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PubMed2006

The macrophage cell surface glyceraldehyde-3-phosphate dehydrogenase is a novel transferrin receptor.

The reticuloendothelial system plays a major role in iron metabolism. Despite this, the manner in which macrophages handle iron remains poorly understood. Mammalian cells utilize transferrin-dependent mechanisms to acquire iron via transferrin receptors 1 and 2 (TfR1 and TfR2) by receptor-mediated endocytosis. Here, we show for the first time that the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is localized on human and murine macrophage cell surface. The expression of this surface GAPDH is regulated by the availability of iron in the medium. We further demonstrate that this GAPDH interacts with transferrin and the GAPDH-transferrin complex is subsequently internalized into the early endosomes. Our work sheds new light on the mechanisms involved in regulation of iron, vital for controlling numerous diseases and maintaining normal immune function. Thus, we propose an entirely new avenue for investigation with respect to transferrin uptake and regulation mechanisms in macrophages.

Animals↗
PubMed1986

Exposure of K562 cells to anti-receptor monoclonal antibody OKT9 results in rapid redistribution and enhanced degradation of the transferrin receptor.

When the human erythroleukemia cell line K562 is treated with OKT9, a monoclonal antibody against the transferrin receptor, effects on receptor dynamics and degradation ensue. The apparent half-life of the receptor is decreased by greater than 50% as a result of OKT9 treatment. The transferrin receptor is also rapidly redistributed in response to OKT9 such that a lower percentage of the cellular receptors are displayed on the cell surface. OKT9 treatment also leads to a decrease in the total number of receptors participating in the transferrin cycle for cellular iron uptake. The reduction in iron uptake that results from the loss of receptors from the cycle leads to enhanced biosynthesis of the receptor. Receptors with bound OKT9 continue to participate in multiple cycles of iron uptake. However, OKT9 treatment appears to result in a relatively small increase per cycle in the departure of receptors from participation in iron uptake to a pathway leading to receptor degradation. Radiolabeled OKT9 is itself degraded by K562 cells and this degradation is inhibitable by leupeptin or chloroquine. In the presence of leupeptin, OKT9 treatment results in the enhanced intracellular accumulation of transferrin. Because the time involved in the transferrin cycle is shorter (12.5 min) than the normal half-life of the receptor (8 h), a small change in recycling efficiency caused by OKT9 treatment could account for the marked decrease in receptor half-life. In this paper the implications of these findings are discussed as they relate to systems in which receptor number is regulated by ligand.

Antibodies, Monoclonal↗
PubMed1993

Molecules internalized by clathrin-independent endocytosis are delivered to endosomes containing transferrin receptors.

We have previously demonstrated that the preendosomal compartment in addition to clathrin-coated vesicles, comprises distinct nonclathrin coated endocytic vesicles mediating clathrin-independent endocytosis (Hansen, S. H., K. Sandvig, and B. van Deurs. 1991. J. Cell Biol. 113:731-741). Using K+ depletion in HEp-2 cells to block clathrin-dependent but not clathrin-independent endocytosis, we have now traced the intracellular routing of these nonclathrin coated vesicles to see whether molecules internalized by clathrin-independent endocytosis are delivered to a unique compartment or whether they reach the same early and late endosomes as encountered by molecules internalized with high efficiency through clathrin-coated pits and vesicles. We find that Con A-gold internalized by clathrin-independent endocytosis is delivered to endosomes containing transferrin receptors. After incubation of K(+)-depleted cells with Con A-gold for 15 min, approximately 75% of Con A-gold in endosomes is colocalized with transferrin receptors. Endosomes containing only Con A-gold may be accounted for either by depletion of existing endosomes for transferrin receptors or by de novo generation of endosomes. Cationized gold and BSA-gold internalized in K(+)-depleted cells are also delivered to endosomes containing transferrin receptors. h-lamp-1-enriched compartments are only reached occasionally within 30 min in K(+)-depleted as well as in control cells. Thus, preendosomal vesicles generated by clathrin-independent endocytosis do not fuse to any marked degree with late endocytic compartments. These data show that in HEp-2 cells, molecules endocytosed without clathrin are delivered to the same endosomes as reached by transferrin receptors internalized through clathrin-coated pits.

Antigens, CD↗
PubMed2001

Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy.

