ArticleProceedings of the National Academy of Sciences of the United States of America2014
Hypochlorite-induced structural modifications enhance the chaperone activity of human α2-macroglobulin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 79 citations in OpenAlex.
- Combating ageing beyond the cell: Emerging roles of extracellular proteostasis.The FEBS journal · 2026Review
- Human α2-Macroglobulin: Architecture, Mechanisms, and Functional Implications.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Review
- Intracellular Signaling Regulated by Activated αInternational journal of molecular sciences · 2026Review
- Review
- Impact of Various Forced Oxidative Stress Factors in Rapid Degradation of mAb: Trastuzumab as a Case Study.Pharmaceutical research · 2025Article
- Half-Curcumin-Based Chemiluminescence Probes and Their Applications in Detecting Quasi-Stable Oxidized Proteins.Angewandte Chemie (International ed. in English) · 2024Article
- Oxidized Melanoma Antigens Promote Activation and Proliferation of Cytotoxic T-Cell Subpopulations.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Cellular oxidants and the proteostasis network: balance between activation and destruction.Trends in biochemical sciences · 2024Review
- Engineering New Protease Inhibitors Using αMethods in molecular biology (Clifton, N.J.) · 2024Article
- Proteomic changes of the bovine blood plasma in response to heat stress in a tropically adapted cattle breed.Frontiers in genetics · 2024Article
- Extracellular protein homeostasis in neurodegenerative diseases.Nature reviews. Neurology · 2023Review
- Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS.Cells · 2023Article
- Article
- Molecular characterization of thioester-containing proteins inFrontiers in immunology · 2022Article
- DNA interstrand cross-links induced by the major oxidative adenine lesion 7,8-dihydro-8-oxoadenine.Nature communications · 2021Article
- The effects of neutrophil-generated hypochlorous acid and other hypohalous acids on host and pathogens.Cellular and molecular life sciences : CMLS · 2021Review
- Alpha-2-Macroglobulin in Inflammation, Immunity and Infections.Frontiers in immunology · 2021Review
- Inhibiting lysine 353 oxidation of GRP78 by a hypochlorous probe targeting endoplasmic reticulum promotes autophagy in cancer cells.Cell death & disease · 2019Article
- Article
- Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia- and Alzheimer's-associated amyloid beta peptide.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
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 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.