Journal articles: 'Receptor mediated transcytosis'

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Dehouck, Bénédicte, Laurence Fenart, Marie-Pierre Dehouck, Annick Pierce, Gérard Torpier, and Roméo Cecchelli. "A New Function for the LDL Receptor: Transcytosis of LDL across the Blood–Brain Barrier." Journal of Cell Biology 138, no. 4 (August 25, 1997): 877–89. http://dx.doi.org/10.1083/jcb.138.4.877.

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Lipoprotein transport across the blood–brain barrier (BBB) is of critical importance for the delivery of essential lipids to the brain cells. The occurrence of a low density lipoprotein (LDL) receptor on the BBB has recently been demonstrated. To examine further the function of this receptor, we have shown using an in vitro model of the BBB, that in contrast to acetylated LDL, which does not cross the BBB, LDL is specifically transcytosed across the monolayer. The C7 monoclonal antibody, known to interact with the LDL receptor-binding domain, totally blocked the transcytosis of LDL, suggesting that the transcytosis is mediated by the receptor. Furthermore, we have shown that cholesterol-depleted astrocytes upregulate the expression of the LDL receptor at the BBB. Under these conditions, we observed that the LDL transcytosis parallels the increase in the LDL receptor, indicating once more that the LDL is transcytosed by a receptor-mediated mechanism. The nondegradation of the LDL during the transcytosis indicates that the transcytotic pathway in brain capillary endothelial cells is different from the LDL receptor classical pathway. The switch between a recycling receptor to a transcytotic receptor cannot be explained by a modification of the internalization signals of the cytoplasmic domain of the receptor, since we have shown that LDL receptor messengers in growing brain capillary ECs (recycling LDL receptor) or differentiated cells (transcytotic receptor) are 100% identical, but we cannot exclude posttranslational modifications of the cytoplasmic domain, as demonstrated for the polymeric immunoglobulin receptor. Preliminary studies suggest that caveolae are likely to be involved in the potential transport of LDL from the blood to the brain.

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Hansen, S. H., and J. E. Casanova. "Gs alpha stimulates transcytosis and apical secretion in MDCK cells through cAMP and protein kinase A." Journal of Cell Biology 126, no. 3 (August 1, 1994): 677–87. http://dx.doi.org/10.1083/jcb.126.3.677.

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Recent evidence suggests a role for heterotrimeric G proteins in vesicular transport. Cholera toxin, which activates Gs alpha by ADP-ribosylation, has been reported to stimulate both apical secretion (Pimplikar, S.W., and K. Simons. 1993. Nature (Lond.). 352:456-458) and apically directed transcytosis (Bomsel, M., and K.E. Mostov. 1993. J. Biol. Chem. 268:25824-25835) in MDCK cells, via a cAMP-independent mechanism. Here, we demonstrate that apical secretion and apically directed transcytosis are significantly stimulated by agents that elevate cellular cAMP. Forskolin, which activates adenylyl cyclase directly, and 8BrcAMP augment both transport processes in MDCK cells. The increase is not limited to receptor-mediated transport (polymeric Ig receptor), since transcytosis of ricin, a galactose-binding lectin, is similarly stimulated. The effects of elevated cellular cAMP on apical secretion and transcytosis are apparently mediated via protein kinase A (PKA), as they are inhibited by H-89, a selective PKA inhibitor. Experiments employing a 17 degrees C temperature block indicate that cAMP/PKA acts at a late, possibly rate-limiting stage in the transcytotic pathway, after translocation of internalized markers into the apical cytoplasm. However, no significant stimulus of apical recycling was observed in the presence of FSK, suggesting that cAMP/PKA either affects transcytosis at a level proximal to apical early endosomes and/or specifically increases the efficiency by which transcytosing molecules are delivered to the apical plasma membrane. Finally, we overexpressed wild-type Gs alpha and a mutant, Q227L, which constitutively activates adenylyl cyclase, in MDCK cells. Although Q227L increased transcytosis more than wild-type Gs alpha, neither construct was as effective as FSK in stimulating transcytosis, arguing against a significant role of Gs alpha in transcytosis independent of cAMP and PKA.

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Nelms, Bradlee, Natasha Furtado Dalomba, and Wayne Lencer. "A targeted RNAi screen identifies factors affecting diverse stages of receptor-mediated transcytosis." Journal of Cell Biology 216, no. 2 (January 9, 2017): 511–25. http://dx.doi.org/10.1083/jcb.201609035.

