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Journal Articles mBio Year : 2022

Copper induces protein aggregation, a toxic process compensated by molecular chaperones

Abstract

Copper is well known for its antimicrobial and antiviral properties. Under aerobic conditions, copper toxicity relies in part on the production of reactive oxygen species (ROS), especially in the periplasmic compartment. However, copper is significantly more toxic under anaerobic conditions, in which ROS cannot be produced. This toxicity has been proposed to arise from the inactivation of proteins through mismetallations. Here, using the bacterium Escherichia coli, we discovered that copper treatment under anaerobic conditions leads to a significant increase in protein aggregation. In vitro experiments using E. coli lysates and tightly controlled redox conditions confirmed that treatment with Cu$^+$ under anaerobic conditions leads to severe ROS-independent protein aggregation. Proteomic analysis of aggregated proteins revealed an enrichment of cysteine- and histidine-containing proteins in the Cu$^+$-treated samples, suggesting that nonspecific interactions of Cu$^+$ with these residues are likely responsible for the observed protein aggregation. In addition, E. coli strains lacking the cytosolic chaperone DnaK or trigger factor are highly sensitive to copper stress. These results reveal that bacteria rely on these chaperone systems to protect themselves against Cu-mediated protein aggregation and further support our finding that Cu toxicity is related to Cu-induced protein aggregation. Overall, our work provides new insights into the mechanism of Cu toxicity and the defense mechanisms that bacteria employ to survive.
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hal-03666635 , version 1 (05-09-2022)

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Lisa Zuily, Nora Lahrach, Rosi Fassler, Olivier Geneste, Peter Faller, et al.. Copper induces protein aggregation, a toxic process compensated by molecular chaperones. mBio, 2022, 13 (2), pp.e03251-21. ⟨10.1128/mbio.03251-21⟩. ⟨hal-03666635⟩
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