Trivalent Arsenic Inhibits the Functions of Chaperonin Complex

Department of Biology and Integrated Imaging Center, The Johns Hopkins University, Baltimore, MD 21218, USA.
Genetics (Impact Factor: 5.96). 10/2010; 186(2):725-34. DOI: 10.1534/genetics.110.117655
Source: PubMed


The exact molecular mechanisms by which the environmental pollutant arsenic works in biological systems are not completely understood. Using an unbiased chemogenomics approach in Saccharomyces cerevisiae, we found that mutants of the chaperonin complex TRiC and the functionally related prefoldin complex are all hypersensitive to arsenic compared to a wild-type strain. In contrast, mutants with impaired ribosome functions were highly arsenic resistant. These observations led us to hypothesize that arsenic might inhibit TRiC function, required for folding of actin, tubulin, and other proteins postsynthesis. Consistent with this hypothesis, we found that arsenic treatment distorted morphology of both actin and microtubule filaments. Moreover, arsenic impaired substrate folding by both bovine and archaeal TRiC complexes in vitro. These results together indicate that TRiC is a conserved target of arsenic inhibition in various biological systems.

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    • "Arsenic is a known carcinogen (Tokar et al. 2010), and the cumulative dose of 2000 mg of arsenic has been reported to increase the risk of bladder cancer (Cuzick et al. 1992). As 2 O 3 (trivalent inorganic arsenic) was reported to inhibit cellular functions and distort intracellular microstructures at the concentration of 1 mmol L À1 in eukaryotic cells (Pan et al. 2010). In the present study, arsenic was detected in MTA Angelus and MM MTA at concentrations of 1.69 and 1.76 ppm, respectively. "
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    ABSTRACT: To investigate the levels of nine metals (aluminium (Al), antimony (Sb), arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr), iron (Fe), lead (Pb), and molybdenum (Mo)) in MTA Angelus, Micro Mega MTA, and Bioaggregate using inductively coupled plasma-optical emission spectrometry (ICP-OES). Each material (0.2 g) was digested using a mixture of hydrochloric and nitric acids and then filtered. The levels of nine metals in the resulting filtrates were measured by ICP-OES. The results were statistically analyzed using one-way ANOVA and the Bonferroni test. MTA Angelus contained more aluminium, beryllium, and chromium than Micro Mega MTA (p<0.05), while their levels of arsenic, cadmium, and iron were similar. Antimony, lead, and molybdenum were not detected in any of the three tested cements. Bioaggregate contained trace amounts of aluminium. MTA Angelus and Micro Mega MTA contained small amounts of seven tested metal oxides. Bioaggregate only contained trace amounts of aluminium. This article is protected by copyright. All rights reserved.
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    • "Although some of the chaperone genes like dnaK2, htpG or hspA have been described to be up-regulated after several stress conditions [37], [38], [39], [40], [41], [42], a general induction of this group has not been previously described. Recently, it has been shown that arsenite is able to inhibit nascent protein folding both in vitro and in vivo in yeast [13], [14], [15] and Archea [15]. These results suggest that in Synechocystis arsenite is also able to cause protein damage and that chaperones and proteases are induced in order to repair or degrade these damaged proteins. "
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    ABSTRACT: Arsenic is a ubiquitous contaminant and a toxic metalloid which presents two main redox states in nature: arsenite [AsIII] and arsenate [AsV]. Arsenic resistance in Synechocystis sp. strain PCC 6803 is mediated by the arsBHC operon and two additional arsenate reductases encoded by the arsI1 and arsI2 genes. Here we describe the genome-wide responses to the presence of arsenate and arsenite in wild type and mutants in the arsenic resistance system. Both forms of arsenic produced similar responses in the wild type strain, including induction of several stress related genes and repression of energy generation processes. These responses were transient in the wild type strain but maintained in time in an arsB mutant strain, which lacks the arsenite transporter. In contrast, the responses observed in a strain lacking all arsenate reductases were somewhat different and included lower induction of genes involved in metal homeostasis and Fe-S cluster biogenesis, suggesting that these two processes are targeted by arsenite in the wild type strain. Finally, analysis of the arsR mutant strain revealed that ArsR seems to only control 5 genes in the genome. Furthermore, the arsR mutant strain exhibited hypersentivity to nickel, copper and cadmium and this phenotype was suppressed by mutation in arsB but not in arsC gene suggesting that overexpression of arsB is detrimental in the presence of these metals in the media.
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    • "It is possible that Cd and Cr do not enter cells as efficiently as As(III). Alternatively, the observed difference in potency could be a consequence of distinct modes of biological action; for example, Cr causes protein mistranslation (Holland et al., 2007) whilst As(III) does not (Fig. 3); As(III) interferes with CCT activity in vitro whilst Cd does not (Pan et al., 2010). The fact that Cd is very efficient in inhibiting protein folding in vitro but less potent in triggering protein aggregation in vivo, could potentially be explained by a lack of CCT inhibition given that CCT participates in the folding of as much as 10–15% of all cytosolic proteins in mammalian cells (Thulasiraman et al., 1999). "
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    ABSTRACT: Several metals and metalloids profoundly affect biological systems, but their impact on the proteome and mechanisms of toxicity are not fully understood. Here, we demonstrate that arsenite causes protein aggregation in Saccharomyces cerevisiae. Various molecular chaperones were found to be associated with arsenite-induced aggregates indicating that this metalloid promotes protein misfolding. Using in vivo and in vitro assays, we show that proteins in the process of synthesis/folding are particularly sensitive to arsenite-induced aggregation, that arsenite interferes with protein folding by acting on unfolded polypeptides, and that arsenite directly inhibits chaperone activity. Thus, folding inhibition contributes to arsenite toxicity in two ways: by aggregate formation and by chaperone inhibition. Importantly, arsenite-induced protein aggregates can act as seeds committing other, labile proteins to misfold and aggregate. Our findings describe a novel mechanism of toxicity that may explain the suggested role of this metalloid in the etiology and pathogenesis of protein folding disorders associated with arsenic poisoning.
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