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Endosome transport by transcytosis is the primary mechanism by which proteins and other large cargo traverse epithelial barriers in normal tissue. Transcytosis is also essential for establishing and maintaining membrane polarity in epithelia and other polarized cells. To identify novel components of this pathway, we conducted a high-throughput RNA interference screen for factors necessary for the bidirectional transcytosis of IgG by the Fcγ receptor FcRn. This screen identified 23 genes whose suppression resulted in a reproducible decrease in FcRn-mediated transcytosis. Pulse-chase kinetic transport assays on four of the top-ranking genes (EXOC2, EXOC7, PARD6B, and LEPROT) revealed distinct effects on the apical and basolateral recycling and transcytotic pathways, demonstrating that these pathways are genetically separable. We also found a strong dependence on PARD6B for apical, but not basolateral, recycling, implicating this cell polarity gene in assembly or maintenance of the apical endosomal system. This dataset yields insights into how vesicular transport is adapted to the specialized functions of differentiated cell types and opens new research avenues into epithelial trafficking.

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Apodaca, G., L. A. Katz, and K. E. Mostov. "Receptor-mediated transcytosis of IgA in MDCK cells is via apical recycling endosomes." Journal of Cell Biology 125, no. 1 (April 1, 1994): 67–86. http://dx.doi.org/10.1083/jcb.125.1.67.

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Classically, the polymeric immunoglobulin receptor and its ligand, IgA, are thought to be sorted from basolateral early endosomes into transcytotic vesicles that directly fuse with the apical plasma membrane. In contrast, we have found that in MDCK cells IgA is delivered from basolateral endosomes to apical endosomes and only then to the apical cell surface. When internalized from the basolateral surface of MDCK cells IgA is found to accumulate under the apical plasma membrane in a compartment that is accessible to two apically added membrane markers: anti-secretory component Fab fragments, and avidin internalized from the biotinylated apical pole of the cell. This accumulation occurs in the presence of apical trypsin, which prevents internalization of the ligand from the apical cell surface. Using a modification of the diaminobenzidine density-shift assay, we estimate that approximately 80% of basolaterally internalized IgA resides in the apical endosomal compartment. In addition, approximately 50% of basolaterally internalized transferrin, a basolateral recycling protein, has access to this apical endosomal compartment and is efficiently recycled back to the basolateral surface. Microtubules are required for the organization of the apical endosomal compartment and it is dispersed in nocodazole-treated cells. Moreover, this compartment is largely inaccessible to fluid-phase markers added to either pole of the cell, and therefore seems analogous to the recycling endosome described in nonpolarized cells. We propose a model in which transcytosis is not a specialized pathway that uses unique transcytotic vesicles, but rather combines portions of pathways used by non-transcytosing molecules.

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Nair, Vidhya, Haaris Khan, Ron Mitchell, and Michael U. Shiloh. "Role of M Cells in Human Mucosal Immunity to Mycobacterium tuberculosis." Open Forum Infectious Diseases 4, suppl_1 (2017): S48. http://dx.doi.org/10.1093/ofid/ofx162.111.

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Abstract Background Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a bacterial pathogen that infects roughly one-third of the worldÕs population and causes 1–2 million deaths per year. The current paradigm is that phagocytosis of Mtb by patrolling alveolar macrophages initiates Mtb infection. While this model can account for pulmonary TB, it does not adequately explain the occurrence of extrapulmonary forms of TB that manifest in the absence of obvious lung involvement, such as tuberculous cervical lymphadenitis, also known as scrofula. We hypothesized that specialized epithelial cells called microfold cells (M cells) may be an alternate portal of entry for Mtb. Previously we demonstrated that Mtb is able to transcytose across an epithelial barrier in an M cell dependent manner and that M cell mediated transcytosis is vital for Mtb pathogenesis in a mouse model of tuberculosis. Methods We used an in vitro M-cell mediated translocation assay and a Mtb mutant lacking a key virulence factor, ESAT6. We used biochemistry and genetics to identify a novel receptor for ESAT6. We also developed a novel explanted human adenoid Mtb infection model to study mucosal immunity. Results We now demonstrate that the Mtb virulence factor ESAT6 is necessary and sufficient to mediate binding and transcytosis by M cells in vitro and in vivo, and that uptake of Mtb by M cells requires a unique cell surface ESAT6 receptor. We developed a novel explanted human adenoid model of M cell biology and demonstrate rapid Mtb transcytosis by primary human tissue within 60–120 minutes. Using flow cytometry we find that Mtb is first ingested by M cells and then after transcytosis, by tissue resident antigen-presenting cells. Explanted adenoids from 10 independent donors display a wide range of Mtb uptake. Conclusion We conclude that Mtb ESAT6 is necessary for Mtb uptake by M-cells and that binding and transcytosis require a host receptor. Because explanted adenoids display a wide range of Mtb uptake, M cell mediated transcytosis may confer differential susceptibility to scrofula and disseminated disease. These findings are significant as M cells could potentially serve as the basis for novel therapeutic targets against primary Mtb infection. Disclosures All authors: No reported disclosures.

