Choline transport for phospholipid synthesis: An emerging role of choline transporter-like protein 1

Hedtke, Vera; Bakovic, Marica

doi:10.1177/1535370219830997

Cited by 39 publications

(43 citation statements)

References 61 publications

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“…Based on our extensive work on CTL1 and Cho transport (3)(4)(5)(6)(7)(8)15) and known similarities between Cho and Etn transports in various conditions (12-14) we postulated that CTL1 could be that long-searched for Etn/Cho transporter and the last missing link between CDP-Cho and CDP-Etn pathways for phospholipids synthesis. We conducted an extensive number of kinetic, metabolic, and genetic experiments to solidify this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…CTL1 and CTL2 mediate Etn transport to mitochondria. CTL1 and CTL2 are present in the mitochondria and are involved in mitochondrial Cho transport (4,5). We used COXIV as a marker of mitochondria isolated from Ctrl and M2 cells and CTL2 mRNA expression for the siRNA knockdown of CTL2 transport (Fig.…”

Section: Pharmacological and Sirna Inhibition Of Etn Transportmentioning

confidence: 99%

“…Cho transport for membrane phospholipid synthesis is mediated by Cho transporter like protein CTL1/SLC44A1 (3). CTL1 is the only well-characterized member of a broader family (CTL1-5/SLC44A1-5) (4,5). CTL1/SLC44A1 is a Cho/H + antiporter at the plasma membrane and mitochondria (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…CTL1 is the only well-characterized member of a broader family (CTL1-5/SLC44A1-5) (4,5). CTL1/SLC44A1 is a Cho/H + antiporter at the plasma membrane and mitochondria (4,5). The role of plasma membrane CTL1 is assigned to Cho transport for PC synthesis, but the exact function of the mitochondrial CTL1 is still not clear.…”

Section: Introductionmentioning

confidence: 99%

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The novel roles of choline transporter-like 1 and 2 in ethanolamine transport

Taylor

Grapentine

Ichhpuniani

et al. 2020

Preprint

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We examined a novel function of mammalian Choline-Transporter-Like proteins CTL1/SLC44A1 and CTL2/SLC44A2 in ethanolamine transport. We established two distinct ethanolamine transport systems of a high affinity (K1 = 55.6 - 66.5 μM), mediated by CTL1, and of a low affinity (K2 = 275 - 299 μM), mediated by CTL2. Both types of transport are Na+-independent and mediated in a pH dependent manner, as expected for ethanolamine/H+ antiporters. Primary human fibroblasts with separate frameshift mutations (M1= SLC44A1ΔAsp517 and M2= SLC44A1ΔSer126) are devoid of CTL1 ethanolamine transport but maintain unaffected CTL2 transport. The lack of CTL1 or CTL2 reduced the ethanolamine transport, the flux by the CDP-ethanolamine Kennedy pathway and PE synthesis. Overexpression of CTL1 in SLC44A1ΔSer126 (M2) cells improved the ethanolamine transport and PE synthesis. The SLC44A1ΔSer126 cells are reliant on CTL2 function and CTL2 siRNA almost completely abolished ethanolamine transport in the whole cells and mitochondria. Overexpression of CTL1 and CTL2 cDNAs increased ethanolamine transport in control and SLC44A1ΔSer126 cells. CTL1 and CTL2 facilitated mitochondrial ethanolamine uptake, but the transport mediated by CTL1 is predominant in the whole cells and mitochondria. These data firmly established that CTL1 and CTL2 are the first identified ethanolamine transporters in the whole cells and mitochondria, with intrinsic roles in de novo PE synthesis by the CDP-Etn Kennedy pathway and compartmentation of intracellular ethanolamine.SignificanceThe lack of Choline Transporter Like 1 (SLC44A1/CTL1) is the primary cause of a new neurodegenerative disorder with elements of childhood-onset parkinsonism and mitochondrial dysfunction. SLC44A2/CTL2 encodes the human neutrophil antigen 3, causes autoimmune hearing loss and Meniere’s disease, and has been recently identified as the main risk factor for thrombosis-the major cause of death in Covid-19 patients. Our investigation provides insights into the novel functions of CTL1 and CTL2 as intrinsic ethanolamine transporters. CTL1 and CTL2 are high and low affinity transporters, with direct roles in the membrane phospholipid synthesis. The work contributes to new knowledge for CTL1 and CTL2 independent transport functions and the optimization of prevention and treatment strategies in those various diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Pharmacological and Sirna Inhibition Of Etn Transportmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The novel roles of choline transporter-like 1 and 2 in ethanolamine transport

