SKN-1 linksC. elegansmesendodermal specification to a conserved oxidative stress response

Abstract

During the earliest stages of Caenorhabditis elegans embryogenesis, the transcription factor SKN-1 initiates development of the digestive system and other mesendodermal tissues. Postembryonic SKN-1 functions have not been elucidated. SKN-1 binds to DNA through a unique mechanism, but is distantly related to basic leucine-zipper proteins that orchestrate the major oxidative stress response in vertebrates and yeast. Here we show that despite its distinct mode of target gene recognition, SKN-1 functions similarly to resist oxidative stress in C. elegans. During postembryonic stages, SKN-1 regulates a key Phase II detoxification gene through constitutive and stress-inducible mechanisms in the ASI chemosensory neurons and intestine, respectively. SKN-1 is present in ASI nuclei under normal conditions, and accumulates in intestinal nuclei in response to oxidative stress. skn-1 mutants are sensitive to oxidative stress and have shortened lifespans. SKN-1 represents a connection between developmental specification of the digestive system and one of its most basic functions, resistance to oxidative and xenobiotic stress. This oxidative stress response thus appears to be both widely conserved and ancient, suggesting that the mesendodermal specification role of SKN-1 was predated by its function in these detoxification mechanisms.

Effects and mechanisms of prolongevity induced by Lactobacillus gasseri SBT2055 in Caenorhabditis elegans

“…SKN‐1, an ortholog of mammalian NRF protein, is activated in response to oxidative stress or by compounds, such as hydrogen peroxide, Paraquat, and juglone, through the induction of phase II detoxification gene transcription (An & Blackwell, 2003). Tullet et al .…”

“…The skn‐1 mutant of C. elegans shows decreased resistance to oxidative stress and a shortened lifespan. In contrast, C. elegans mutants overexpressing SKN‐1, which constitutively localizes to the nuclei of intestinal cells, show increased resistance to oxidative stress and increased longevity (An & Blackwell, 2003; An et al ., 2005; Tullet et al ., 2008). …”

“…SKN‐1 is present in nuclei constitutively in the ASI neurons (putative hypothalamus) (An & Blackwell, 2003), where it is required for longevity to be extended by dietary restriction (DR), a condition that increases longevity in organisms as diverse as yeast and rodents (Bishop & Guarente, 2007). The stress resistance function of SKN‐1 is mediated by its expression in the intestine (digestive system) (Bishop & Guarente, 2007), where SKN‐1 accumulates in nuclei and activates phase 2 gene expression inducibly in response to stress (An & Blackwell, 2003). We observed that feeding with LG2055 no longer conferred a median lifespan of C. elegans mutants carrying the skn‐1 alleles (trials repeated in triplicate per strain; Fig.…”

“…The stress resistance function of SKN‐1 is known to be mediated by its expression in the intestines (Bishop & Guarente, 2007) where SKN‐1 accumulates in nuclei and activates the inducibility of phase 2 gene expression in response to stress (An & Blackwell, 2003). In the intestine, mitogen‐activated protein kinase (PMK‐1) phosphorylates SKN‐1, which then translocates to the nuclei of intestinal cells and induces the transcription of phase 2 detoxification genes (Inoue et al ., 2005).…”

GLB‐13 is associated with oxidative stress resistance in caenorhabditis elegans

“…Fujii et al reported that neurons are direct targets of paraquat in C. elegans (30). Like in mammals, C. elegans SOD and glutathione are ubiquitously expressed in many tissues (43)(44)(45)(46)(47)(48). Unlike these antioxidant enzymes, GLB-13 is only expressed in few neuronal cells, although the evidence that how the signals are processed and integrated with other signals to specify oxidative stress is still unclear.…”