Zinc homeostasis and signaling in the roundworm C. elegans

Earley, Brian J.; Mendoza, Adelita D.; Tan, Chieh-Hsiang; Kornfeld, Kerry

doi:10.1016/j.bbamcr.2020.118882

Cited by 13 publications

(6 citation statements)

References 84 publications

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“…Cadmium activates numr-1/2 , and some previously characterized activities of ETP natural products are hypothesized to involve displacement of physiological zinc. − At 200 μM, metal chelator TPEN strongly reduces free cytosolic zinc levels and disrupts C. elegans reproduction. , As shown in Figure A, 200 μM TPEN increased numr-1p::GFP fluorescence by 1.3-fold; this is statistically significant, but far less than the over 15-fold induction by 12.5 μM chaetocin (Figure A) suggesting that numr-1/2 is not strongly activated by broad depletion of cellular zinc.…”

Section: Resultsmentioning

confidence: 99%

Chemical Genetics in C. elegans Identifies Anticancer Mycotoxins Chaetocin and Chetomin as Potent Inducers of a Nuclear Metal Homeostasis Response

Abraham,

Athapaththu,

Atanasova

et al. 2024

ACS Chem. Biol.

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C. elegans numr-1/2 (nuclear-localized metalresponsive) is an identical gene pair encoding a nuclear protein previously shown to be activated by cadmium and disruption of the integrator RNA metabolism complex. We took a chemical genetic approach to further characterize regulation of this novel metal response by screening 41,716 compounds and extracts for numr-1p::GFP activation. The most potent activator was chaetocin, a fungal 3,6-epidithiodiketopiperazine (ETP) with promising anticancer activity. Chaetocin activates numr-1/2 strongly in the alimentary canal but is distinct from metal exposure, because it represses canonical cadmium-responsive metallothionine genes. Chaetocin has diverse targets in cancer cells including thioredoxin reductase, histone lysine methyltransferase, and acetyltransferase p300/CBP; further work is needed to identify the mechanism in C. elegans as genetic disruption and RNAi screening of homologues did not induce numr-1/2 in the alimentary canal and chaetocin did not affect markers of integrator dysfunction. We demonstrate that disulfides in chaetocin and chetomin, a dimeric ETP analog, are required to induce numr-1/2. ETP monomer gliotoxin, despite possessing a disulfide linkage, had almost no effect on numr-1/2, suggesting a dimer requirement. Chetomin inhibits C. elegans growth at low micromolar levels, and loss of numr-1/2 increases sensitivity; C. elegans and Chaetomiaceae fungi inhabit similar environments raising the possibility that numr-1/2 functions as a defense mechanism. There is no direct orthologue of numr-1/2 in humans, but RNaseq suggests that chaetocin affects expression of cellular processes linked to stress response and metal homeostasis in colorectal cancer cells. Our results reveal interactions between metal response gene regulation and ETPs and identify a potential mechanism of resistance to this versatile class of preclinical compounds.

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Section: Resultsmentioning

confidence: 99%

Chemical Genetics in C. elegans Identifies Anticancer Mycotoxins Chaetocin and Chetomin as Potent Inducers of a Nuclear Metal Homeostasis Response

Abraham,

Athapaththu,

Atanasova

et al. 2024

ACS Chem. Biol.

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show abstract

“…Cadmium activates numr-1/2 and some previously characterized activities of ETP natural products are hypothesized to involve displacement of physiological zinc [59][60][61] . At 200 μM, metal chelator TPEN strongly reduces free cytosolic zinc levels and disrupts C. elegans reproduction [62][63] . As shown in Figure 4A, 200 μM TPEN increased numr-1p::GFP fluorescence by 1.3-fold; this is statistically significant, but far less than the over 15-fold induction by 12.5 μM chaetocin (Fig.…”

Section: Interactions Between Chaetocin and Cadmiummentioning

confidence: 99%

Chemical genetics inC. elegansidentifies anticancer mycotoxins chaetocin and chetomin as potent inducers of a nuclear metal homeostasis response

