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

Amy R. Wyatt, Janet R. Kumita, Richard W. Mifsud, Cherrie A. Gooden, Mark R. Wilson, Christopher Martin Dobson

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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 ?2-macroglobulin (?2M) markedly increase its chaperone activity by generating species, particularly dimers formed by dissociation of the native tetramer, which have enhanced surface hydrophobicity. Moreover, dimeric ?2M is generated in whole-blood plasma in the presence of physiologically relevant amounts of hypochlorite. The chaperone activity of hypochlorite-modified ?2M involves the formation of stable soluble complexes with misfolded client proteins, including heat-denatured enzymes, oxidized fibrinogen, oxidized LDL, and native or oxidized amyloid ?-peptide (A?1-42). Here, we show that hypochlorite-modified ?2M delivers its misfolded cargo to lipoprotein receptors on macrophages and reduces A?1-42 neurotoxicity. Our results support the conclusion that ?2M is a specialized chaperone that prevents the extracellular accumulation of misfolded and potentially pathogenic proteins, particularly during innate immune system activity.

Original languageEnglish
Pages (from-to)E2081-E2090
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number20
DOIs
Publication statusPublished - 20 May 2014
Externally publishedYes

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