Regulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3

Abstract

Oxidative stress plays a central role in many human diseases and in aging. In Caenorhabditis elegans the SKN-1 protein induces phase II detoxification gene transcription, a conserved oxidative stress response, and is required for oxidative stress resistance and longevity. Oxidative stress induces SKN-1 to accumulate in intestinal nuclei, depending on p38 mitogen-activated protein kinase signaling. Here we show that, in the absence of stress, phosphorylation by glycogen synthase kinase-3 (GSK-3) prevents SKN-1 from accumulating in nuclei and functioning constitutively in the intestine. GSK-3 sites are conserved in mammalian SKN-1 orthologs, indicating that this level of regulation may be conserved. If inhibition by GSK-3 is blocked, background levels of p38 signaling are still required for SKN-1 function. WT and constitutively nuclear SKN-1 comparably rescue the skn-1 oxidative stress sensitivity, suggesting that an inducible phase II response may provide optimal stress protection. We conclude that (i) GSK-3 inhibits SKN-1 activity in the intestine, (ii) the phase II response integrates multiple regulatory signals, and (iii), by inhibiting this response, GSK-3 may influence redox conditions. longevity ͉ p38 mitogen-activated protein kinase ͉ stress response ͉ Phase II gene

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

“…Increased expression of antioxidants is expected to attenuate the ROS‐mediated positive feedback (Fig. 3), and the observation that Nrf2 activity shows dose‐dependent effects on lifespan (An et al ., 2005) is consistent with this attenuation. However, Nrf2 activity declines with age (Suh et al ., 2004), which likely occurs at least in part by increased Tor‐dependent inhibition of Nrf2 activity (Robida‐Stubbs et al ., 2012; Lerner et al ., 2013).…”

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

“…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). …”

A redox-sensitive peroxiredoxin that is important for longevity has tissue- and stress-specific roles in stress resistance

“…This suggests that loss of PRDX-2 must increase phase II gene expression by a different mechanism. SKN-1 activity is also subject to negative regulation by GSK-3 and insulin-like growth factor signaling pathways (20,21). Hence it was possible that PRDX-2 regulates gcs-1 expression by promoting inhibition of SKN-1 by these pathways.…”