SKN-1/Nrf (NF-E2 related factor) is a transcription factor that regulates redox regulators, such as glutathione S-transferase, and lipid metabolism in Caenorhabditis elegans (C. elegans). SKN-1 counters damage caused by reactive oxygen species, which is often implicated in age-associated diseases such as Alzheimer's disease, and arteriolosclerosis. Recently, SKN-1 was shown to mediate fat accumulation and oxidative stress resistance in worms missing germline stem cells (GSC(-)). The mechanism by which this occurs is still unknown. A preliminary genome-wide screen identified Kruppel-like family of transcription factors (KLF) as possible mediators of SKN-1, under GSC(-) conditions. KLF proteins have roles in adipogenesis and autophagy, suggesting they may mediate SKN-1 regulated fat accumulation and oxidative stress resistance in GSC(-) worms. To evaluate the role of KLF transcription factors, we assessed the role of
klf-1 and
klf-2 in SKN-1 activation, SKN-1 mediated stress resistance, lipid metabolism, and longevity. We found that the knockdown of
klf-1, under GSC (-) conditions, decreased SKN-1 activity, specifically the SKN-1c isoform, eliminated stress resistance, reduced lipid accumulation, and eliminated lifespan extension.
klf-2 had less of an effect on SKN-1 however the knockdown of
klf-2 surprisingly increased lipid accumulation under both basal and GSC(-) conditions suggesting that while
klf-1 positively regulates SKN-1c,
klf-2 may negatively regulate SKN-1c, possibly through lipids.