A Novel Mechanism To Prevent H2S Toxicity in <i>Caenorhabditis elegans</i>

Horsman, Joseph W.; Heinis, Frazer I.; Miller, Dana L.

doi:10.1534/genetics.119.302326

Cited by 23 publications

(23 citation statements)

References 44 publications

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“…The cysteine synthases CYSL-1 and CYSL-2 have previously been reported to break down hydrogen cyanide 34 . In addition, RHY-1 was recently reported to function downstream of SKN-1 to promote resistance to hydrogen sulfide 36 . Similar to our observations, RHY-1 function downstream of SKN-1 was found to be independent of EGL-9/HIF-1 signaling 36 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, RHY-1 was recently reported to function downstream of SKN-1 to promote resistance to hydrogen sulfide 36 . Similar to our observations, RHY-1 function downstream of SKN-1 was found to be independent of EGL-9/HIF-1 signaling 36 . Collectively, these observations suggest that C. elegans might heritably adapt to infection by P. vranovensis by increasing the expression of CYSL-1, CYSL-2, and RHY-1 in offspring, which in turn protects offspring by breaking down bacterially produced toxins such as hydrogen cyanide.…”

Section: Discussionmentioning

confidence: 99%

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Cysteine synthases CYSL-1 and CYSL-2 mediate C. elegans heritable adaptation to P. vranovensis infection

et al. 2020

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Parental exposure to pathogens can prime offspring immunity in diverse organisms. The mechanisms by which this heritable priming occurs are largely unknown. Here we report that the soil bacteria Pseudomonas vranovensis is a natural pathogen of the nematode Caenorhabditis elegans and that parental exposure of animals to P. vranovensis promotes offspring resistance to infection. Furthermore, we demonstrate a multigenerational enhancement of progeny survival when three consecutive generations of animals are exposed to P. vranovensis. By investigating the mechanisms by which animals heritably adapt to P. vranovensis infection, we found that parental infection by P. vranovensis results in increased expression of the cysteine synthases cysl-1 and cysl-2 and the regulator of hypoxia inducible factor rhy-1 in progeny, and that these three genes are required for adaptation to P. vranovensis. These observations establish a CYSL-1, CYSL-2, and RHY-1 dependent mechanism by which animals heritably adapt to infection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cysteine synthases CYSL-1 and CYSL-2 mediate C. elegans heritable adaptation to P. vranovensis infection

et al. 2020

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Feng

Zhai

Shao

et al. 2021

Preprint

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During development, homeostasis, and disease, organisms must balance responses that allow adaptation to low oxygen (hypoxia) with those that protect cells from oxidative stress. The evolutionarily conserved hypoxia-inducible factors are central to these processes, as they orchestrate transcriptional responses to oxygen deprivation. Here, we employ genetic strategies in C. elegans to identify stress-responsive genes and pathways that modulate the HIF-1 hypoxia?inducible factor and facilitate oxygen homeostasis. Through a genome-wide RNAi screen, we show that RNAi-mediated mitochondrial or proteasomal dysfunction increases the expression of hypoxia-responsive reporter Pnhr-57:GFP in C. elegans . Interestingly, only a subset of these effects requires hif-1 . Of particular importance, we found that skn-1 RNAi increases the expression of hypoxia-responsive reporter Pnhr-57:GFP and elevates HIF-1 protein levels. The SKN-1/NRF transcription factor has been shown to promote oxidative stress resistance. We present evidence that the crosstalk between HIF-1 and SKN-1 is mediated by EGL-9, the prolyl hydroxylase that targets HIF-1 for oxygen-dependent degradation. Treatment that induces SKN?1, such as heat, increases expression of a Pegl-9:GFP reporter, and this effect requires skn-1 function and a putative SKN-1 binding site in egl-9 regulatory sequences. Collectively, these data support a model in which SKN-1 promotes egl-9 transcription, thereby inhibiting HIF-1. We propose that this interaction enables animals to adapt quickly to changes in cellular oxygenation and to better survive accompanying oxidative stress.

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“…This suggests that RHY-1 may have secondary, HIF-1-263 independent roles that influence longevity. Published reports showing that rhy-1;hif-1 compound 264 mutants have a synthetic deleterious effect on fertility and that RHY-1 modulates hydrogen-sulfide 265 resistance in a HIF-1-independent manner also suggest interesting HIF-1-independent roles for RHY-1 266 (Horsman et al, 2019;Shen et al, 2006). 267…”

Section: 238mentioning

confidence: 99%

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

Kruempel

Schaller

et al. 2020

Preprint

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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 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.

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A Novel Mechanism To Prevent H2S Toxicity in Caenorhabditis elegans

Cited by 23 publications

References 44 publications

Cysteine synthases CYSL-1 and CYSL-2 mediate C. elegans heritable adaptation to P. vranovensis infection

Cysteine synthases CYSL-1 and CYSL-2 mediate C. elegans heritable adaptation to P. vranovensis infection

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

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

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