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Perez Bay, Andres E., Ryan Schreiner, Ignacio Benedicto, and Enrique J. Rodriguez-Boulan. "Galectin-4-mediated transcytosis of transferrin receptor." Journal of Cell Science 127, no. 20 (September 1, 2014): 4457–69. http://dx.doi.org/10.1242/jcs.153437.

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Marinò, Michele, Luca Chiovato, Nicholas Mitsiades, Francesco Latrofa, David Andrews, Sophia Tseleni-Balafouta, A. Bernard Collins, Aldo Pinchera, and Robert T. McCluskey. "Circulating Thyroglobulin Transcytosed by Thyroid Cells Is Complexed with Secretory Components of Its Endocytic Receptor Megalin*." Journal of Clinical Endocrinology & Metabolism 85, no. 9 (September 1, 2000): 3458–67. http://dx.doi.org/10.1210/jcem.85.9.6804.

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Abstract After its endocytosis from the colloid, some thyroglobulin (Tg) is transcytosed intact across thyrocytes, accounting in part for its presence in the circulation. We previously showed that megalin (gp330), an endocytic Tg receptor, mediates apical to basolateral Tg transcytosis. Here we investigated whether a portion of megalin remains combined with Tg after its transcytosis, using studies with cultured thyroid cells and in vivo observations. FRTL-5 cells, a rat thyroid cell line, cultured on filters in dual chambers form tight junctions and exhibit features of polarity, with expression of megalin exclusively on the upper (apical) surface. After the addition of unlabeled Tg to the upper chamber and incubation at 37 C, some Tg was transcytosed intact across FRTL-5 cells into the lower chamber. Two antimegalin ectodomain antibodies precipitated transcytosed Tg in fluids collected from the lower chamber. After the addition of Tg to surface-biotinylated FRTL-5 cells, an anti-Tg antibody and the two antimegalin ectodomain antibodies precipitated high molecular mass biotinylated material in fluids collected from the lower chamber, corresponding to much of the megalin ectodomain, as well as smaller amounts of lower molecular mass material. The results indicate that Tg transcytosed across FRTL-5 cells remains complexed with megalin ectodomain components, which we refer to as megalin secretory components. In aminotriazole-treated rats, which develop increased megalin-mediated Tg transcytosis, antimegalin antibodies precipitated some of the Tg in the serum. Tg was also precipitated by antimegalin antibodies in sera from patients with Graves’ disease, in which we found increased megalin expression on the apical surface of thyrocytes. In contrast, in thyroidectomized patients with metastatic papillary thyroid carcinoma, in whom Tg is directly secreted by neoplastic thyroid cells into the circulation rather than transcytosed, serum Tg was not precipitated by antimegalin antibodies. The detection of Tg-megalin complexes may help identify the source of serum Tg in patients with thyroid diseases.

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Xiao, Guangqing, and Liang-Shang Gan. "Receptor-Mediated Endocytosis and Brain Delivery of Therapeutic Biologics." International Journal of Cell Biology 2013 (2013): 1–14. http://dx.doi.org/10.1155/2013/703545.

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Transport of macromolecules across the blood-brain-barrier (BBB) requires both specific and nonspecific interactions between macromolecules and proteins/receptors expressed on the luminal and/or the abluminal surfaces of the brain capillary endothelial cells. Endocytosis and transcytosis play important roles in the distribution of macromolecules. Due to the tight junction of BBB, brain delivery of traditional therapeutic proteins with large molecular weight is generally not possible. There are multiple pathways through which macromolecules can be taken up into cells through both specific and nonspecific interactions with proteins/receptors on the cell surface. This review is focused on the current knowledge of receptor-mediated endocytosis/transcytosis and brain delivery using the Angiopep-2-conjugated system and the molecular Trojan horses. In addition, the role of neonatal Fc receptor (FcRn) in regulating the efflux of Immunoglobulin G (IgG) from brain to blood, and approaches to improve the pharmacokinetics of therapeutic biologics by generating Fc fusion proteins, and increasing the pH dependent binding affinity between Fc and FcRn, are discussed.

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Cammisotto, Philippe G., Moise Bendayan, Alain Sané, Michel Dominguez, Carole Garofalo, and Émile Levy. "Receptor-Mediated Transcytosis of Leptin through Human Intestinal Cells In Vitro." International Journal of Cell Biology 2010 (2010): 1–13. http://dx.doi.org/10.1155/2010/928169.

