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Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium
Haider H. Dar, … , Hülya Bayır, Valerian E. Kagan
Haider H. Dar, … , Hülya Bayır, Valerian E. Kagan
Published September 10, 2018
Citation Information: J Clin Invest. 2018;128(10):4639-4653. https://doi.org/10.1172/JCI99490.
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Research Article Cell biology Infectious disease Article has an altmetric score of 13

Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium

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Abstract

Ferroptosis is a death program executed via selective oxidation of arachidonic acid–phosphatidylethanolamines (AA-PE) by 15-lipoxygenases. In mammalian cells and tissues, ferroptosis has been pathogenically associated with brain, kidney, and liver injury/diseases. We discovered that a prokaryotic bacterium, Pseudomonas aeruginosa, that does not contain AA-PE can express lipoxygenase (pLoxA), oxidize host AA-PE to 15-hydroperoxy-AA-PE (15-HOO-AA-PE), and trigger ferroptosis in human bronchial epithelial cells. Induction of ferroptosis by clinical P. aeruginosa isolates from patients with persistent lower respiratory tract infections was dependent on the level and enzymatic activity of pLoxA. Redox phospholipidomics revealed elevated levels of oxidized AA-PE in airway tissues from patients with cystic fibrosis (CF) but not with emphysema or CF without P. aeruginosa. We believe that the evolutionarily conserved mechanism of pLoxA-driven ferroptosis may represent a potential therapeutic target against P. aeruginosa–associated diseases such as CF and persistent lower respiratory tract infections.

Authors

Haider H. Dar, Yulia Y. Tyurina, Karolina Mikulska-Ruminska, Indira Shrivastava, Hsiu-Chi Ting, Vladimir A. Tyurin, James Krieger, Claudette M. St. Croix, Simon Watkins, Erkan Bayir, Gaowei Mao, Catherine R. Armbruster, Alexandr Kapralov, Hong Wang, Matthew R. Parsek, Tamil S. Anthonymuthu, Abiola F. Ogunsola, Becca A. Flitter, Cody J. Freedman, Jordan R. Gaston, Theodore R. Holman, Joseph M. Pilewski, Joel S. Greenberger, Rama K. Mallampalli, Yohei Doi, Janet S. Lee, Ivet Bahar, Jennifer M. Bomberger, Hülya Bayır, Valerian E. Kagan

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Figure 4

Evolutionary analysis and computational modeling of pLoxA sequence and structure.

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Evolutionary analysis and computational modeling of pLoxA sequence and s...
(A) Comparing sequences of LOX homologs. The panels show sequence identity matrices obtained from 218 LOX sequences from all domains of life. High sequence similarity is in red, intermediate in yellow/green, and low in blue. Matrix generated for the entire LOX sequence (left panel) shows blocks evident for plants, animals, and bacteria, indicating their divergence. Light blue shading between these blocks indicates a degree of sequence similarity higher than to the block of other eukaryotes at the bottom (dark blue off-diagonal). High conservation for the catalytic site is shown in the middle panel. Residues involved in substrate recognition (right panel) exhibit a moderate level of conservation and species-specific differentiation, evidenced by the blocks for plants, animals, and bacteria. (B) Conservation propensity of LOX. The ordinate displays the Shannon entropy, subtracted from maximum entropy, plotted as a function of residue index; the peaks represent the most conserved residues. Note that catalytic residues (labeled) are among them. Residues involved in ligand coordination are indicated by the black dots. (C) Structural comparison of pLoxA and mammalian LOXes — 15LOX1 and 15LOX2. The structures resolved for pLoxA (yellow ribbon), 15LOX1 (green), and 15LOX2 (blue) are superimposed and display the missing β-barrel of the bacterial pLoxA and its additional α-helical hairpin motif at the C-terminus. (D) Comparison of the global motions of pLoxA and 15LOX1 complexed with PEBP1. Displacements of residues along the global mode axis obtained from GNM analysis of pLoxA (left, top) and 15LOX1-PEBP1 complex (left, bottom) dividing the structure into 2 domains that exhibit anticorrelated motion (above and below the dashed line). Residues at the crossover region (hinge centers or anchors) are labeled. The anticorrelated groups of residues are shown in red or blue (right, top and bottom).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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