The biological functions of immunoglobulin (Ig)A antibodies depend primarily on their interaction with cell surface receptors. Four IgA receptors are presently characterized. The FcalphaRI (CD89) expressed by myeloid cells selectively binds IgA1 and IgA2 antibodies, whereas the poly-IgR, Fcalpha/muR, and asialoglycoprotein receptors bind other ligands in addition to IgA. IgA binding by mesangial cells, epithelial cells, and proliferating lymphocytes is also well documented, but the nature of the IgA receptors on these cells remains elusive. A monoclonal antibody (A24) is described here that specifically blocks IgA binding to epithelial and B lymphocyte cell lines. Both the A24 antibody and IgA1 myelomas bind a cell surface protein that is identified as the transferrin receptor (CD71). The transferrin receptor selectively binds IgA1 antibodies, monomeric better than polymeric forms, and the IgA1 binding is inhibitable by transferrin. Transferrin receptor expression is upregulated on cultured mesangial cells as well as on glomerular mesangial cells in patients with IgA nephropathy. The characterization of transferrin receptor as a novel IgA1 receptor on renal mesangial cells suggests its potential involvement in the pathogenesis of IgA nephropathy.

Animals↗
PubMed1997

Transferrin-liposome-mediated p53 sensitization of squamous cell carcinoma of the head and neck to radiation in vitro.

Wild-type (wt) p53 DNA was transfected into the radioresistant human cell line JSQ-3, established from a squamous cell carcinoma of the head and neck (SCCHN), using a transferrin-liposome system, and the ability of the introduced wt p53 to sensitize the transfected JSQ-3 cells to ionizing radiation was examined. Transferrin increased the in vitro transfection efficiency of cationic liposomes up to 70-80% in JSQ-3 cells, representing a 6- to 10-fold increase over liposome transfection alone. The exogenous wt p53 was expressed at high levels in transferrin-liposome-DNA-transfected cells and resulted in the reversion of the radioresistant phenotype of the JSQ-3 cells in a DNA dose-dependent manner. The D10 values were reduced from 6.36 +/- 0.54 Gy to 4.13 +/- 0.06 Gy, a value in the radiosensitive range. In vivo, the intratumoral injection of the transferrin-liposome system resulted in a higher number of transfected tumor cells in the JSQ-3 induced nude mouse xenografts when compared with transfection by liposome alone. The results indicate that the combination of p53 replacement gene transduction, mediated by the relatively safe transferrin-liposome system, and conventional ionizing radiation may provide a more effective treatment for head and neck cancer.

Animals↗
PubMed2005

Phospholipase D2 is required for efficient endocytic recycling of transferrin receptors.

RNA interference-mediated depletion of phospholipase D2 (PLD2), but not PLD1, inhibited recycling of transferrin receptors in HeLa cells, whereas the internalization rate was unaffected by depletion of either PLD. Although reduction of both PLD isoforms inhibits PLD activity stimulated by phorbol 12-myristic 13-acetate, only depletion of PLD2 decreased nonstimulated activity. Cells with reduced PLD2 accumulated a greater fraction of transferrin receptors in a perinuclear compartment that was positive for Rab11, a marker of recycling endosomes. EFA6, an exchange factor for Arf6, has been proposed to stimulate the recycling of transferrin receptors. Thus, one consequence of EFA6 overexpression would be a reduction of the internal pool of receptors. We confirmed this observation in control HeLa cells; however, overexpression of EFA6 failed to decrease the internal pool of transferrin receptors that accumulate in cells previously depleted of PLD2. These observations suggest that either PLD2 is required for a constitutive Arf6-mediated recycling pathway or in the absence of PLD2 transferrin receptors accumulate in recycling endosomes that are not responsive to overexpression of EFA6.

ADP-Ribosylation Factor 6↗
PubMed1987

Dissociated response of plasma albumin and transferrin to protein-calorie restriction in squirrel monkeys (Saimiri sciureus).

The responses of albumin and transferrin to selective nutritional interventions were assessed in 31 infant monkeys. Diets were restricted in protein, calories, or both from age 2 to 8 wk (study A) or protein alone from age 4 to 24 wk (study B)--in both cases to prevent growth. Transferrin levels in study A were significantly lower than control in all three restricted groups whereas albumin levels were decreased only in both low-protein groups. In study B albumin and transferrin concentrations were significantly decreased during the first 12 wk of intervention. A sharp recovery in the transferrin concentrations, however, was observed when a minimal increase in protein intake was allowed in the latter portion of the study. It appears that the response of albumin is linked to amino acid availability whereas the response of transferrin is influenced by variables such as acute dietary manipulation and rate of growth, among others. The value of these indices as single predictors of nutritional status is questioned.

