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

AbstractHIF-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 onlyC. elegans 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 invhl-1 substantially extendingC. elegans 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 inegl-9 andrhy-1 frequently fail to extend lifespan. Here, we show thategl-9 andrhy-1 mutants suppress the long-lived phenotype ofvhl-1 mutants. We also show that RNAi ofrhy-1 extends lifespan of wild-type worms while decreasing lifespan ofvhl-1 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 regul...
Source: AGE - Category: Geriatrics Source Type: research