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.
Highlights
Chemosensation is a genetically tractable phenotype in various model organisms
As suggested by a role of P32 glycoprotein (PGP) in ivermectin resistance, we found that osm-3 mutants fully developed to adults in the presence of μg/mL ivermectin that is lethal to wild type (WT) animals (Figure 4E)
We found that osm-3 mutants as well as other long-lived Dyf mutants are resistant to the endoplasmic reticulum (ER) toxin TM
Summary
Chemosensation is a genetically tractable phenotype in various model organisms. InC. elegans, many mutants with defective chemosensation have been identified.Sensory phenotypes are complex in nature and many of the classical chemosensory mutants were originally characterized by their behavioral phenotypes. Mutations in components of neuronal G-protein coupled receptor (GPCR) signaling, such as tax-4 and odr-1, cause atypical chemosensory behavior (Bargmann, 2006). These mutants are characterized by a failure to adequately respond to their environment, but show additional phenotypes linked to various life traits including pathogen resistance, increased lifespan, and drug detoxification (Gaglia et al, 2012, Apfeld and Kenyon, 1999, Dent et al, 2000). Many chemosensory mutants are longlived and this phenotype depends on the DAF-16/FOXO transcription factor that is regulated by the insulin signaling pathway (Apfeld and Kenyon, 1999)
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