Bleach Activates a Redox-Regulated Chaperone by Oxidative Protein Unfolding

Abstract

Summary Hypochlorous acid (HOCl), the active ingredient of household bleach, is an effective antimicrobial produced by the mammalian host defense to kill invading microorganisms. Despite the widespread use of HOCl, surprisingly little is known about its mode of action. In this study we demonstrate that low molar ratios of HOCl to protein cause oxidative protein unfolding in vitro and target thermolabile proteins for irreversible aggregation in vivo. As a defense mechanism, bacteria employ the redox-regulated chaperone Hsp33, which responds to bleach treatment with the reversible oxidative unfolding of its C-terminal redox switch domain. HOCl-mediated unfolding turns inactive Hsp33 into a highly active chaperone holdase, which protects essential E. coli proteins against HOCl-induced aggregation and increases bacterial HOCl-resistance. Our results substantially improve our molecular understanding about HOCl’s functional mechanism. They suggest that the antimicrobial effects of bleach are largely based on HOCl’s ability to cause aggregation of essential bacterial proteins.

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

“…(4,6,38). As has been shown for many other proteins, incubation of FGN or LDL with hypochlorite induces their self-aggregation into high-molecular mass complexes (1,39,40). In contrast, α 2 M is able to withstand high concentrations of hypochlorite without self-aggregating (Fig.…”

“…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.…”

Harnessing host ROS-generating machinery for the robust genome replication of a plant RNA virus

“…They govern the functions of various proteins, including redox-sensitive chaperone Hsp33 and calcium/calmodulin-dependent protein kinase CaMKII, through regulation of disulfide bond formation or oxidation of methionine residues (49,50). Oxidizing agents enhance the guanyltransferase activity of flavivirus NS5 or alphavirus nsP1 in vitro (51).…”

Synergistic Roles of Helicobacter pylori Methionine Sulfoxide Reductase and GroEL in Repairing Oxidant-damaged Catalase

“…Other studies reported oxidation-induced loss of secondary structure in several proteins (9,36,51,52). A recent study suggested oxidative unfolding and consequent aggregation as a major mechanism of HOCl-mediated protein inactivation (40). As sulfoxides are more hydrophilic than Met residues, their formation can change the overall surface charge of a protein (8,38).…”