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Ce-Duox1/BLI-3 generated reactive oxygen species trigger protective SKN-1 activity via p38 MAPK signaling during infection in C. elegans.
PLoS Pathog. 2011 Dec; 7(12):e1002453.PP

Abstract

Infected animals will produce reactive oxygen species (ROS) and other inflammatory molecules that help fight pathogens, but can inadvertently damage host tissue. Therefore specific responses, which protect and repair against the collateral damage caused by the immune response, are critical for successfully surviving pathogen attack. We previously demonstrated that ROS are generated during infection in the model host Caenorhabditis elegans by the dual oxidase Ce-Duox1/BLI-3. Herein, an important connection between ROS generation by Ce-Duox1/BLI-3 and upregulation of a protective transcriptional response by SKN-1 is established in the context of infection. SKN-1 is an ortholog of the mammalian Nrf transcription factors and has previously been documented to promote survival, following oxidative stress, by upregulating genes involved in the detoxification of ROS and other reactive compounds. Using qRT-PCR, transcriptional reporter fusions, and a translational fusion, SKN-1 is shown to become highly active in the C. elegans intestine upon exposure to the human bacterial pathogens, Enterococcus faecalis and Pseudomonas aeruginosa. Activation is dependent on the overall pathogenicity of the bacterium, demonstrated by a weakened response observed in attenuated mutants of these pathogens. Previous work demonstrated a role for p38 MAPK signaling both in pathogen resistance and in activating SKN-1 upon exposure to chemically induced oxidative stress. We show that NSY-1, SEK-1 and PMK-1 are also required for SKN-1 activity during infection. Evidence is also presented that the ROS produced by Ce-Duox1/BLI-3 is the source of SKN-1 activation via p38 MAPK signaling during infection. Finally, for the first time, SKN-1 activity is shown to be protective during infection; loss of skn-1 decreases resistance, whereas increasing SKN-1 activity augments resistance to pathogen. Overall, a model is presented in which ROS generation by Ce-Duox1/BLI-3 activates a protective SKN-1 response via p38 MAPK signaling.

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Authors+Show Affiliations

Hoeven Rv
Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
McCallum KC
No affiliation info available
Cruz MR
No affiliation info available
Garsin DA
No affiliation info available

MeSH

AnimalsCaenorhabditis elegansCaenorhabditis elegans ProteinsDNA-Binding ProteinsEnterococcus faecalisEnzyme ActivationGram-Positive Bacterial InfectionsImmunity, InnateIntestinal MucosaIntestinesMAP Kinase Signaling SystemOxidoreductasesPseudomonas InfectionsPseudomonas aeruginosaReactive Oxygen SpeciesTranscription Factorsp38 Mitogen-Activated Protein Kinases

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22216003

Citation

Hoeven, Ransome van der, et al. "Ce-Duox1/BLI-3 Generated Reactive Oxygen Species Trigger Protective SKN-1 Activity Via P38 MAPK Signaling During Infection in C. Elegans." PLoS Pathogens, vol. 7, no. 12, 2011, pp. e1002453.
Hoeven Rv, McCallum KC, Cruz MR, et al. Ce-Duox1/BLI-3 generated reactive oxygen species trigger protective SKN-1 activity via p38 MAPK signaling during infection in C. elegans. PLoS Pathog. 2011;7(12):e1002453.
Hoeven, R. v., McCallum, K. C., Cruz, M. R., & Garsin, D. A. (2011). Ce-Duox1/BLI-3 generated reactive oxygen species trigger protective SKN-1 activity via p38 MAPK signaling during infection in C. elegans. PLoS Pathogens, 7(12), e1002453. https://doi.org/10.1371/journal.ppat.1002453
Hoeven Rv, et al. Ce-Duox1/BLI-3 Generated Reactive Oxygen Species Trigger Protective SKN-1 Activity Via P38 MAPK Signaling During Infection in C. Elegans. PLoS Pathog. 2011;7(12):e1002453. PubMed PMID: 22216003.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ce-Duox1/BLI-3 generated reactive oxygen species trigger protective SKN-1 activity via p38 MAPK signaling during infection in C. elegans. AU - Hoeven,Ransome van der, AU - McCallum,Katie C, AU - Cruz,Melissa R, AU - Garsin,Danielle A, Y1 - 2011/12/22/ PY - 2011/05/11/received PY - 2011/11/07/accepted PY - 2012/1/5/entrez PY - 2012/1/5/pubmed PY - 2012/4/25/medline SP - e1002453 EP - e1002453 JF - PLoS pathogens JO - PLoS Pathog VL - 7 IS - 12 N2 - Infected animals will produce reactive oxygen species (ROS) and other inflammatory molecules that help fight pathogens, but can inadvertently damage host tissue. Therefore specific responses, which protect and repair against the collateral damage caused by the immune response, are critical for successfully surviving pathogen attack. We previously demonstrated that ROS are generated during infection in the model host Caenorhabditis elegans by the dual oxidase Ce-Duox1/BLI-3. Herein, an important connection between ROS generation by Ce-Duox1/BLI-3 and upregulation of a protective transcriptional response by SKN-1 is established in the context of infection. SKN-1 is an ortholog of the mammalian Nrf transcription factors and has previously been documented to promote survival, following oxidative stress, by upregulating genes involved in the detoxification of ROS and other reactive compounds. Using qRT-PCR, transcriptional reporter fusions, and a translational fusion, SKN-1 is shown to become highly active in the C. elegans intestine upon exposure to the human bacterial pathogens, Enterococcus faecalis and Pseudomonas aeruginosa. Activation is dependent on the overall pathogenicity of the bacterium, demonstrated by a weakened response observed in attenuated mutants of these pathogens. Previous work demonstrated a role for p38 MAPK signaling both in pathogen resistance and in activating SKN-1 upon exposure to chemically induced oxidative stress. We show that NSY-1, SEK-1 and PMK-1 are also required for SKN-1 activity during infection. Evidence is also presented that the ROS produced by Ce-Duox1/BLI-3 is the source of SKN-1 activation via p38 MAPK signaling during infection. Finally, for the first time, SKN-1 activity is shown to be protective during infection; loss of skn-1 decreases resistance, whereas increasing SKN-1 activity augments resistance to pathogen. Overall, a model is presented in which ROS generation by Ce-Duox1/BLI-3 activates a protective SKN-1 response via p38 MAPK signaling. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/22216003/Ce_Duox1/BLI_3_generated_reactive_oxygen_species_trigger_protective_SKN_1_activity_via_p38_MAPK_signaling_during_infection_in_C__elegans_ L2 - https://dx.plos.org/10.1371/journal.ppat.1002453 DB - PRIME DP - Unbound Medicine ER -