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Gastric Leptin is absorbed by duodenal enterocytes and released on the basolateral side towards the bloodstream. We investigated in vitro some of the mechanisms of this transport. Caco-2/15 cells internalize leptin from the apical medium and release it through transcytosis in the basal medium in a time- temperature-dependent and saturable fashion. Leptin receptors are revealed on the apical brush-border membrane of the Caco-2 cells. RNA-mediated silencing of the receptor led to decreases in the uptake and basolateral release. Leptin in the basal medium was found bound to the soluble form of its receptor. An inhibitor of clathrin-dependent endocytosis (chlorpromazine) decreased leptin uptake. Confocal immunocytochemistry and the use of brefeldin A and okadaic acid revealed the passage of leptin through the Golgi apparatus. We propose that leptin transcytosis by intestinal cells depends on its receptor, on clathrin-coated vesicles and transits through the Golgi apparatus.

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Haqqani, Arsalan S., Christie E. Delaney, Eric Brunette, Ewa Baumann, Graham K. Farrington, William Sisk, John Eldredge, Wen Ding, Tammy-Lynn Tremblay, and Danica B. Stanimirovic. "Endosomal trafficking regulates receptor-mediated transcytosis of antibodies across the blood brain barrier." Journal of Cerebral Blood Flow & Metabolism 38, no. 4 (November 15, 2017): 727–40. http://dx.doi.org/10.1177/0271678x17740031.

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Current methods for examining antibody trafficking are either non-quantitative such as immunocytochemistry or require antibody labeling with tracers. We have developed a multiplexed quantitative method for antibody ‘tracking’ in endosomal compartments of brain endothelial cells. Rat brain endothelial cells were co-incubated with blood-brain barrier (BBB)-crossing FC5, monovalent FC5Fc or bivalent FC5Fc fusion antibodies and control antibodies. Endosomes were separated using sucrose-density gradient ultracentrifugation and analyzed using multiplexed mass spectrometry to simultaneously quantify endosomal markers, receptor-mediated transcytosis (RMT) receptors and the co-incubated antibodies in each fraction. The quantitation showed that markers of early endosomes were enriched in high-density fractions (HDF), whereas markers of late endosomes and lysosomes were enriched in low-density fractions (LDF). RMT receptors, including transferrin receptor, showed a profile similar to that of early endosome markers. The in vitro BBB transcytosis rates of antibodies were directly proportional to their partition into early endosome fractions of brain endothelial cells. Addition of the Fc domain resulted in facilitated antibody ‘redistribution’ from LDF into HDF and additionally into multivesicular bodies (MVB). Sorting of various FC5 antibody formats away from late endosomes and lysosomes and into early endosomes and a subset of MVB results in increased antibody transcytosis at the abluminal side of the BBB.

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Ellinger, Isabella, and Renate Fuchs. "Receptor-Mediated and Fluid-Phase Transcytosis of Horseradish Peroxidase across Rat Hepatocytes." Journal of Biomedicine and Biotechnology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/850320.

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Horseradish peroxidase (HRP) is often used as a fluid-phase marker to characterize endocytic and transcytotic processes. Likewise, it has been applied to investigate the mechanisms of biliary secretion of fluid in rat liver hepatocytes. However, HRP contains mannose residues and thus binds to mannose receptors (MRs) on liver cells, including hepatocytes. To study the role of MR-mediated endocytosis of HRP transport in hepatocytes, we determined the influence of the oligosaccharid mannan on HRP biliary secretion in the isolated perfused rat liver. A 1-minute pulse of HRP was applied followed by marker-free perfusion. HRP appeared in bile with biphasic kinetics: a first peak at 7 minutes and a second peak at 15 minutes after labeling. Perfusion with 0.8 mg/mL HRP in the presence of a twofold excess of mannan reduced the first peak by 41% without effect on the second one. Together with recently published data on MR expression in rat hepatocytes this demonstrates two different mechanisms for HRP transcytosis: a rapid, receptor-mediated transport and a slower fluid-phase transport.

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SIMIONESCU, N. "Receptor-mediated transcytosis of albumin by endothelial cells." Cell Biology International Reports 14 (September 1990): 32. http://dx.doi.org/10.1016/0309-1651(90)90238-t.

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Raheel, Hira, Siavash Ghaffari, Negar Khosraviani, Victoria Mintsopoulos, Derek Auyeung, Changsen Wang, Yun Hye Kim, et al. "CD36 mediates albumin transcytosis by dermal but not lung microvascular endothelial cells: role in fatty acid delivery." American Journal of Physiology-Lung Cellular and Molecular Physiology 316, no. 5 (May 1, 2019): L740—L750. http://dx.doi.org/10.1152/ajplung.00127.2018.