Age Factors↗
PubMed1994

Assessment of iron status of Zairean women of childbearing age by serum transferrin receptor.

Soluble transferrin receptor (sTfR), previously shown to be a sensitive indicator of tissue iron deficiency, was used to assess iron status of 104 Zairean women (69 lactating, 19 pregnant, and 16 nonpregnant, nonlactating women). Thirteen iron-sufficient female laboratory employees were also studied. Mean sTfR concentrations were higher in pregnant women (9.90 mg/L) than in lactating women (8.55 mg/L), nonlactating women (7.74 mg/L), and laboratory employees (5.11 mg/L) (P < 0.005). Mean serum ferritin and transferrin saturation were lower in pregnant than nonpregnant women. sTfR negatively correlated with hemoglobin (P < 0.05) and transferrin saturation (P < 0.05), and nonsignificantly with ferritin and transferrin. With 7.26 mg sTfR/L (the upper limit of laboratory employees) as the cutoff value, sTfR identified 67% of women with tissue iron deficiency compared with 11.5-57% for transferrin saturation, hemoglobin, or ferritin. Despite the moderate sensitivity (68.5%), 90% of women with sTfR > 7.26 mg/L also had another index below normal and 54% had serum ferritin < or = 50 micrograms/L.

Adult↗
PubMed1984

Transferrin in disease. I: A potential prognostic indicator in patients undergoing bone marrow transplantation.

Transferrin levels were measured immunochemically and the levels of several other plasma proteins were estimated by high resolution agarose gel electrophoresis in serial serum samples from nine patients undergoing bone marrow transplantation for aplastic anemia or leukemia. Three of five patients with low pretreatment transferrin levels died during initial hospitalization, and the other two suffered severe complications prior to recovery. All four patients with pretreatment transferrin levels within the normal range were discharged, three of them with minimal complications. Serial studies demonstrated that transferrin levels fell with the onset of infections or graft-versus-host disease and rose with recovery. Similar changes were not seen with any of the other plasma proteins measured. These results suggest that measurement of serum transferrin may reveal important prognostic information about patients undergoing bone marrow transplantation.

Adolescent↗
PubMed2000

N-glycan patterns of human transferrin produced in Trichoplusia ni insect cells: effects of mammalian galactosyltransferase.

The N-glycans of human serum transferrin produced in Trichopulsia ni cells were analyzed to examine N-linked oligosaccharide processing in insect cells. Metabolic radiolabeling of the intra- and extracellular protein fractions revealed the presence of multiple transferrin glycoforms with molecular weights lower than that observed for native human transferrin. Consequently, the N-glycan structures of transferrin in the culture medium were determined using three-dimensional high performance liquid chromatography. The attached oligosaccharides included high mannose, paucimannosidic, and hybrid structures with over 50% of these structures containing one fucose, alpha(1,6)-, or two fucoses, alpha(1,6)- and alpha(1,3)-, linked to the Asn-linked N-acetylglucosamine. Neither sialic acid nor galactose was detected on any of the N-glycans. However, when transferrin was coexpressed with beta(1,4)-galactosyltransferase three additional galactose-containing hybrid oligosaccharides were obtained. The galactose attachments were exclusive to the alpha(1, 3)-mannose branch and the structures varied by the presence of zero, one, or two attached fucose residues. Furthermore, the presence of the galactosyltransferase appeared to reduce the number of paucimannosidic structures, which suggests that galactose attachment inhibits the ability of hexosaminidase activity to remove the terminal N-acetylglucosamine. The ability to promote galactosylation and reduce paucimannosidic N-glycans suggests that the oligosaccharide processing pathway in insect cells may be manipulated to mimic more closely that of mammalian cells.

Animals↗
PubMed1992

Iron acquisition in Haemophilus influenzae: receptors for human transferrin.

As an adaptation to the iron-limited environment of the host, Haemophilus influenzae has a transferrin receptor-mediated mechanism of iron acquisition such that it can acquire iron directly from human transferrin. The absence of detectable siderophore production and the presence of transferrin binding in a collection of type b and nontypeable H. influenzae strains indicate that the mechanism is widespread in this species. Growth and binding studies have consistently shown that the receptor is specific for human transferrin, which correlates with the host range of this pathogen. Inhibitor experiments indicate that iron regulation of receptor activity is mediated at the gene level. Affinity isolation experiments indicate that, as observed with other bacterial pathogens, the receptor is composed of two iron-repressible outer membrane proteins, transferrin binding proteins 1 and 2.

