Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions

Antony, Asok; Yingsheng, Tang; Khan, Rehana A.; Biju, Mangatt P.; Xiao, Xu; Liu, Qingjun; Sun, Xin-Lai; Jayaram, Hiremagalur N.; Stabler, Sally P.

doi:10.1172/jci200411548

Cited by 61 publications

(31 citation statements)

References 65 publications

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“…12 For normal expression of FR1 on the cell membrane surface and proper functioning of this folate receptor mediated endocytosis, many cooperating genetic and non-genetic factors have been identified as important determinants, such as intracellular homocystein concentration, the extent of N-glycosylation of FR1, and the sphingolipid and cholesterol content in membranes. [17][18][19][20] At the apical surface of choroid epithelial cells RFC1 facilitates folate export. RFC1 is also located at vessel membranes of the blood-brain barrier, where its contribution to the main bulk of folate transport is of minor importance because it has low folate affinity and will only bind folate concentrations within the micromolar range.…”

Section: Folate Metabolism and Transportmentioning

confidence: 99%

Cerebral folate deficiency

Ramaekers¹,

Blau²

2004

Dev Med Child Neurol

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Cerebral folate deficiency (CFD) can be defined as any neurological syndrome associated with low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), the active folate metabolite, in the presence of normal folate metabolism outside the nervous system. CFD could result from either disturbed folate transport or from increased folate turnover within the central nervous system (CNS). We report on a novel neurometabolic syndrome in 20 children, which we term 'idiopathic CFD'. Typical features became manifest from the age of 4 months, starting with marked unrest, irritability, and sleep disturbances followed by psychomotor retardation, cerebellar ataxia, spastic paraplegia, and dyskinesia; epilepsy developed in about one third of the children. Most children showed deceleration ofhead growth from the age of 4 to 6 months. Visual disturbances began to develop around the age of 3 years and progressive sensorineural hearing loss started from the age of 6 years. Neuroimaging showed atrophy of frontotemporal regions and periventricular demyelination in seven children, slowly progressive supra- and infratentorial atrophy in three children, and normal findings in the remainder. Because active folate transport to the CNS occurs through receptor-mediated folate receptor protein 1 (FR1) endocytosis, DNA sequencing of the FR1 gene was performed and found to be normal. However, CSF protein analysis revealed a non-functional FR1 protein, suspected to result from either post-translational defects of FR1 protein N-glycosylation, the presence of folate antagonists with irreversible binding, or autoantibodies blocking the folate binding site of FR1. Oral treatment with 5-formyltetrahydrofolate (folinic acid) should be started in low doses at 0.5-1mg/kg/day, but in some patients higher daily doses of folinic acid at 2-3 mg/kg/day are required to normalize CSF 5MTHF values. This proposed treatment protocol resulted in a favourable clinical response in patients identified before the age of six years while partial recovery with poorer outcome was found beyond the age of 6 years. Careful clinical and EEG monitoring should be performed 1, 3, and 6 months after the beginning of treatment. After four to six months of folinic acid treatment, CSF analysis should be repeated in order to prevent over- or under-dosage of folinic acid. Secondary forms of CFD have been recognized during chronic use of antifolate and anticonvulsant drugs and in various known conditions such as Rett syndrome, Aicardi-Goutières syndrome, 3-phosphoglycerate dehydrogenase deficiency, dihydropteridine reductase deficiency, aromatic amino acid decarboxylase deficiency, and Kearns-Sayre syndrome. The pathogenic link between these underlying specific disease entities and the observed secondary CFD has not been resolved.

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Section: Folate Metabolism and Transportmentioning

confidence: 99%

Cerebral folate deficiency

Ramaekers¹,

Blau²

2004

Dev Med Child Neurol

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“…Folate dependent regulation of FR-α expression in cervical carcinoma cells was attributed to the interaction of an mRNA binding transfactor called heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1), with an 18-base cis-element in the 5′ UTR of the FR-α transcript (169;170). When these cells were grown in low-folate media, FR-α expression was up-regulated without any significant change in the expression of hnRNP E1 (168). The increase in FR-α expression was attributed to the accumulation of homocysteine in these cells which led to an increase in the interaction of hnRNP E1 with the 18 base cis-element of FR-α (168).…”

Section: Regulation By Folatementioning

confidence: 95%

“…When these cells were grown in low-folate media, FR-α expression was up-regulated without any significant change in the expression of hnRNP E1 (168). The increase in FR-α expression was attributed to the accumulation of homocysteine in these cells which led to an increase in the interaction of hnRNP E1 with the 18 base cis-element of FR-α (168). Interestingly, in vivo, a number of tissues of gestational day 17 fetuses from pregnant dams fed a low folate diet (400 nmol folate/kg chow) up-regulated both hnRNP E1 and FR-α expression compared to dams fed a higher folate diet (1200 nmol folate/kg chow) (171).…”

