期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 20, 页码 E2081-E2090出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1403379111
关键词
molecular chaperone; inflammation; protein folding; clearance
资金
- National Health and Medical Research Council, Australia
- Wolfson College, Cambridge, UK
- Wellcome Trust
- Centre for Medical and Molecular Bioscience at the University of Wollongong
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 alpha(2)-macroglobulin (alpha M-2) markedly increase its chaperone activity by generating species, particularly dimers formed by dissociation of the native tetramer, which have enhanced surface hydrophobicity. Moreover, dimeric alpha M-2 is generated in whole-blood plasma in the presence of physiologically relevant amounts of hypochlorite. The chaperone activity of hypochlorite-modified alpha M-2 involves the formation of stable soluble complexes with misfolded client proteins, including heat-denatured enzymes, oxidized fibrinogen, oxidized LDL, and native or oxidized amyloid beta-peptide (A beta(1-42)). Here, we show that hypochlorite-modified alpha M-2 delivers its misfolded cargo to lipoprotein receptors on macrophages and reduces A beta(1-42) neurotoxicity. Our results support the conclusion that alpha M-2 is a specialized chaperone that prevents the extracellular accumulation of misfolded and potentially pathogenic proteins, particularly during innate immune system activity.
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