Abraham,

Athapaththu,

Atanasova

et al. 2024

Preprint

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C. elegans numr-1/2(nuclear-localizedmetal-responsive) is an identical gene pair encoding a nuclear protein previously shown to be activated by cadmium and disruption of the integrator RNA metabolism complex. We took a chemical genetic approach to further characterize regulation of this novel metal response by screening 41,716 compounds and extracts fornumr-1p::GFPactivation. The most potent activator was chaetocin, a fungal 3,6-epidithiodiketopiperazine (ETP) with promising anticancer activity. Chaetocin activatesnumr-1/2strongly in the alimentary canal but is distinct from metal exposure because it represses canonical cadmium-responsive metallothionine genes. Chaetocin has diverse targets in cancer cells including thioredoxin reductase, histone lysine methyltransferase, and acetyltransferase p300/CBP; further work is needed to identify the mechanism inC. elegansas genetic disruption and RNAi screening of homologs did not inducenumr-1/2in the alimentary canal and chaetocin did not affect markers of integrator dysfunction. We demonstrate that disulfides in chaetocin and chetomin, a dimeric ETP analog, are required to inducenumr-1/2.ETP monomer gliotoxin, despite possessing a disulfide linkage, had almost no effect onnumr-1/2, suggesting a dimer requirement. Chetomin inhibitsC. elegansgrowth at low micromolar levels and loss ofnumr-1/2increases sensitivity;C. elegansand Chaetomiaceae fungi inhabit similar environments raising the possibility thatnumr-1/2functions as a defense mechanism. There is no direct ortholog ofnumr-1/2in humans, but RNAseq suggests that chaetocin affects expression of cellular processes linked to stress response and metal homeostasis in colorectal cancer cells. Our results reveal interactions between metal response gene regulation and ETPs and identify a potential mechanism of resistance to this versatile class of preclinical compounds.

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“…One explanation for the relative harmlessness of the amyloidogenesis for nematodes may be the insufficient amounts of molecular components that are present in the human amyloid plaques, namely, zinc ions and isoD7-Aβ. Under the normal nematode life conditions, the concentration of zinc ions in their body cannot reach peak values [ 132 , 133 ]. Also, the occurrence of isoD7-Aβ in nematodes is unlikely, since spontaneous isomerization of Asp7 within Aβ requires substantial time [ 134 ], exceeding the life span of these animals.…”

Section: Molecular Tools Switching On/off the Aggregation Of Endogeno...mentioning

confidence: 99%

Switching On/Off Amyloid Plaque Formation in Transgenic Animal Models of Alzheimer’s Disease

Kozin,

Kechko,

Adzhubei

et al. 2023

IJMS

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A hallmark of Alzheimer’s disease (AD) are the proteinaceous aggregates formed by the amyloid-beta peptide (Aβ) that is deposited inside the brain as amyloid plaques. The accumulation of aggregated Aβ may initiate or enhance pathologic processes in AD. According to the amyloid hypothesis, any agent that has the capability to inhibit Aβ aggregation and/or destroy amyloid plaques represents a potential disease-modifying drug. In 2023, a humanized IgG1 monoclonal antibody (lecanemab) against the Aβ-soluble protofibrils was approved by the US FDA for AD therapy, thus providing compelling support to the amyloid hypothesis. To acquire a deeper insight on the in vivo Aβ aggregation, various animal models, including aged herbivores and carnivores, non-human primates, transgenic rodents, fish and worms were widely exploited. This review is based on the recent data obtained using transgenic animal AD models and presents experimental verification of the critical role in Aβ aggregation seeding of the interactions between zinc ions, Aβ with the isomerized Asp7 (isoD7-Aβ) and the α4β2 nicotinic acetylcholine receptor.

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Zinc homeostasis and signaling in the roundworm C. elegans

Cited by 13 publications

References 84 publications

Chemical Genetics in C. elegans Identifies Anticancer Mycotoxins Chaetocin and Chetomin as Potent Inducers of a Nuclear Metal Homeostasis Response

Chemical Genetics in C. elegans Identifies Anticancer Mycotoxins Chaetocin and Chetomin as Potent Inducers of a Nuclear Metal Homeostasis Response

Chemical genetics inC. elegansidentifies anticancer mycotoxins chaetocin and chetomin as potent inducers of a nuclear metal homeostasis response

Switching On/Off Amyloid Plaque Formation in Transgenic Animal Models of Alzheimer’s Disease

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