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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03251-21 |
| _version_ | 1818115901420994560 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Lisa Zuily |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T04:13:59Z |
| format | Article |
| id | doaj.art-d2b88acbd8ca489194f154fe226ef8b8 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-11T04:13:59Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-d2b88acbd8ca489194f154fe226ef8b82022-12-22T01:21:18ZengAmerican Society for MicrobiologymBio2150-75112022-04-0113210.1128/mbio.03251-21Copper Induces Protein Aggregation, a Toxic Process Compensated by Molecular ChaperonesLisa Zuily0Nora Lahrach1Rosi Fassler2Olivier Genest3Peter Faller4Olivier Sénèque5Yann Denis6Marie-Pierre Castanié-Cornet7Pierre Genevaux8Ursula Jakob9Dana Reichmann10Marie-Thérèse Giudici-Orticoni11Marianne Ilbert12Aix-Marseille Université, CNRS, BIP, UMR 7281, IMM, Marseille, FranceAix-Marseille Université, CNRS, BIP, UMR 7281, IMM, Marseille, FranceDepartment of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem, IsraelAix-Marseille Université, CNRS, BIP, UMR 7281, IMM, Marseille, FranceBiometals and Biology Chemistry, Institut de Chimie (CNRS UMR7177), Université de Strasbourg, Strasbourg, FranceUniversité Grenoble Alpes, CNRS, CEA, IRIG/DIESE, LCBM (UMR 5249), Grenoble, FrancePlateforme Transcriptome, Aix-Marseille Université, CNRS, IMM-FR3479, Marseille, FranceLaboratoire de Microbiologie et Génétique Moléculaires, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, FranceLaboratoire de Microbiologie et Génétique Moléculaires, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, FranceDepartment of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USADepartment of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem, IsraelAix-Marseille Université, CNRS, BIP, UMR 7281, IMM, Marseille, FranceAix-Marseille Université, CNRS, BIP, UMR 7281, IMM, Marseille, FranceABSTRACT 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.https://journals.asm.org/doi/10.1128/mbio.03251-21copper stressmolecular chaperoneprotein aggregationcopper homeostasisEscherichia coliDnaK |
| spellingShingle | 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 Copper Induces Protein Aggregation, a Toxic Process Compensated by Molecular Chaperones mBio copper stress molecular chaperone protein aggregation copper homeostasis Escherichia coli DnaK |
| title | Copper Induces Protein Aggregation, a Toxic Process Compensated by Molecular Chaperones |
| title_full | Copper Induces Protein Aggregation, a Toxic Process Compensated by Molecular Chaperones |
| title_fullStr | Copper Induces Protein Aggregation, a Toxic Process Compensated by Molecular Chaperones |
| title_full_unstemmed | Copper Induces Protein Aggregation, a Toxic Process Compensated by Molecular Chaperones |
| title_short | Copper Induces Protein Aggregation, a Toxic Process Compensated by Molecular Chaperones |
| title_sort | copper induces protein aggregation a toxic process compensated by molecular chaperones |
| topic | copper stress molecular chaperone protein aggregation copper homeostasis Escherichia coli DnaK |
| url | https://journals.asm.org/doi/10.1128/mbio.03251-21 |
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