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In healthy blood vessels, albumin crosses the endothelium to leave the circulation by transcytosis. However, little is known about the regulation of albumin transcytosis or how it differs in different tissues; its physiological purpose is also unclear. Using total internal reflection fluorescence microscopy, we quantified transcytosis of albumin across primary human microvascular endothelial cells from both lung and skin. We then validated our in vitro findings using a tissue-specific knockout mouse model. We observed that albumin transcytosis was saturable in the skin but not the lung microvascular endothelial cells, implicating a receptor-mediated process. We identified the scavenger receptor CD36 as being both necessary and sufficient for albumin transcytosis across dermal microvascular endothelium, in contrast to the lung where macropinocytosis dominated. Mutations in the apical helical bundle of CD36 prevented albumin internalization by cells. Mice deficient in CD36 specifically in endothelial cells exhibited lower basal permeability to albumin and less basal tissue edema in the skin but not in the lung. Finally, these mice also exhibited a smaller subcutaneous fat layer despite having identical total body weights and circulating fatty acid levels as wild-type animals. In conclusion, CD36 mediates albumin transcytosis in the skin but not the lung. Albumin transcytosis may serve to regulate fatty acid delivery from the circulation to tissues.

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Marinò, Michele, and Robert T. McCluskey. "Role of thyroglobulin endocytic pathways in the control of thyroid hormone release." American Journal of Physiology-Cell Physiology 279, no. 5 (November 1, 2000): C1295—C1306. http://dx.doi.org/10.1152/ajpcell.2000.279.5.c1295.

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Thyroglobulin (Tg), the thyroid hormone precursor, is synthesized by thyrocytes and secreted into the colloid. Hormone release requires uptake of Tg by thyrocytes and degradation in lysosomes. This process must be precisely regulated. Tg uptake occurs mainly by micropinocytosis, which can result from both fluid-phase pinocytosis and receptor-mediated endocytosis. Because Tg is highly concentrated in the colloid, fluid-phase pinocytosis or low-affinity receptors should provide sufficient Tg uptake for hormone release; high-affinity receptors may serve to target Tg away from lysosomes, through recycling into the colloid or by transcytosis into the bloodstream. Several apical receptors have been suggested to play roles in Tg uptake and intracellular trafficking. A thyroid asialoglycoprotein receptor may internalize and recycle immature forms of Tg back to the colloid, a function also attributed to an as yet unidentified N-acetylglucosamine receptor. Megalin mediates Tg uptake by thyrocytes, especially under intense thyroid-stimulating hormone stimulation, resulting in transcytosis of Tg from the colloid to the bloodstream, a function that prevents excessive hormone release.

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Tao, Bo, Jan R. Kraehling, Siavash Ghaffari, Cristina M. Ramirez, Sungwoon Lee, Joseph W. Fowler, Warren L. Lee, Carlos Fernandez-Hernando, Anne Eichmann, and William C. Sessa. "BMP-9 and LDL crosstalk regulates ALK-1 endocytosis and LDL transcytosis in endothelial cells." Journal of Biological Chemistry 295, no. 52 (October 23, 2020): 18179–88. http://dx.doi.org/10.1074/jbc.ra120.015680.

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Bone morphogenetic protein-9 (BMP-9) is a circulating cytokine that is known to play an essential role in the endothelial homeostasis and the binding of BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence. Previously, using an unbiased screen, we identified ALK-1 as a high-capacity receptor for low-density lipoprotein (LDL) in endothelial cells that mediates its transcytosis in a nondegradative manner. Here we examine the crosstalk between BMP-9 and LDL and how it influences their interactions with ALK-1. Treatment of endothelial cells with BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin heavy chain. Knockdown of CAV-1 reduces BMP-9–mediated internalization of ALK-1, BMP-9–dependent signaling and gene expression. Similarly, treatment of endothelial cells with LDL reduces BMP-9–induced SMAD1/5 phosphorylation and gene expression and silencing of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization. Interestingly, BMP-9–mediated ALK-1 internalization strongly re-duces LDL transcytosis to levels seen with ALK-1 deficiency. Thus, BMP-9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and LDL transcytosis.

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Descamps, L., M. P. Dehouck, G. Torpier, and R. Cecchelli. "Receptor-mediated transcytosis of transferrin through blood-brain barrier endothelial cells." American Journal of Physiology-Heart and Circulatory Physiology 270, no. 4 (April 1, 1996): H1149—H1158. http://dx.doi.org/10.1152/ajpheart.1996.270.4.h1149.

