism at the extracellular space. In case of neurons, a major role of extracellular space involves the maintenance of a normal neuronal structure for effective signal generation and transduction along with coordinated synaptic transmission of the neuronal signals.…”

Section: Ecs In Ameliorating Cns Amyloidosismentioning

confidence: 99%

Extracellular Chaperones in Neuronal Proteinopathies: Protecting and Facilitating Neuronal Function

Satapathy¹

2017

CCI

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Extracellular Chaperones and Proteostasis

Cited by 161 publications

References 244 publications

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

Extracellular Chaperones in Neuronal Proteinopathies: Protecting and Facilitating Neuronal Function

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Extracellular Chaperones and Proteostasis

Cited by 161 publications

References 244 publications

Hypochlorite-induced structural modifications enhance the chaperone activity of human α2-macroglobulin

Hypochlorite-induced structural modifications enhance the chaperone activity of human α2-macroglobulin

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

Extracellular Chaperones in Neuronal Proteinopathies: Protecting and Facilitating Neuronal Function

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Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin