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Dysregulation of Cytosolic c-di-GMP in Edwardsiella piscicida Promotes Cellular Non-Canonical Ferroptosis
Programmed cell death plays an important role in modulating host immune defense and pathogen infection. Ferroptosis is a type of inflammatory cell death induced by intracellular iron-dependent accumulation of toxic lipid peroxides. Although ferroptosis has been associated with cancer and other steri...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855483/ https://www.ncbi.nlm.nih.gov/pubmed/35186798 http://dx.doi.org/10.3389/fcimb.2022.825824 |
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author | Wen, Ying Wang, Ying Chen, Shouwen Zhou, Xiangshan Zhang, Yuanxing Yang, Dahai Núñez, Gabriel Liu, Qin |
author_facet | Wen, Ying Wang, Ying Chen, Shouwen Zhou, Xiangshan Zhang, Yuanxing Yang, Dahai Núñez, Gabriel Liu, Qin |
author_sort | Wen, Ying |
collection | PubMed |
description | Programmed cell death plays an important role in modulating host immune defense and pathogen infection. Ferroptosis is a type of inflammatory cell death induced by intracellular iron-dependent accumulation of toxic lipid peroxides. Although ferroptosis has been associated with cancer and other sterile diseases, very little is known about the role of ferroptosis in modulating host-pathogen interactions. We show that accumulation of the secondary messenger bis-(3′,5′)-cyclic dimeric GMP (c-di-GMP) in the pathogenic bacterium Edwardsiella piscicida (E. piscicida) triggers a non-canonical ferroptosis pathway in infected HeLa cells. Moreover, we observed that the dysregulation of c-di-GMP in E. piscicida promotes iron accumulation, mitochondrial dysfunction, and production of reactive oxygen species, all of which that can be blocked by iron chelator. Importantly, unlike classical ferroptosis that is executed via excess lipid peroxidation, no lipid peroxidation was detected in the infected cells. Furthermore, lipoxygenases inhibitors and lipophilic antioxidants are not able to suppress morphological changes and cell death induced by E. piscicida mutant producing excess c-di-GMP, and this c-di-GMP dysregulation attenuates bacterial virulence in vivo. Collectively, our results reveal a novel non-canonical ferroptosis pathway mediated by bacterial c-di-GMP and provide evidence for a role of ferroptosis in the regulation of pathogen infection. |
format | Online Article Text |
id | pubmed-8855483 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-88554832022-02-19 Dysregulation of Cytosolic c-di-GMP in Edwardsiella piscicida Promotes Cellular Non-Canonical Ferroptosis Wen, Ying Wang, Ying Chen, Shouwen Zhou, Xiangshan Zhang, Yuanxing Yang, Dahai Núñez, Gabriel Liu, Qin Front Cell Infect Microbiol Cellular and Infection Microbiology Programmed cell death plays an important role in modulating host immune defense and pathogen infection. Ferroptosis is a type of inflammatory cell death induced by intracellular iron-dependent accumulation of toxic lipid peroxides. Although ferroptosis has been associated with cancer and other sterile diseases, very little is known about the role of ferroptosis in modulating host-pathogen interactions. We show that accumulation of the secondary messenger bis-(3′,5′)-cyclic dimeric GMP (c-di-GMP) in the pathogenic bacterium Edwardsiella piscicida (E. piscicida) triggers a non-canonical ferroptosis pathway in infected HeLa cells. Moreover, we observed that the dysregulation of c-di-GMP in E. piscicida promotes iron accumulation, mitochondrial dysfunction, and production of reactive oxygen species, all of which that can be blocked by iron chelator. Importantly, unlike classical ferroptosis that is executed via excess lipid peroxidation, no lipid peroxidation was detected in the infected cells. Furthermore, lipoxygenases inhibitors and lipophilic antioxidants are not able to suppress morphological changes and cell death induced by E. piscicida mutant producing excess c-di-GMP, and this c-di-GMP dysregulation attenuates bacterial virulence in vivo. Collectively, our results reveal a novel non-canonical ferroptosis pathway mediated by bacterial c-di-GMP and provide evidence for a role of ferroptosis in the regulation of pathogen infection. Frontiers Media S.A. 2022-02-04 /pmc/articles/PMC8855483/ /pubmed/35186798 http://dx.doi.org/10.3389/fcimb.2022.825824 Text en Copyright © 2022 Wen, Wang, Chen, Zhou, Zhang, Yang, Núñez and Liu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cellular and Infection Microbiology Wen, Ying Wang, Ying Chen, Shouwen Zhou, Xiangshan Zhang, Yuanxing Yang, Dahai Núñez, Gabriel Liu, Qin Dysregulation of Cytosolic c-di-GMP in Edwardsiella piscicida Promotes Cellular Non-Canonical Ferroptosis |
title | Dysregulation of Cytosolic c-di-GMP in Edwardsiella piscicida Promotes Cellular Non-Canonical Ferroptosis |
title_full | Dysregulation of Cytosolic c-di-GMP in Edwardsiella piscicida Promotes Cellular Non-Canonical Ferroptosis |
title_fullStr | Dysregulation of Cytosolic c-di-GMP in Edwardsiella piscicida Promotes Cellular Non-Canonical Ferroptosis |
title_full_unstemmed | Dysregulation of Cytosolic c-di-GMP in Edwardsiella piscicida Promotes Cellular Non-Canonical Ferroptosis |
title_short | Dysregulation of Cytosolic c-di-GMP in Edwardsiella piscicida Promotes Cellular Non-Canonical Ferroptosis |
title_sort | dysregulation of cytosolic c-di-gmp in edwardsiella piscicida promotes cellular non-canonical ferroptosis |
topic | Cellular and Infection Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855483/ https://www.ncbi.nlm.nih.gov/pubmed/35186798 http://dx.doi.org/10.3389/fcimb.2022.825824 |
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