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A cell culture model of the blood-brain barrier consisting of a coculture of bovine brain capillary endothelial cells (BBCECs) and astrocytes has been used to examine the mechanism of iron transport to the brain. Binding experiments showed that BBCECs express 35,000 high-affinity (concn at 50% receptor saturation = 11.3 +/- 2.1 nM) transferin (Tf) receptors per cell. In contrast to apo-transferrin (apoTf) we observed a specific transport of holo-transferrin (holoTf) across BBCECs. This transport was inhibited completely at low temperature. Moreover, the anti-Tf receptor antibody (OX-26) competitively inhibited holoTf uptake by BBCECs. Pulse-chase experiments demonstrated that only 10% of Tf was recycled to the luminal side of the cells, whereas the majority of Tf was transcytosed to the abluminal side; double-labeling experiments clearly demonstrated that iron crosses BBCECs bound to Tf. No intraendothelial degradation of Tf was observed, suggesting that the intraendothelial pathway through BBCECs bypasses the lysosomal compartment. These results clearly show that the iron-Tf complex is transcytosed across brain capillary endothelial cells by a receptor-mediated pathway without any degradation.

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Cardone, MH, BL Smith, W. Song, D. Mochly-Rosen, and KE Mostov. "Phorbol myristate acetate-mediated stimulation of transcytosis and apical recycling in MDCK cells." Journal of Cell Biology 124, no. 5 (March 1, 1994): 717–27. http://dx.doi.org/10.1083/jcb.124.5.717.

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We observed that phorbol myristate acetate (PMA) stimulates transcytosis of the polymeric immunoglobulin receptor (pIgR) in MDCK cells. Apical release of pre-endocytosed ligand (dimeric IgA) bound to the pIgR can be stimulated twofold within 7 min of addition of PMA while recycling of the ligand from the basal surface is not affected. In addition, apical surface delivery of pIgR and cleavage of its ectodomain to secretory component (SC) is also stimulated by PMA. The recycling of apically internalized ligand back to the apical surface is similarly stimulated. These results suggest that the stimulation of apical delivery is from an apical recycling compartment. The effect of PMA suggests that protein kinase C (PKC) is involved in the regulation of pIgR trafficking in MDCK cells. To test this we down regulated PKC activity by pre-treating cells with PMA for 16 h and observed that transcytosis could no longer be stimulated by PMA. Western blots show that the PKC isozymes alpha and to a lesser extent epsilon, are depleted from MDCK cells which have been pre-treated with PMA for 16 h and that treatment of MDCK cells with PMA for 5 min causes a dramatic translocation of the PKC alpha isozyme and a partial translocation of the epsilon isozyme from the cytosol to the membrane fraction of cell homogenates. This translocation suggests that the alpha and/or epsilon isozymes may be involved in PMA mediated stimulation of transcytosis. A mutant pIgR in which serines 664 and 726, the major sites of phosphorylation, are replaced by alanine is stimulated to transcytose by PMA, suggesting that phosphorylation of pIgR at these sites is not required for the effect of PMA. These results suggest that PMA-mediated stimulation of pIgR transcytosis may involve the activation of PKC alpha and/or epsilon, and that this stimulation occurs independently of the major phosphorylation sites on the pIgR. Finally, PMA stimulates transcytosis of basolaterally internalized transferrin, suggesting that PMA acts to generally stimulate delivery of endocytosed proteins to the apical surface.

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Breitfeld, P. P., J. M. Harris, and K. E. Mostov. "Postendocytotic sorting of the ligand for the polymeric immunoglobulin receptor in Madin-Darby canine kidney cells." Journal of Cell Biology 109, no. 2 (August 1, 1989): 475–86. http://dx.doi.org/10.1083/jcb.109.2.475.

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The polymeric immunoglobulin receptor (pIg-R) is responsible for the receptor-mediated transcytosis of polymeric immunoglobulins (IgA and IgM) across various epithelia. We have expressed the cDNA for the pIg-R in Madin-Darby canine kidney (MDCK) cells and found that this system mimics that found in vivo (Mostov, K. E., and D. L. Deitcher. 1986. Cell. 46:613-621). We have now investigated the postendocytotic pathway of the ligand for the pIg-R. After a 5-min internalization at the basolateral surface, approximately 45% of internalized ligand recycles to the basolateral medium and 30% is transcytosed to the apical medium. We have also examined why transcytosis of ligand is unidirectional, going only from basolateral to apical, but not from apical to basolateral. Several factors could explain this, such as proteolytic cleavage of the pIg-R at the apical surface, decreased apical endocytosis of ligand, or an intracellular sorting event. In this report, we show that the protease inhibitor, leupeptin, inhibits the cleavage of the pIg-R but does not alter the unidirectionality of transcytosis. In addition, we demonstrate that there is a significant amount of apical endocytosis of ligand (70% of that observed basolaterally). Finally, we demonstrate that apically endocytosed ligand can return only to the apical surface. Thus, once ligand reaches the apical surface, it is "trapped" and cannot return to the basolateral surface. We propose that the unidirectionality of transcytosis is the result of intracellular sorting, and that this results from a signal(s) present on the pIg-R.