Bacterial Outer Membrane Proteins↗
PubMed2003

Transcriptional profiling reveals multifunctional roles for transferrin in the honeybee, Apis mellifera.

Transferrins belong to a family of iron-binding proteins that have been implicated in innate immunity and in vitellogenesis in insects. Here we have sequenced and characterized a full-length cDNA encoding a putative iron-binding transferrin (AmTRF) in the honeybee. AmTRF shows high level of sequence identity with transferrins in both vertebrates and insects (26-46%) suggesting that the primary function of the predicted 712 amino acid protein is binding and transporting of iron. AmTRF is expressed ubiquitously, but particularly high levels of its mRNA are found in the central brain and in the compound eye. Using northern blotting and a microarray based approach we have examined the levels of AmTRF mRNA by expression profiling under a wide range of conditions including developmental stages, septic injury and juvenile hormone treatment. Increased expression of AmTRF is seen during early pupal stages, in the brain of mature foragers and in the abdomen of virgin queens, whereas treatment with juvenile hormone leads to a decrease of AmTRF levels in the abdomen. We show that a transcriptional response of transferrin to septic injury with E. coli is relatively moderate as compared to a dramatic up-regulation of an antibacterial polypeptide, Hymenoptaecin, under similar conditions. We conclude that major fluctuations of AmTRF mRNA in time and space are consistent with context-dependent functional significance and suggest broader multifunctional roles for transferrin in insects.

Amino Acid Sequence↗
PubMed1989

Biochemical exploration of azoospermia: interest of the seminal transferrin assay.

Seminal transferrin is considered a good index of Sertoli cell function. In this study, including 19 control subjects, four vasectomized subjects and 65 non-vasectomized subjects with azoospermia, transferrin was measured concomitantly with other classical biochemical seminal markers such as L-carnitine, fructose and zinc. This parameter should provide additional information for differentiation between obstructive and non-obstructive azoospermia. A threshold value of 85 micrograms/ejaculate for transferrin was defined in the control and the vasectomized groups. The 65 subjects with azoospermia were divided into five groups according to L-carnitine and transferrin threshold values; the nature of azoospermia (obstructive or non-obstructive) was considered in each group. In the biological investigation of sterility, the measurement of transferrin provided information as to the aetiology of azoospermia. However, the determination of L-carnitine and fructose remains important in the localization of any obstruction.

Adult↗
PubMed1992

Regulation of the synthesis and secretion of transferrin and cyclic protein-2/cathepsin L by mature rat Sertoli cells in culture.

While numerous studies have examined the response of immature rat Sertoli cells to specific hormones and growth factors, the regulation of mature cells in vitro has not been well examined because highly purified cells have been difficult to isolate. We now describe a detailed method for isolating Sertoli cells from mature (> 60 days of age) rats and generating primary cultures of these cells greater than 90% in purity. We demonstrate that cell density, hormones, and growth factors regulate the synthesis or secretion of two Sertoli cell products, transferrin and Cyclic Protein-2 (CP-2)/cathepsin L. Cell density modulated the response of mature Sertoli cells to some hormones; insulin (at 10 micrograms/ml) and epidermal growth factor (EGF) acted synergistically to stimulate transferrin synthesis by 80% when cells were cultured at a density of 1.65 x 10(5) cells/cm2 but had no effect on transferrin synthesis by cells cultured at 1.46 x 10(5) cells/cm2. A mixture of FSH, retinol, and testosterone increased transferrin synthesis by 30% at both cell densities, and this stimulation was independent of the effect of EGF and insulin. CP-2/cathepsin L synthesis was significantly stimulated by increased cell density. FSH, retinol, and testosterone also stimulated CP-2/cathepsin L synthesis by 30%; however, this stimulation just missed being statistically significant. Finally, we demonstrated that secretion of transferrin and CP-2 was reduced when cells were cultured in the presence of interleukin-1 alpha, a cytokine synthesized by Sertoli cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The effect of ethanol on the uptake, binding, and desialylation of transferrin by rat liver endothelium: implications in the pathogenesis of alcohol-associated hepatic siderosis.