Taylor

Grapentine

Ichhpuniani

et al. 2020

Preprint

Self Cite

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“…Following uptake into the cell, choline is metabolized into molecules necessary for the body and is known to be involved in various physiological functions. There are three known metabolic pathways of choline, acetylation, phosphorylation, and oxidation, each of which metabolizes choline into substances utilized as part of physiological functions in the cell [6][7][8]. The intracellular transport system of choline is an important function of the rate-limiting step of the choline metabolic system, which is mediated by transporter molecules.…”

Section: Introductionmentioning

confidence: 99%

Anticancer Activity of Amb4269951, a Choline Transporter-Like Protein 1 Inhibitor, in Human Glioma Cells

et al. 2020

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Choline transporter-like protein 1 (CTL1) is highly expressed in glioma cells, and inhibition of CTL1 function induces apoptotic cell death. Therefore, CTL1 is a potential target molecule for glioma therapy. Here, we investigated the therapeutic mechanism underlying the antitumor effects of Amb4269951, a recently discovered novel CTL1 inhibitor, in the human glioma cell line U251MG, and evaluated its in vivo effects in a mouse xenograft model. Amb4269951 inhibited choline uptake and cell viability and increased caspase-3/7 activity. CTL1-mediated choline uptake is associated with cell viability, and the functional inhibition of CTL1 by Amb4269951 may promote apoptotic cell death via ceramide-induced suppression of the expression of survivin, an apoptotic inhibitory factor. Finally, Amb4269951 demonstrated an antitumor effect in a mice xenograft model by significantly inhibiting tumor growth without any weight loss. Amb4269951 is the lead compound in the treatment of glioma and exhibits a novel therapeutic mechanism. These results may lead to the development of novel anticancer drugs targeting the choline transporter CTL1, which has a different mechanism of action than conventional anticancer drugs against gliomas.

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A Pellino‐2 variant is associated with constitutive NLRP3 inflammasome activation in a family with ocular pterygium–digital keloid dysplasia

et al. 2023

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Edited by Wilfried EllmeierOcular pterygium-digital keloid dysplasia (OPDKD) is a rare hereditary disease characterized by corneal ingrowth of vascularized conjunctival tissue early in life. Later, patients develop keloids on fingers and toes but are otherwise healthy. In a recently described family with OPDKD, we report the presence of a de novo c.770C > T, p.(Thr257Ile) variant in PELI2 in the affected individual. PELI2 encodes for the E3 ubiquitin ligase Pellino-2. In transgenic U87MG cells overexpressing Pellino-2 with the p.(Thr257Ile) amino acid substitution, constitutive activation of the NLRP3 inflammasome was observed. However, the Thr257Ile variant did not affect Pellino-2 intracellular localization, its binding to known interaction partners, nor its stability. Our findings indicate that constitutive autoactivation of the NLRP3 inflammasome contributes to the development of PELI2-associated OPDKD.

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Choline transport for phospholipid synthesis: An emerging role of choline transporter-like protein 1

Cited by 39 publications

References 61 publications

The novel roles of choline transporter-like 1 and 2 in ethanolamine transport

The novel roles of choline transporter-like 1 and 2 in ethanolamine transport

Anticancer Activity of Amb4269951, a Choline Transporter-Like Protein 1 Inhibitor, in Human Glioma Cells

A Pellino‐2 variant is associated with constitutive NLRP3 inflammasome activation in a family with ocular pterygium–digital keloid dysplasia

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