Abstract
Iron plays an essential role in many biological processes, but also catalyzes the formation of reactive oxygen species (ROS), which can cause molecular damage. Iron homeostasis is therefore a critical determinant of fitness. In Caenorhabditis elegans, insulin/IGF-1 signaling (IIS) promotes growth and reproduction but limits stress resistance and lifespan through inactivation of the DAF-16/FoxO transcription factor (TF). We report that long-lived daf-2 insulin/IGF-1 receptor mutants show a daf-16–dependent increase in expression of ftn-1, which encodes the iron storage protein H-ferritin. To better understand the regulation of iron homeostasis, we performed a TF–limited genetic screen for factors influencing ftn-1 gene expression. The screen identified the heat-shock TF hsf-1, the MAD bHLH TF mdl-1, and the putative histone acetyl transferase ada-2 as activators of ftn-1 expression. It also revealed that the HIFα homolog hif-1 and its binding partner aha-1 (HIFβ) are potent repressors of ftn-1 expression. ftn-1 expression is induced by exposure to iron, and we found that hif-1 was required for this induction. In addition, we found that the prolyl hydroxylase EGL-9, which represses HIF-1 via the von Hippel-Lindau tumor suppressor VHL-1, can also act antagonistically to VHL-1 in regulating ftn-1. This suggests a novel mechanism for HIF target gene regulation by these evolutionarily conserved and clinically important hydroxylases. Our findings imply that the IIS and HIF pathways act together to regulate iron homeostasis in C. elegans. We suggest that IIS/DAF-16 regulation of ftn-1 modulates a trade-off between growth and stress resistance, as elevated iron availability supports growth but also increases ROS production.
Highlights
In order to survive in a changing environment, organisms have evolved abilities to sense their surroundings and adaptively adjust their physiology
Levels of cellular iron must be just right: too much or too little iron can cause illnesses, such as anemia and hemochromatosis, respectively. Animals carefully control their iron levels by regulating of iron uptake, transport, and storage within protein capsules called ferritins. How do they coordinate this? Using the model organism C. elegans, we have discovered a network of genes and pathways that control iron homeostasis
We find that ferritin is regulated by insulin/IGF-1 signaling, which controls growth and resistance to oxidative stress in response to harsh environmental conditions
Summary
In order to survive in a changing environment, organisms have evolved abilities to sense their surroundings and adaptively adjust their physiology. The nematode Caenorhabditis elegans is capable of postponing reproduction if conditions are unsuitable for growth and reproduction by forming dauer larvae [1,2,3]. This developmentally arrested third larval stage is resistant to starvation and other stressors, allowing the animal to survive until conditions improve. DAF-16 is required for the longevity of IIS mutants, for example those with defects in the DAF-2 insulin/ IGF-1 receptor [11] Both of these roles of DAF-16, the promotion of stress resistance and longevity, will improve the chances of living through periods of adversity. Whether the same downstream mechanisms cause increased stress protection and longevity remains unclear [12]
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