title: Endoplasmic reticulum-derived reactive oxygen species (ROS) is involved in toxicity of cell wall stress to Candida albicans.
abstract: The cell wall is an important cell structure in both fungi and bacteria, and hence becomes a common antimicrobial target. The cell wall-perturbing agents disrupt synthesis and function of cell wall components, leading to cell wall stress and consequent cell death. However, little is known about the detailed mechanisms by which cell wall stress renders fungal cell death. In this study, we found that ROS scavengers drastically attenuated the antifungal effect of cell wall-perturbing agents to the model fungal pathogen Candida albicans, and these agents caused remarkable ROS accumulation and activation of oxidative stress response (OSR) in this fungus. Interestingly, cell wall stress did not cause mitochondrial dysfunction and elevation of mitochondrial superoxide levels. Furthermore, the iron chelator 2,2'-bipyridyl (BIP) and the hydroxyl radical scavengers could not attenuate cell wall stress-caused growth inhibition and ROS accumulation. However, cell wall stress up-regulated expression of unfold protein response (UPR) genes, enhanced protein secretion and promoted protein folding-related oxidation of Ero1, an important source of ROS production. These results indicated that oxidation of Ero1 in the endoplasmic reticulum (ER), rather than mitochondrial electron transport and Fenton reaction, contributed to cell wall stress-related ROS accumulation and consequent growth inhibition. Our findings uncover a novel link between cell wall integrity (CWI), ER function and ROS production in fungal cells, and shed novel light on development of strategies promoting the antifungal efficacy of cell wall-perturbing agents against fungal infections.
authors.affiliation: Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Science, Nankai University, Tianjin 300071, PR China.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Science, Nankai University, Tianjin 300071, PR China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Science, Nankai University, Tianjin 300071, PR China.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Li
authors.affiliation: Tianjin Traditional Chinese Medicine University, Tianjin 300193, PR China.
authors.forename: Biao
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Science, Nankai University, Tianjin 300071, PR China.
authors.forename: Honggang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Science, Nankai University, Tianjin 300071, PR China. Electronic address: nklimingchun@163.com.
authors.forename: Mingchun
authors.initials: M
authors.lastname: Li
mesh_terms: D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D000077336:Caspofungin; D002473:Cell Wall / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002614:Chelating Agents / Q000494:pharmacology; D054714:Echinocandins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D055666:Lipopeptides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics* / Q000378:metabolism; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D001557:Benzenesulfonates; D002614:Chelating Agents; D054714:Echinocandins; D016166:Free Radical Scavengers; D005656:Fungal Proteins; D055666:Lipopeptides; D017382:Reactive Oxygen Species; D015082:2,2'-Dipyridyl; C007061:C.I. Fluorescent Brightening Agent 28; D050862:Oxidoreductases Acting on Sulfur Group Donors; D000077336:Caspofungin; D000111:Acetylcysteine
keywords: Cell wall stress; Endoplasmic reticulum (ER); Ero1; Protein folding; Reactive oxygen species (ROS)