Section: Regulation By Folatementioning

confidence: 97%

Role of folate receptor genes in reproduction and related cancers

Elnakat

Ratnam

2006

Front Biosci

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The expression patterns of folate receptor (FR) isoforms, alpha and beta, in normal and malignant male and female reproductive tissues is described. The significance of the receptor in reproductive and developmental physiology is discussed. The potential value of the receptor expressed in malignant tissues including ovarian and endometrial cancers as a diagnostic marker and a therapeutic target is reviewed. Finally, the various transcriptional and post-transcriptional mechanisms that govern the tissue/tumor-specificity of the receptor and its regulation by folate and steroid receptor ligands are described; the potential value of this knowledge in developing better methods for the early detection and treatment of certain cancers is discussed.

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“…This raises the possibility of an interrelated physiologic mechanism for the coexpression of hnRNP-E1 with folate receptors. Such an occurrence could explain clinical observations in which folate receptors and hnRNP-E1 are concordantly overexpressed in various human and murine tissues (1,(4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 95%

“…Folate deficiency triggers the upregulation of folate receptors, which serves to optimize cellular folate uptake and help restore folate homeostasis to normal (1,2). The molecular basis for upregulation of folate receptors likely involves the progressive homocysteinylation of heterogeneous nuclear ribonucleoprotein E1 (hnRNP-E1) 10 in proportion to the degree of folate deficiency (3), with replacement of key cysteine S-S cysteine disulfide bonds in hnRNP-E1 by homocysteine S-S cysteine mixed disulfide bonds, which results in the gradual unmasking of an underlying mRNAbinding site in hnRNP-E1.…”

Section: Introductionmentioning

confidence: 99%

Evidence Favoring a Positive Feedback Loop for Physiologic Auto Upregulation of hnRNP-E1 during Prolonged Folate Deficiency in Human Placental Cells

Tang

Khan

Xiao

et al. 2017

The Journal of Nutrition

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Previously, we determined that heterogeneous nuclear ribonucleoprotein E1 (hnRNP-E1) functions as an intracellular physiologic sensor of folate deficiency. In this model, l-homocysteine, which accumulates intracellularly in proportion to the extent of folate deficiency, covalently binds to and thereby activates homocysteinylated hnRNP-E1 to interact with folate receptor-α mRNA; this high-affinity interaction triggers the translational upregulation of cell surface folate receptors, which enables cells to optimize folate uptake from the external milieu. However, integral to this model is the need for ongoing generation of hnRNP-E1 to replenish homocysteinylated hnRNP-E1 that is degraded. We searched for an interrelated physiologic mechanism that could also maintain the steady-state concentration of hnRNP-E1 during prolonged folate deficiency. A novel RNA-protein interaction was functionally characterized by using molecular and biochemical approaches in vitro and in vivo. l-homocysteine triggered a dose-dependent high-affinity interaction between hnRNP-E1 and a 25-nucleotide element within the 5'-untranslated region of mRNA; this led to a proportionate increase in these RNA-protein complexes, and translation of hnRNP-E1 both in vitro and within placental cells. Targeted perturbation of this RNA-protein interaction either by specific 25-nucleotide antisense oligonucleotides or mutation within this element or by small interfering RNA to mRNA significantly reduced cellular biosynthesis of hnRNP-E1. Conversely, transfection of hnRNP-E1 mutant proteins that mimicked homocysteinylated hnRNP-E1 stimulated both cellular hnRNP-E1 and folate receptor biosynthesis. In addition, ferrous sulfate heptahydrate [iron(II)], which also binds hnRNP-E1, significantly perturbed this l-homocysteine-triggered RNA-protein interaction in a dose-dependent manner. Finally, folate deficiency induced dual upregulation of hnRNP-E1 and folate receptors in cultured human cells and tumor xenografts, and more selectively in various fetal tissues of folate-deficient dams. This novel positive feedback loop amplifies hnRNP-E1 during prolonged folate deficiency and thereby maximizes upregulation of folate receptors in order to restore folate homeostasis toward normalcy in placental cells. It will also functionally impact several other mRNAs of the nutrition-sensitive, folate-responsive posttranscriptional RNA operon that is orchestrated by homocysteinylated hnRNP-E1.

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Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions

Abstract: region (UTR); heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1); pteroylglutamate (PteGlu); Dulbecco's PBS (D-PBS); chloramphenicol acetyltransferase (CAT); with a cis-element (+cis); lacking a cis-element (-cis).

Cited by 61 publications

References 65 publications

Cerebral folate deficiency

Cerebral folate deficiency

Role of folate receptor genes in reproduction and related cancers

Evidence Favoring a Positive Feedback Loop for Physiologic Auto Upregulation of hnRNP-E1 during Prolonged Folate Deficiency in Human Placental Cells

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