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

Abstract

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.

Data availability

Raw sequencing data were deposited to the NCBI Gene Expression Omnibus (GEO) under the accession number GSE144675.

The following data sets were generated

Article and author information

Author details

  1. Gabriel A Guerrero

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Maxime J Derisbourg

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    For correspondence
    mderisbourg@age.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
  3. Felix AMC Mayr

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Laura E Wester

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Marco Giorda

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. J Eike Dinort

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Matias D. Hartman

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Klara Schilling

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. María José Alonso

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Ryan J Lu

    University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Bérénice A Benayoun

    University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7401-4777
  12. Martin Sebastian Denzel

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    For correspondence
    mdenzel@age.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5691-3349

Funding

H2020 European Research Council (ERC-StG 640254)

  • Martin Sebastian Denzel

Max-Planck-Gesellschaft

  • Gabriel A Guerrero

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Elçin Ünal, University of California, Berkeley, United States

Version history

  1. Preprint posted: October 30, 2019 (view preprint)
  2. Received: October 30, 2019
  3. Accepted: August 25, 2021
  4. Accepted Manuscript published: August 27, 2021 (version 1)
  5. Version of Record published: September 23, 2021 (version 2)

Copyright

© 2021, Guerrero et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Gabriel A Guerrero
  2. Maxime J Derisbourg
  3. Felix AMC Mayr
  4. Laura E Wester
  5. Marco Giorda
  6. J Eike Dinort
  7. Matias D. Hartman
  8. Klara Schilling
  9. María José Alonso
  10. Ryan J Lu
  11. Bérénice A Benayoun
  12. Martin Sebastian Denzel
(2021)
NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants
eLife 10:e53174.
https://doi.org/10.7554/eLife.53174

Share this article

https://doi.org/10.7554/eLife.53174

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