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

  1. Gabriel A Guerrero
  2. Maxime J Derisbourg  Is a corresponding author
  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  Is a corresponding author
  1. Max Planck Institute for Biology of Ageing, Germany
  2. University of Southern California, United States

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

Publication 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.

Metrics

  • 1,130
    Page views
  • 162
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Developmental Biology
    2. Genetics and Genomics
    Ankit Sabharwal, Mark D Wishman ... Stephen C Ekker
    Research Advance Updated

    The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (Ichino et al., 2020), including the lrpprc locus. Here, we present and characterize a new genetic revertible animal model that recapitulates components of Leigh Syndrome French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the LRPPRC gene, involved in mitochondrial mRNA polyadenylation and translation. lrpprc zebrafish homozygous mutants displayed biochemical and mitochondrial phenotypes similar to clinical manifestations observed in patients, including dysfunction in lipid homeostasis. We were able to rescue these phenotypes in the disease model using a liver-specific genetic model therapy, functionally demonstrating a previously under-recognized critical role for the liver in the pathophysiology of this disease.

    1. Genetics and Genomics
    2. Neuroscience
    Michael J Lafferty, Nil Aygün ... Jason L Stein
    Research Article Updated

    Expression quantitative trait loci (eQTL) data have proven important for linking non-coding loci to protein-coding genes. But eQTL studies rarely measure microRNAs (miRNAs), small non-coding RNAs known to play a role in human brain development and neurogenesis. Here, we performed small-RNA sequencing across 212 mid-gestation human neocortical tissue samples, measured 907 expressed miRNAs, discovering 111 of which were novel, and identified 85 local-miRNA-eQTLs. Colocalization of miRNA-eQTLs with GWAS summary statistics yielded one robust colocalization of miR-4707–3p expression with educational attainment and brain size phenotypes, where the miRNA expression increasing allele was associated with decreased brain size. Exogenous expression of miR-4707–3p in primary human neural progenitor cells decreased expression of predicted targets and increased cell proliferation, indicating miR-4707–3p modulates progenitor gene regulation and cell fate decisions. Integrating miRNA-eQTLs with existing GWAS yielded evidence of a miRNA that may influence human brain size and function via modulation of neocortical brain development.