Therapeutic Effects of Systemic Administration of Chaperone αB-Crystallin Associated with Binding Proinflammatory Plasma Proteins

Rothbard, Jonathan B.; Kurnellas, Michael; Brownell, Sara E.; Adams, Chris; Su, Leon; Axtell, Robert C.; Chen, Rong; Fathman, C. Garrison; Robinson, William H.; Steinman, Lawrence

doi:10.1074/jbc.m111.337691

Cited by 83 publications

(103 citation statements)

References 35 publications

(34 reference statements)

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“…Inflammation is a state in which many stresses capable of inducing protein misfolding and aggregation are elevated; therefore, it is likely that proteostasis mechanisms will be enhanced during inflammatory events. Moreover, it has been shown that many acute-phase proteins are susceptible to stress-induced misfolding and major endogenous clients for holdase chaperones in human blood plasma (65)(66)(67). To survive periods of increased physiological stress, cells use several different strategies to prevent the accumulation of misfolded proteins (68)(69)(70)(71).…”

Section: Discussionmentioning

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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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%

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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“…In another manuscript (29) we have explored this hypothesis by defining the set of proteins HspB5 binds in plasma from patients with multiple sclerosis, rheumatoid arthritis, and amyloidosis. In each case, the sHsp precipitate was enriched relative to the normal plasma concentration with a set of ϳ65 proteins, over half of which are members of the acute phase, complement, and coagulation pathways.…”

Section: Tablementioning

confidence: 99%

“…Further analyses in these animal models concluded that the protein was immunosuppressive. The anti-inflammatory property was not due to influencing the adaptive immune response directly, but rather there was binding and resultant modulation of the proinflammatory mediators in plasma (29). These observations are at the basis of the therapeutic effects seen in both autoimmune and ischemic models of disease, including EAE, stroke, myocardial infarction, and retinal ischemia (25)(26)(27)(28).…”

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confidence: 91%

Chaperone Activity of Small Heat Shock Proteins Underlies Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

Kurnellas

Brownell

et al. 2012

Journal of Biological Chemistry

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Background:The small heat shock protein, HspB5, is therapeutic in experimental autoimmune encephalomyelitis. Results: Eight other human sHsps, a mycobacterial sHsp, and a linear peptide from HspB5 were equally effective therapeutics. Conclusion: All of the therapeutic proteins and peptides were also molecular chaperones. Significance: Correlation between chaperone activity and therapeutic function supports data demonstrating sHsps bind inflammatory mediators in plasma.

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“…Meanwhile, Rothbard and another outstanding postdoc, Mike Kurnellas, had done structure function experiments narrowing the domains of amyloid proteins that might exert their immunesuppressive activity (89,90). Finally, Rothbard and Kurnellas realized that Eisenberg's amyloid fibril hexapeptides might indeed have immune-suppressive properties.…”

Section: Translational Research At Stanford Over the Past 20 Yearsmentioning

confidence: 99%

“…The amyloid structures bind inflammatory mediators in plasma (89)(90)(91). Amyloid hexapeptide structures elicit a type 1 interferon response (93).…”

Section: Translational Research At Stanford Over the Past 20 Yearsmentioning

confidence: 99%

A Journey in Science: The Privilege of Exploring the Brain and the Immune System

Steinman

2016

Mol Med

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Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Molecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these histories. The monographs recount the seminal events as told in the voice of the original investigators who provided the crucial early insight. These essays capture the essence of discovery, chronicling the birth of ideas that created new fields of research; and launched trajectories that persisted and ultimately influenced how disease is prevented, diagnosed, and treated. In this volume, the Cerami Award Monograph is by Lawrence Steinman, MD, of Stanford University in California. A visionary in the field of neurology, this is the story of Dr. Steinman's scientific journey.

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Therapeutic Effects of Systemic Administration of Chaperone αB-Crystallin Associated with Binding Proinflammatory Plasma Proteins

Cited by 83 publications

References 35 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

Chaperone Activity of Small Heat Shock Proteins Underlies Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

A Journey in Science: The Privilege of Exploring the Brain and the Immune System

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Therapeutic Effects of Systemic Administration of Chaperone αB-Crystallin Associated with Binding Proinflammatory Plasma Proteins

Cited by 83 publications

References 35 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

Chaperone Activity of Small Heat Shock Proteins Underlies Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

A Journey in Science: The Privilege of Exploring the Brain and the Immune System

Contact Info

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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