Copper Induces Protein Aggregation, a Toxic Process Compensated by Molecular Chaperones

Lisa Zuily, Nora Lahrach, Rosi Fassler, Olivier Genest, Peter Faller, Olivier Sénèque, Yann Denis, Marie Pierre Castanié-Cornet, Pierre Genevaux, Ursula Jakob, Dana Reichmann, Marie Thérèse Giudici-Orticoni, Marianne Ilbert

Research output: Contribution to journalArticlepeer-review

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 Cu1 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 Cu1-treated samples, suggesting that nonspecific interactions of Cu1 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 Cuinduced protein aggregation. Overall, our work provides new insights into the mechanism of Cu toxicity and the defense mechanisms that bacteria employ to survive.

Original languageAmerican English
JournalmBio
Volume13
Issue number2
DOIs
StatePublished - Apr 2022

Keywords

  • DnaK
  • Escherichia coli
  • copper homeostasis
  • copper stress
  • copper tolerance
  • heat shock
  • molecular chaperone
  • protein aggregation
  • proteostasis
  • stress response
  • trigger factor

All Science Journal Classification (ASJC) codes

  • Virology
  • Microbiology

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