HIF-1 Has a Central Role in Caenorhabditis elegans Organismal Response to Selenium

Abstract

Selenium is a trace element for most organisms; its deficiency and excess are detrimental. Selenium beneficial effects are mainly due to the role of the 21 st genetically encoded amino acid selenocysteine (Sec). Selenium also exerts Sec-independent beneficial effects. Its harmful effects are thought to be mainly due to non-specific incorporation in protein synthesis. Yet the selenium response in animals is poorly understood. In Caenorhabditis elegans, Sec is genetically incorporated into a single selenoprotein. Similar to mammals, a 20-fold excess of the optimal selenium requirement is harmful. Sodium selenite (Na 2 SeO 3) excess causes development retardation, impaired growth, and neurodegeneration of motor neurons. To study the organismal response to selenium we performed a genetic screen for C. elegans mutants that are resistant to selenite. We isolated nonsense and missense egl-9/EGLN mutants that confer robust resistance to selenium. In contrast, hif-1/HIF null mutant was highly sensitive to selenium, establishing a role for this transcription factor in the selenium response. We showed that EGL-9 regulates HIF-1 activity through VHL-1, and identified CYSL-1 as a key sensor that transduces the selenium signal. Finally, we showed that the key enzymes involved in sulfide and sulfite stress (sulfide quinone oxidoreductase and sulfite oxidase) are not required for selenium resistance. In contrast, knockout strains in the persulfide dioxygenase ETHE-1 and the sulfurtransferase MPST-7 affect the organismal response to selenium. In sum, our results identified a transcriptional pathway as well as enzymes possibly involved in the organismal selenium response.

Differential regulation of degradation and immune pathways underlies adaptation of the ectosymbiotic nematode Laxus oneistus to oxic-anoxic interfaces

“…The mpst-7 gene, involved in organismal response to selenium and switched on in hypoxic C. elegans 175 , was upregulated in H nematodes (Fig. 6 ).…”

Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor in Caenorhabditis elegans

“…Also, while C . elegans SKN-1 and HIF-1 have distinct roles in peroxide and hypoxia stress responses, their functions overlap in selenium and hydrogen sulfide stress responses [ 13 , 15 , 35 – 37 ].…”

“…For example, C. elegans SKN-1 can be activated by arsenite or by t-butyl hydroperoxide, but only a subset of SKN-1 targets are activated by either toxicant [32]. Also, while C. elegans SKN-1 and HIF-1 have distinct roles in peroxide and hypoxia stress responses, their functions overlap in selenium and hydrogen sulfide stress responses [13,15,[35][36][37].…”

“…elegans has been proven to be an excellent model system for studying the regulatory networks that govern oxygen homeostasis. The C. elegans genome encodes a single hypoxiainducible factor alpha subunit (HIF-1), and the hif-1 gene has been shown to have important roles in stress response and in aging [13][14][15][16][17]. HIF protein levels and HIF activity are tightly regulated.…”

Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor inCaenorhabditis elegans

“…For example, C. elegans SKN-1 can be activated by arsenite or by t-butyl hydroperoxide, but only a subset of SKN-1 targets are activated by either toxicant [32]. Also, while C. elegans SKN-1 and HIF-1 have distinct roles in peroxide and hypoxia stress responses, their functions overlap in selenium and hydrogen sulfide stress responses [13, 15, 35–37]. Similarly, the mammalian NRF and HIF transcription factors are very sensitive to environmental and physiological cues or stresses, and their regulatory relationships are context specific.…”