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Hunziker, W., and I. Mellman. "Expression of macrophage-lymphocyte Fc receptors in Madin-Darby canine kidney cells: polarity and transcytosis differ for isoforms with or without coated pit localization domains." Journal of Cell Biology 109, no. 6 (December 1, 1989): 3291–302. http://dx.doi.org/10.1083/jcb.109.6.3291.

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Many cells of the immune system and certain epithelia express receptors for the Fc domain of IgG (FcR). On mouse macrophages and lymphocytes, two distinct receptor isoforms have been identified, designated FcRII-B1 and FcRII-B2. The isoforms are identical except for an in-frame insertion of 47 amino acids in the cytoplasmic tail of FcRII-B1 that blocks its ability to be internalized by clathrin-coated pits. We have recently found that at least one IgG-transporting epithelium, namely placental syncytial trophoblasts, expresses transcripts encoding a receptor similar or identical to macrophage-lymphocyte FcRII. To determine whether FcRII of hematopoietic cells might also function as a transcytotic receptor if expressed in epithelial cells, FcRII-B1 and -B2 were transfected into Madin-Darby canine kidney (MDCK) cells and grown on permeable filter units. The two FcRII isoforms exhibited different patterns of polarized expression: FcRII-B1 was localized mainly to the apical plasma membrane domain, whereas FcRII-B2 was found predominantly on the basolateral surface. As expected for FcR in placenta, FcRII-B2 and to a lesser extent FcRII-B1 mediated transcellular transport of IgG-complexes from the apical to the basolateral plasma membrane. Neither receptor mediated transcytosis in the opposite direction, although FcRII-B2 also delivered ligand to lysosomes when internalized from either the basolateral or apical domains. Furthermore, FcRII-B2 was capable of transporting monovalent antireceptor antibody Fab fragments across the cell, suggesting that transcytosis was not dependent on receptor cross-linking. These findings suggest the possibility that FcRII can mediate transepithelial IgG transport when expressed in placental syncytial trophoblasts in addition to its "classical" endocytic and signaling activities when expressed in macrophages. Because FcRII-B1 and -B2 are expressed with distinct polarities, the results also suggest that interactions with clathrin-coated pits may play a role in generating the polarized distribution of at least some plasma membrane proteins in MDCK cells.

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Maratos-Flier, E., C. Y. Kao, E. M. Verdin, and G. L. King. "Receptor-mediated vectorial transcytosis of epidermal growth factor by Madin-Darby canine kidney cells." Journal of Cell Biology 105, no. 4 (October 1, 1987): 1595–601. http://dx.doi.org/10.1083/jcb.105.4.1595.

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Transcellular transport of a variety of ligands may be an important mechanism by which regulatory substances reach their site of action. We have studied the transcellular transport of two 6,000-mol-wt proteins, epidermal growth factor (EGF) and insulin, across polarized Madin-Darby canine kidney (MDCK) cells grown on dual-sided chambers on a nitrocellulose filter substrate. When grown on these chambers, MDCK cells are polarized and express distinct basal and apical surfaces. MDCK cells are capable of unidirectional transport of EGF from the basal-to-apical direction, 50% of bound EGF transported in 2 h. Transport was inhibited by the addition of unlabeled EGF in a dose-dependent manner. Anti-EGF receptor Ab, which inhibited binding, also inhibited transport. No transport in the apical-to-basal direction is noted. Insulin transport is not observed in either direction. Transport correlates with the presence of ligand-specific receptors on the cell surface. Hence, EGF receptors (Ro = 48,000, Kd = 3.5 X 10(-10) M) are found only on the basal surface of the MDCK cells and neither surface expresses insulin receptors. Characterization of the EGF receptors on MDCK cells, as assessed by affinity, molecular mass, and anti-receptor antibody binding reveals that this receptor has similar characteristics to EGF receptors previously described on a variety of cells. Hence, the EGF receptor can function as a transporter of EGF across an epithelial cell barrier.

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Davis, Albert A. "Plasma proteins have a ticket to ride the blood-brain barrier." Science Translational Medicine 12, no. 552 (July 15, 2020): eabd3610. http://dx.doi.org/10.1126/scitranslmed.abd3610.

