Hypoxic response regulators RHY-1 and EGL-9/PHD promote longevity through a VHL-1 independent transcriptional response

Abstract

<jats:title>Abstract</jats:title><jats:p>HIF-1-mediated adaptation to changes in oxygen availability is a critical aspect of healthy physiology. HIF is regulated by a conserved mechanism whereby EGLN/PHD family members hydroxylate HIF in an oxygen-dependent manner, targeting it for ubiquitination by Von-Hippel-Lindau (VHL) family members, leading to its proteasomal degradation. The activity of the only <jats:italic>C. elegans</jats:italic> PHD family member, EGL-9, is also regulated by a hydrogen sulfide sensing cysteine-synthetase-like protein, CYSL-1, which is, in turn, regulated by RHY-1/acyltransferase. Over the last decade multiple seminal studies have established a role for the hypoxic response in regulating longevity, with mutations in <jats:italic>vhl-1</jats:italic> substantially extending <jats:italic>C. elegans</jats:italic> lifespan through a HIF-1-dependent mechanism. However, studies on other components of the hypoxic signaling pathway that similarly stabilize HIF-1 have shown more mixed results, suggesting that mutations in <jats:italic>egl-9</jats:italic> and <jats:italic>rhy-1</jats:italic> frequently fail to extend lifespan. Here, we show that <jats:italic>egl-9</jats:italic> and <jats:italic>rhy-1</jats:italic> mutants suppress the long-lived phenotype of <jats:italic>vhl-1</jats:italic> mutants. We also show that RNAi of <jats:italic>rhy-1</jats:italic> extends lifespan of wild-type worms while decreasing lifespan of <jats:italic>vhl-1</jats:italic> mutant worms. We further identify VHL-1-independent gene expression changes mediated by EGL-9 and RHY-1 and find that a subset of these genes contributes to longevity regulation. The resulting data suggest that changes in HIF-1 activity derived by interactions with EGL-9 likely contribute greatly to its role in regulation of longevity.</jats:p>