Post-translational regulation of the major drug transporters in the families of organic anion transporters and organic anion–transporting polypeptides

Lee, Wooin; Ha, Jae Jung; Sugiyama, Yuichi

doi:10.1074/jbc.rev120.009132

Cited by 33 publications

(23 citation statements)

References 152 publications

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“…4b and c), however interestingly, removal of iron by DFO also led to a decrease (p = 0.032, one sample t test) in VIT-HA levels despite no change in RNA levels. As well as regulation at the mRNA and protein level, the function of transporters can also be regulated by changes in localisation (Lee et al, 2020).…”

Section: Vit Expression Is Regulated By Iron Availabilitymentioning

confidence: 99%

The vacuolar iron transporter mediates iron detoxification in Toxoplasma gondii

Aghabi

Sloan

Dou

et al. 2022

Preprint

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Iron is essential to living cells, acting as a cofactor in a number of important enzymes in metabolism; however in the absence of correct storage iron forms dangerous oxygen radicals. In both yeast and plants, iron is stored in a membrane-bound vacuole through the action of a vacuolar iron transporter (VIT). This transporter is conserved in the apicomplexan family of obligate intracellular parasites, including in Toxoplasma gondii, a pathogen of medical and veterinary importance. Here, we assess the role of VIT, and iron storage, in T. gondii. We show that iron is restricted to a compartment in the parasite that does not overlap with zinc. By deleting VIT we find a slight growth defect in vitro, however the absence of VIT leads to hypersensitivity to iron, confirming its essential role in iron detoxification in the parasite. This hypersensitivity can be rescued by scavenging of oxygen radicals. In the absence of VIT, parasites store less iron and are at a growth disadvantage when moving into an iron-depleted environment. We show parasite VIT expression is regulated by iron levels at both the transcript and protein level, and by altering the distribution of VIT within the cell. In the absence of VIT, we find that T. gondii responds by altering expression of genes with a role in iron metabolism and by increasing the activity of the antioxidant protein catalase. We also show that iron detoxification has an important role both in parasite survival within macrophages and in virulence in a mouse model. Together, by demonstrating a critical role for VIT during iron detoxification in T. gondii, we reveal the importance of iron storage in the parasite and provide the first insight into the machinery involved.

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Section: Vit Expression Is Regulated By Iron Availabilitymentioning

confidence: 99%

The vacuolar iron transporter mediates iron detoxification in Toxoplasma gondii

Aghabi

Sloan

Dou

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The expression, localisation and activity of transporters are frequently regulated by the availability of the substrate. This has been well established in model organisms (Conte and Walker, 2011;Gao and Dubos, 2021;Lee et al, 2020;Sorribes-Dauden et al, 2020) and was recently reported for the arginine transporter ApiAT1 in T. gondii (Rajendran et al, 2021). To determine if iron affects expression of VIT we performed qRT-PCR on the vit gene.…”

Section: Vit Expression Is Regulated By Iron Availabilitymentioning

confidence: 89%

“…4B and C), however interestingly, removal of iron by DFO also led to a decrease (p = 0.032, one sample t test) in VIT-HA levels despite no change in RNA levels. As well as regulation at the mRNA and protein level, the function of transporters can also be regulated by changes in localisation (Lee et al, 2020). We assessed the localisation of VIT-HA upon changes in iron levels.…”

Section: Vit Expression Is Regulated By Iron Availabilitymentioning

confidence: 99%

The vacuolar iron transporter mediates iron detoxification inToxoplasma gondii

Aghabi

Sloan

Dou

et al. 2021

Preprint

View full text Add to dashboard Cite

Iron is essential to living cells, acting as a cofactor in a number of essential enzymes in metabolism; however, iron requires proper storage or it can be dangerous to the cell. In both yeast and plants, iron is stored in a vacuole through the action of a vacuolar iron transporter (VIT). This transporter is conserved in the apicomplexan family of obligate intracellular parasites, including in Toxoplasma gondii, a pathogen of medical and veterinary importance. Here, we assess the role of VIT in T. gondii. We show that deletion of VIT causes a slight growth defect in vitro, however leads to hypersensitivity in the presence of excess iron, confirming its essential role in iron detoxification in the parasite. In the absence of VIT, parasites contain less iron and are at a growth disadvantage when moving into an iron-depleted environment. We show parasite VIT expression is regulated by environmental iron levels at both the transcript and protein level, and by altering the distribution of VIT within the cell. In the absence of VIT, we find that the T. gondii responds by altering expression of genes with a role in iron metabolism and by increasing the activity of the antioxidant protein catalase. We also show that iron detoxification has an important role both in parasite survival within macrophages and in pathogenesis in a mouse model. Together, by demonstrating a critical role for VIT during iron detoxification in T. gondii, we reveal the importance of iron storage in the parasite and provide the first insight into the machinery involved.

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“…The Oat1 siRNA knockdown study showed a marked increase in the uptake of paeonol only in the MT cell line, whereas no significant change in the transport was observed in the WT cell line. Previous studies have shown several reasons for the variations in Oats and organic anion transporting polypeptides (OATPs), including post-translational modifications, cellular trafficking, and other degradation mechanisms [ 62 ]. Therefore, we hypothesized that there might be some alteration or mutation in the diseased MT cell line that results in the elevated uptake of [ 3 H]paeonol.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant and Neuroprotective Effects of Paeonol against Oxidative Stress and Altered Carrier-Mediated Transport System on NSC-34 Cell Lines

et al. 2022

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Paeonol is a naturally occurring phenolic agent that attenuates neurotoxicity in neurodegenerative diseases. We aimed to investigate the antioxidant and protective effects of paeonol and determine its transport mechanism in wild-type (WT; NSC-34/hSOD1WT) and mutant-type (MT; NSC-34/hSOD1G93A) motor neuron-like amyotrophic lateral sclerosis (ALS) cell lines. Cytotoxicity induced by glutamate, lipopolysaccharides, and H2O2 reduced viability of cell; however, the addition of paeonol improved cell viability against neurotoxicity. The [3H]paeonol uptake was increased in the presence of H2O2 in both cell lines. Paeonol recovered ALS model cell lines by reducing mitochondrial oxidative stress induced by glutamate. The transport of paeonol was time-, concentration-, and pH-dependent in both NSC-34 cell lines. Kinetic parameters showed two transport sites with altered affinity and capacity in the MT cell line compared to the WT cell line. [3H]Paeonol uptake increased in the MT cell line transfected with organic anion transporter1 (Oat1)/Slc22a6 small interfering RNA compared to that in the control. Plasma membrane monoamine transporter (Pmat) was also involved in the uptake of paeonol by ALS model cell lines. Overall, paeonol exhibits neuroprotective activity via a carrier-mediated transport system and may be a beneficial therapy for preventing motor neuronal damage under ALS-like conditions.

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Post-translational regulation of the major drug transporters in the families of organic anion transporters and organic anion–transporting polypeptides

Cited by 33 publications

References 152 publications

The vacuolar iron transporter mediates iron detoxification in Toxoplasma gondii

The vacuolar iron transporter mediates iron detoxification in Toxoplasma gondii

The vacuolar iron transporter mediates iron detoxification inToxoplasma gondii

Antioxidant and Neuroprotective Effects of Paeonol against Oxidative Stress and Altered Carrier-Mediated Transport System on NSC-34 Cell Lines

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