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NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants

Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory-defective Caenorhabditis elegans mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene...

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Autores principales: Guerrero, Gabriel A, Derisbourg, Maxime J, Mayr, Felix AMC, Wester, Laura E, Giorda, Marco, Dinort, J Eike, Hartman, Matías D, Schilling, Klara, Alonso-De Gennaro, María José, Lu, Ryan J, Benayoun, Bérénice A, Denzel, Martin S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460253/
https://www.ncbi.nlm.nih.gov/pubmed/34448454
http://dx.doi.org/10.7554/eLife.53174
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author Guerrero, Gabriel A
Derisbourg, Maxime J
Mayr, Felix AMC
Wester, Laura E
Giorda, Marco
Dinort, J Eike
Hartman, Matías D
Schilling, Klara
Alonso-De Gennaro, María José
Lu, Ryan J
Benayoun, Bérénice A
Denzel, Martin S
author_facet Guerrero, Gabriel A
Derisbourg, Maxime J
Mayr, Felix AMC
Wester, Laura E
Giorda, Marco
Dinort, J Eike
Hartman, Matías D
Schilling, Klara
Alonso-De Gennaro, María José
Lu, Ryan J
Benayoun, Bérénice A
Denzel, Martin S
author_sort Guerrero, Gabriel A
collection PubMed
description Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory-defective Caenorhabditis elegans mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene osm-3 were significantly protected from tunicamycin-induced ER stress. While osm-3 lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not. osm-3 mutants are protected from bacterial pathogens, which is pmk-1 p38 MAP kinase dependent, while TM resistance was pmk-1 independent. Expression of P-glycoprotein (PGP) xenobiotic detoxification genes was elevated in osm-3 mutants and their knockdown or inhibition with verapamil suppressed tunicamycin resistance. The nuclear hormone receptor nhr-8 was necessary to regulate a subset of PGPs. We thus identify a cell-nonautonomous regulation of xenobiotic detoxification and show that separate pathways are engaged to mediate longevity, pathogen resistance, and xenobiotic detoxification in osm-3 mutants.
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spelling pubmed-84602532021-09-24 NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants Guerrero, Gabriel A Derisbourg, Maxime J Mayr, Felix AMC Wester, Laura E Giorda, Marco Dinort, J Eike Hartman, Matías D Schilling, Klara Alonso-De Gennaro, María José Lu, Ryan J Benayoun, Bérénice A Denzel, Martin S eLife Genetics and Genomics Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory-defective Caenorhabditis elegans mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene osm-3 were significantly protected from tunicamycin-induced ER stress. While osm-3 lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not. osm-3 mutants are protected from bacterial pathogens, which is pmk-1 p38 MAP kinase dependent, while TM resistance was pmk-1 independent. Expression of P-glycoprotein (PGP) xenobiotic detoxification genes was elevated in osm-3 mutants and their knockdown or inhibition with verapamil suppressed tunicamycin resistance. The nuclear hormone receptor nhr-8 was necessary to regulate a subset of PGPs. We thus identify a cell-nonautonomous regulation of xenobiotic detoxification and show that separate pathways are engaged to mediate longevity, pathogen resistance, and xenobiotic detoxification in osm-3 mutants. eLife Sciences Publications, Ltd 2021-08-27 /pmc/articles/PMC8460253/ /pubmed/34448454 http://dx.doi.org/10.7554/eLife.53174 Text en © 2021, Guerrero et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Genetics and Genomics
Guerrero, Gabriel A
Derisbourg, Maxime J
Mayr, Felix AMC
Wester, Laura E
Giorda, Marco
Dinort, J Eike
Hartman, Matías D
Schilling, Klara
Alonso-De Gennaro, María José
Lu, Ryan J
Benayoun, Bérénice A
Denzel, Martin S
NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants
title NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants
title_full NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants
title_fullStr NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants
title_full_unstemmed NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants
title_short NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants
title_sort nhr-8 and p-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory c. elegans mutants
topic Genetics and Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460253/
https://www.ncbi.nlm.nih.gov/pubmed/34448454
http://dx.doi.org/10.7554/eLife.53174
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