Cadmium-mediated activation of the HSP90/HSF1 pathway regulated by reactive persulfides/polysulfides

Abstract

Cadmium is an environmental electrophile that modifies reactive thiols in proteins, indicating that this heavy metal may modulate redox-signal transduction pathways. The current consensus is that reactive persulfides and polysulfides produced by cystathionine c-lyase (CSE) and cystathionine b-synthase are highly nucleophilic and thus cadmium may be captured by these reactive sulfur species. It has previously been found that electrophile-mediated covalent modifications of the heat shock protein (HSP) are involved in the activation of heat shock factor 1 (HSF1) pathway. The effects of cadmium on the activation of HSP/HSF1 pathway were investigated in this study. Exposure of bovine aortic endothelial cells to cadmium resulted in modification of HSP90 and HSF1 activation, thereby up-regulating the downstream protein HSP70. The siRNA-mediated knockdown of HSF1 enhanced the cytotoxicity induced by cadmium, suggesting that the HSP90/HSF1 pathway contributes to protection against cadmium toxicity. The knockdown of CSE and/or cystathionine b-synthase decreased the levels of reactive sulfur species in the cells and increased the degree of HSP70 induction and cytotoxicity caused by exposure to cadmium. Overexpression of CSE diminished cadmium-mediated up-regulation of HSP70 and cytotoxicity. These results suggest that cadmium activates HSF1 by modifying HSP90 and that reactive sulfur species regulate the redox signal transduction pathway presumably via capture of cadmium, resulting in protection against cadmium toxicity under toxic conditions.

Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both

“…2015b), suggesting that CSE participates in diminishment of environmental electrophile-mediated toxicity through formation of sulfur adducts. Although we have reported that knockdown or deletion of CSE enhances Cd-mediated toxicity both in vitro (Shinkai et al. 2017) and in vivo (Akiyama et al.…”

Biological hydropersulfides and related polysulfides – a new concept and perspective in redox biology

“…Abiko and coworkers [60] found that detoxification of methyl mercury can occur via interaction with H 2 S, hydropersulfides and polysulfides. Similarly, Cd 2+ toxicity can also be abated by the presence of hydropersulfides [61]. Importantly, Zn 2+ and Cd 2+ are chemically and biochemically similar in that they both readily bind thiol proteins and indeed a facet of Cd 2+ toxicity is thought to involve interference with Zn 2+ homeostasis [62].…”

Nrf2 Activation and Its Coordination with the Protective Defense Systems in Response to Electrophilic Stress

“…The metabolite analysis of wild-type (WT) and CSE knockout (KO) mice exposed to MeHg showed that (MeHg) 2 S was present at significant levels in various WT mouse tissues, but not at appreciable levels in CSE KO mouse tissues [79], suggesting that CSE is a critical enzyme involved in capturing xenobiotic electrophiles through formation of sulfur adducts in vivo. Furthermore, knockdown of CSE enhanced Cd-induced cytotoxicity, whereas overexpression of CSE protected cells from this electrophile-induced cytotoxicity [83]. In vivo studies have shown that CSE deletion in mice causes increased sensitivity to acetaminophen-induced hepatotoxicity, Cd-induced hepatotoxicity and MeHg-induced toxicity [20,77,84].…”