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 C. 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 in vhl-1 substantially extending C. 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 in egl-9 and rhy-1 frequently fail to extend lifespan. Here, we show that egl-9 and rhy-1 mutants suppress the long-lived phenotype of vhl-1 mutants. We also show that RNAi of rhy-1 extends lifespan of wild-type worms while decreasing lifespan of vhl-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 regulation of longevity.

HIF-1 介导的对氧气可用性变化的适应是健康生理学的一个关键方面。HIF 受保守机制的调节，EGLN/PHD 家族成员以氧依赖的方式羟基化 HIF，使其被 Von-Hippel-Lindau (VHL) 家族成员泛素化，导致其蛋白酶体降解。唯一的秀丽隐杆线虫PHD 家族成员 EGL-9的活性也受硫化氢感应半胱氨酸合成酶样蛋白 CYSL-1 的调节，CYSL-1 反过来又受 RHY-1/酰基转移酶的调节。在过去的十年中，多项开创性研究已经确定了缺氧反应在调节寿命中的作用，其中vhl-1的突变显着延长了秀丽隐杆线虫通过 HIF-1 依赖性机制延长寿命。然而，对同样稳定 HIF-1 的缺氧信号通路的其他成分的研究显示出更多不同的结果，这表明egl-9和rhy-1的突变经常不能延长寿命。在这里，我们显示egl-9和rhy-1突变体抑制 vhl-1 突变体的长寿命表型。我们还表明rhy-1的 RNAi延长了野生型蠕虫的寿命，同时降低了vhl-1的寿命变异蠕虫。我们进一步确定了由 EGL-9 和 RHY-1 介导的 VHL-1 非依赖性基因表达变化，并发现这些基因的一个子集有助于长寿调节。结果数据表明，通过与 EGL-9 相互作用而产生的 HIF-1 活性变化可能极大地促进了其在调节寿命中的作用。