eLife (Aug 2021)

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

  • Gabriel A Guerrero,
  • Maxime J Derisbourg,
  • Felix AMC Mayr,
  • Laura E Wester,
  • Marco Giorda,
  • J Eike Dinort,
  • Matías D Hartman,
  • Klara Schilling,
  • María José Alonso-De Gennaro,
  • Ryan J Lu,
  • Bérénice A Benayoun,
  • Martin S Denzel

DOI
https://doi.org/10.7554/eLife.53174
Journal volume & issue
Vol. 10

Abstract

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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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