PT  - JOURNAL ARTICLE
AU  - Wyatt, Amy R.
AU  - Kumita, Janet R.
AU  - Mifsud, Richard W.
AU  - Gooden, Cherrie A.
AU  - Wilson, Mark R.
AU  - Dobson, Christopher M.
TI  - Hypochlorite-induced structural modifications enhance the chaperone activity of human α<sub>2</sub>-macroglobulin
AID  - 10.1073/pnas.1403379111
DP  - 2014 May 02
TA  - Proceedings of the National Academy of Sciences
PG  - 201403379
4099  - http://www.pnas.org/content/early/2014/05/01/1403379111.short
4100  - http://www.pnas.org/content/early/2014/05/01/1403379111.full
AB  - Hypochlorite is a powerful oxidant that is generated within the body by activated innate immune cells. When hypochlorite is produced, the host organism sustains collateral damage, particularly to proteins, and the accumulation of damaged (misfolded) proteins is a hallmark of inflammatory processes (e.g., in Alzheimer’s disease, atherosclerosis, and arthritis). In the present study, we show that the chaperone activity of human α2-macroglobulin, a highly abundant secreted protein, is dramatically increased by hypochlorite-induced structural modifications. The data support the conclusion that α2-macroglobulin is a unique component of the innate immune system that is posttranslationally regulated by hypochlorite to facilitate the clearance of potentially pathogenic misfolded proteins.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 α2-macroglobulin (α2M) markedly increase its chaperone activity by generating species, particularly dimers formed by dissociation of the native tetramer, which have enhanced surface hydrophobicity. Moreover, dimeric α2M is generated in whole-blood plasma in the presence of physiologically relevant amounts of hypochlorite. The chaperone activity of hypochlorite-modified α2M 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 (Aβ1–42). Here, we show that hypochlorite-modified α2M delivers its misfolded cargo to lipoprotein receptors on macrophages and reduces Aβ1–42 neurotoxicity. Our results support the conclusion that α2M is a specialized chaperone that prevents the extracellular accumulation of misfolded and potentially pathogenic proteins, particularly during innate immune system activity.