Epoxides Derived from Dietary Dihomo-Gamma-Linolenic Acid Induce Germ Cell Death in C. elegans

Deline, Marshall L.; Keller, Julia; Rothe, Michael; Schunck, Wolf‐Hagen; Menzel, Ralph; Watts, Jennifer L.

doi:10.1038/srep15417

Cited by 28 publications

(33 citation statements)

References 45 publications

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“…Cif hydrolyzes this molecule. While much remains to be learned about the four EpFA categories evaluated in Figure 7, even less is known about 14,15-EED (Deline et al, 2015). Cif may be employed as a molecular scalpel, helping to dissect yet-to-be-described EpFA signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

Active-Site Flexibility and Substrate Specificity in a Bacterial Virulence Factor: Crystallographic Snapshots of an Epoxide Hydrolase

et al. 2017

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Summary The CFTR inhibitory factor (Cif) is an epoxide-hydrolase virulence factor from Pseudomonas aeruginosa, with catalytic activity that perturbs essential host-defense networks. Its targets are largely unknown, but include an epoxy-fatty acid. In this class of signaling molecules, chirality can be an important determinant of physiological output and potency. Here we explore the active-site chemistry of this two-step α/β-hydrolase and its implications for an emerging class of virulence enzymes. In combination with hydrolysis data, crystal structures of 15 trapped hydroxyalkyl-enzyme intermediates reveal the stereochemical basis of Cif’s substrate specificity, as well as its regioisomeric and enantiomeric preferences. The structures also reveal distinct sets of conformational changes that enable the active site to expand dramatically in two directions, accommodating a surprising array of potential physiological epoxide targets. These new substrates may contribute to Cif’s diverse effects in vivo, and thus to the success of P. aeruginosa and other pathogens during infection.

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Section: Resultsmentioning

confidence: 99%

Active-Site Flexibility and Substrate Specificity in a Bacterial Virulence Factor: Crystallographic Snapshots of an Epoxide Hydrolase

et al. 2017

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“…For example, LA-derived eicosanoids include leukotoxin and iso-leukotoxin, which inhibit mitochondrial function and can trigger apoptosis in mammals (Sakai, Ishizaki et al, 1995, Stevens & Czuprynski, 1996. In C. elegans, eicosanoid derivatives of the PUFA DGLA induce germ cell death (Deline, Keller et al, 2015). Moreover, we cannot rule out the possibility that the true signaling molecules that regulate UPS activity are either novel molecules derived from classic eicosanoids through additional steps beyond P450, or nonclassical eicosanoids derived from PUFAs, similar to endocannabinoids (Cascio & Marini, 2015).…”

Section: Discussionmentioning

confidence: 98%

Biogenic Amine Neurotransmitters Promote Eicosanoid Production And Protein Homeostasis

Rongo

Joshi

Matlack

et al. 2020

Preprint

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Multicellular organisms use multiple pathways to restore protein homeostasis (proteostasis) in response to adverse physiological conditions, changing environment, and developmental aging.The nervous system can regulate proteostasis in different tissues, but it is unclear how it mobilizes proteostasis pathways to offset physiological decline. Here we show that C. elegans employs the humoral biogenic amine neurotransmitters dopamine, serotonin, and tyramine to regulate proteostasis and the activity of the Ubiquitin Proteasome System (UPS) in epithelial tissues. Mutants for biogenic amine synthesis show decreased poly-ubiquitination and turnover of a GFP-based UPS substrate. Using RNA-seq, we determined the expression profile of genes regulated by biogenic amine signaling. We find that biogenic amines promote the expression of a subset of cytochrome P450 monooxygenases involved in eicosanoid production from polyunsaturated fatty acids (PUFAs). Mutants for these P450s share the same UPS phenotype observed in biogenic amine mutants. The production of n-3 PUFAs is required for UPS substrate turnover, whereas mutants that accumulate n-3 PUFAs show accelerated turnover of this GFP-based substrate. Our results suggest that neurosecretory sensory neurons release biogenic amines to modulate the lipid signaling profile, which in turn activates stress response pathways to maintain proteostasis.

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“…Dietary DGLA triggers ferroptotic germ cell death. Dietary DGLA is a potent inducer of germ cell death in C. elegans, with genetic evidence suggesting this could be in part an oxidative process (Deline et al, 2015;Watts and Browse, 2006;Webster et al, 2013). To test whether this process involved ferroptosis, we co-treated wild-type animals with dietary DGLA and the ferroptosis-specific lipophilic radical trapping antioxidant ferrostatin-1 (Fer-1) (Dixon et al, 2012;Zilka et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

Dietary Induction and Modulation of Ferroptosis in Caenorhabditis elegans

Perez

Magtanong

Dixon

et al. 2019

Preprint

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Highlights: -Dietary dihomogamma-linolenic acid (DGLA)-induced germ cell death in C. elegans is alleviated by small molecule antioxidants and iron chelators -Dietary and endogenous oleic acid protects from DGLA-induced ferroptosis -Ether-lipid deficiency increases sensitivity to DGLA-induced ferroptosis -DGLA specifically induces ferroptosis in human cancer cells 2 SUMMARY Ferroptosis is an iron-dependent form of regulated cell death associated with oxidized polyunsaturated phospholipids. Understanding the role of this process in vivo has been slowed by the lack of readily accessible model systems. Exposing the nematode Caenorhabditis elegans to the polyunsaturated fatty acid dihomogamma-linolenic acid (DGLA; 20:3n-6) causes germ cell death and sterility that is largely independent of the canonical apoptosis pathway. Here we demonstrate that DGLA-induced germ cell death is modulated by small molecule ferroptosis inhibitors, genetic manipulation of ferritin, NADPH oxidase, and glutathione peroxidases, and by dietary co-supplementation with oleic acid. Thus, DGLA-induced germ cell death in C. elegans is highly analogous to ferroptosis in mammalian cells. DGLA can also induce ferroptosis in human cells, further highlighting this omega-6 PUFA as a metabolic instigator of ferroptosis. Together, these results establish C. elegans as a powerful animal model to study the induction and modulation of ferroptosis by dietary fats.

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Epoxides Derived from Dietary Dihomo-Gamma-Linolenic Acid Induce Germ Cell Death in C. elegans

Cited by 28 publications

References 45 publications

Active-Site Flexibility and Substrate Specificity in a Bacterial Virulence Factor: Crystallographic Snapshots of an Epoxide Hydrolase

Active-Site Flexibility and Substrate Specificity in a Bacterial Virulence Factor: Crystallographic Snapshots of an Epoxide Hydrolase

Biogenic Amine Neurotransmitters Promote Eicosanoid Production And Protein Homeostasis

Dietary Induction and Modulation of Ferroptosis in Caenorhabditis elegans

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