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

mBio

Marie-Thérèse Giudici-Orticoni¹  Lisa Zuily¹  Marianne Ilbert¹  Nora Lahrach¹  Olivier Genest¹  Peter Faller²  Dana Reichmann³  Rosi Fassler³  Ursula Jakob⁴  Marie-Pierre Castanié-Cornet⁵  Pierre Genevaux⁵  Yann Denis⁶  Olivier Sénèque⁷ 

[1] Aix-Marseille Université, CNRS, BIP, UMR 7281, IMM, Marseille, France;Biometals and Biology Chemistry, Institut de Chimie (CNRS UMR7177), Université de Strasbourg, Strasbourg, France;Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem, Israel;Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA;Laboratoire de Microbiologie et Génétique Moléculaires, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France;Plateforme Transcriptome, Aix-Marseille Université, CNRS, IMM-FR3479, Marseille, France;Université Grenoble Alpes, CNRS, CEA, IRIG/DIESE, LCBM (UMR 5249), Grenoble, France;

关键词: copper stress;    molecular chaperone;    protein aggregation;    copper homeostasis;    Escherichia coli;    DnaK;   

DOI  :  10.1128/mbio.03251-21

来源: DOAJ

【 摘 要 】

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. IMPORTANCE With the increase of antibiotic drug resistance, alternative antibacterial treatment strategies are needed. Copper is a well-known antimicrobial and antiviral agent; however, the underlying molecular mechanisms by which copper causes cell death are not yet fully understood. Herein, we report the finding that Cu+, the physiologically relevant copper species in bacteria, causes widespread protein aggregation. We demonstrate that the molecular chaperones DnaK and trigger factor protect bacteria against Cu-induced cell death, highlighting, for the first time, the central role of these chaperones under Cu+ stress. Our studies reveal Cu-induced protein aggregation to be a central mechanism of Cu toxicity, a finding that will serve to guide future mechanistic studies and drug development.

【 授权许可】

Unknown