Chronic alcoholism has been reported to be associated with a reduced carbohydrate content of transferrin (TF), particularly, its reduced sialylation state. Low sialylation state of TF now serves as an objective marker of chronic alcohol abuse. To investigate the pathophysiological significance of this finding in relation to hepatic siderosis, also commonly associated with chronic alcoholism, the authors have investigated the effect of ethanol on the uptake, binding, and desialylation of transferrin by isolated rat liver endothelium in vitro. In pulse-chase experiments, transferrin labeled with either 125I (protein-labeled) or 3H (sialic acid-labeled) was incubated with isolated, fractionated liver endothelium with and without ethanol, and the supernates were subjected to column chromatography using RCA120- agarose. Incubation of the endothelium with increasing concentrations of ethanol resulted in a progressive increase in the desialylation rate of transferrin which was maximal when 160 mM concentration of ethanol was used. These data indicate that ethanol significantly promotes the desialylation of transferrin by rat liver endothelium. The implications of these findings in the pathogenesis of hepatic siderosis of the alcoholic are discussed.

Acetaldehyde↗
PubMed1993

Serum transferrin as a prognostic indicator of spontaneous closure and mortality in gastrointestinal cutaneous fistulas.

OBJECTIVE: This study determined whether there are any laboratory or other features that will enable prediction of spontaneous closure in patients with gastrointestinal cutaneous fistulas. SUMMARY BACKGROUND DATA: Although the anatomic criteria for spontaneous closure of gastrointestinal cutaneous fistulas have been presented by several authors, less than 50% of such fistulas tend to close, even in the most recent series. METHODS: A group of patients with gastrointestinal cutaneous fistulas with anatomical features favorable to study were investigated with respect to a series of parameters including the usual demographic parameters, plus fistula output, number of blood transfusions, presence of sepsis, as well as metabolic parameters including serum transferrin, retinol-binding protein, thyroxin-binding prealbumin, and serum albumin. RESULTS: Of 79 patients with 116 fistulas, 16 (20.3%) died. Causes of death were uncontrolled sepsis in eight patients and cancer in five patients. Postoperative fistulas constituted 80% of the group. The presence of local sepsis, systemic sepsis, remote sepsis (such as pneumonia or line sepsis), the number of fistulas, fistula output, and the number of blood transfusions were not predictive of spontaneous closure, whereas serum transferrin was predictive of spontaneous closure. Serum transferrin, retinol-binding protein, and thyroxin-binding prealbumin were predictive of mortality. CONCLUSIONS: Serum transferrin does not appear to be an entirely independent variable, but seems to identify those patients with significant remote sepsis, systemic sepsis, and neoplasia in whom these processes are clinically significant. The results, if confirmed, and provided that nutritional needs are met, suggest that short-turnover proteins, particularly serum transferrin, might be useful in predicting which patients with gastrointestinal cutaneous fistulas should undergo surgery despite anatomic criteria favorable for spontaneous closure.

Adolescent↗
PubMed1990

Lactoferrin and transferrin damage of the gram-negative outer membrane is modulated by Ca2+ and Mg2+.

Lactoferrin and transferrin have antimicrobial activity against selected Gram-negative bacteria, but the mechanism of action has not been defined. We studied the ability of lactoferrin and transferrin to damage the Gram-negative outer membrane. Lipopolysaccharide release by the proteins could be blocked by concurrent addition of Ca2+ and Mg2+. Addition of Ca2+ also blocked the ability of lactoferrin to increase the susceptibility of Escherichia coli to rifampicin. Transferrin, but not lactoferrin, increased susceptibility of Gram-negative bacteria to deoxycholate, with reversal of sensitivity occurring with exposure to Ca2+ or Mg2+. In transmission electron microscopy studies polymyxin B caused finger-like membrane projections, but no morphological alterations were seen in cells exposed to EDTA, lactoferrin or transferrin. These data provide further evidence that lactoferrin and transferrin act as membrane-active agents with the effects modulated by Ca2+ and Mg2+.

Calcium↗
PubMed1995

Staphylococcus aureus but not Staphylococcus epidermidis can acquire iron from transferrin.

Staphylococci grow and cause infection under the iron-restricted conditions found in vivo. They therefore must possess mechanisms to obtain iron for metabolism from this environment. To determine if staphylococci can extract iron bound to human transferrin, we labelled transferrin with 55Fe and performed uptake assays on cells grown in iron-restricted and iron-plentiful conditions. Growing cultures of Staphylococcus aureus NCTC 8532 could take up radioactive iron during mid- to late-exponential phase of growth. This process was iron-regulated and did not require direct contact between the cell and the labelled transferrin. Siderophore production was detected during this phase, but reductase or protease activity was not. S. epidermidis ATCC 14990 could not access 55Fe bound to transferrin, nor did this isolate produce siderophore, reductase or protease. This difference in the ability to acquire iron bound to transferrin may contribute to the increased virulence of S. aureus when compared to S. epidermidis.

Biological Transport↗