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22

Rose, Jayna M., and Kenneth L. Audus. "Receptor-mediated angiotensin II transcytosis by brain microvessel endothelial cells." Peptides 19, no. 6 (June 1998): 1023–30. http://dx.doi.org/10.1016/s0196-9781(98)00054-0.

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23

Fillebeen, Carine, Laurence Descamps, Marie-Pierre Dehouck, Laurence Fenart, Monique Benaı̈ssa, Geneviève Spik, Roméo Cecchelli, and Annick Pierce. "Receptor-mediated Transcytosis of Lactoferrin through the Blood-Brain Barrier." Journal of Biological Chemistry 274, no. 11 (March 12, 1999): 7011–17. http://dx.doi.org/10.1074/jbc.274.11.7011.

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24

Fishman, J. B., J. B. Rubin, J. V. Handrahan, J. R. Connor, and R. E. Fine. "Receptor-mediated transcytosis of transferrin across the blood-brain barrier." Journal of Neuroscience Research 18, no. 2 (1987): 299–304. http://dx.doi.org/10.1002/jnr.490180206.

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25

White, Kendra D., and J. Donald Capra. "Targeting Mucosal Sites by Polymeric Immunoglobulin Receptor-directed Peptides." Journal of Experimental Medicine 196, no. 4 (August 19, 2002): 551–55. http://dx.doi.org/10.1084/jem.20020581.

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Polymeric immunoglobulins provide first line humoral defense at mucosal surfaces to which they are specifically transported by the polymeric immunoglobulin receptor (pIgR) on mucosal and glandular epithelial cells. Previous studies from our laboratory suggested that amino acids 402–410 of the Cα3 domain of dimeric IgA (dIgA) represented a potential binding site for the pIgR. Here by binding human secretory component to overlapping decapeptides of Cα3, we confirm these residues and also uncover an additional site. Furthermore, we show that the Cα3 motif appears to be sufficient to direct transport of green fluorescent protein through the pIgR-specific cellular transcytosis system. An alternative approach identified phage peptides, selected from a library by the in vitro Madin Darby Canine Kidney transcytosis assay, for pIgR-mediated transport through epithelial cells. Some transcytosis-selected peptides map to the same 402–410 pIgR-binding Cα3 site. Further in vivo studies document that at least one of these peptides is transported in a rat model measuring hepatic bile transport. In addition to identifying small peptides that are both bound and transported by the pIgR, this study provides evidence that the pIgR-mediated mucosal secretion system may represent a means of targeting small molecule therapeutics and genes to mucosal epithelial cells.

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Watanabe, J., K. Kanai, and S. Kanamura. "Glucagon receptors in endothelial and Kupffer cells of mouse liver." Journal of Histochemistry & Cytochemistry 36, no. 9 (September 1988): 1081–89. http://dx.doi.org/10.1177/36.9.2841370.

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To determine whether hepatic sinusoidal cells contain glucagon receptors and, if so, to study the significance of the receptors in the cells, binding of [125I]-glucagon to nonparenchymal cells (mainly endothelial cells and Kupffer cells) isolated from mouse liver was examined by quantitative autoradiography and biochemical methods. Furthermore, the pathway of intracellular transport of colloidal gold-labeled glucagon (AuG) was examined in vivo. Autoradiographic and biochemical results demonstrated many glucagon receptors in both endothelial cells and Kupffer cells, and more receptors being present in endothelial cells than in Kupffer cells. In vivo, endothelial cells internalized AuG particles into coated vesicles via coated pits and transported the particles to endosomes, lysosomes, and abluminal plasma membrane. Therefore, receptor-mediated transcytosis of AuG occurs in endothelial cells. The number of particles present on the abluminal plasma membrane was constant if the amount of injected AuG increased. Therefore, the magnitude of receptor-mediated transcytosis of AuG appears to be regulated by endothelial cells. Kupffer cells internalized the ligand into cytoplasmic tubular structures via plasma membrane invaginations and transported the ligand exclusively to endosomes and lysosomes, suggesting that the ligand is degraded by Kupffer cells.

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27

Pal, Kasturi, Charlotte S. Kaetzel, Kathleen Brundage, Cynthia A. Cunningham, and Christopher F. Cuff. "Regulation of polymeric immunoglobulin receptor expression by reovirus." Journal of General Virology 86, no. 8 (August 1, 2005): 2347–57. http://dx.doi.org/10.1099/vir.0.80690-0.

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Polymeric immunoglobulin receptor (pIgR) transcytoses dimeric IgA and IgA-coated immune complexes from the lamina propria across epithelia and into secretions. The effect of reovirus infection on regulation of pIgR expression in the human intestinal epithelial cell line HT-29 was characterized in this report. Both replication-competent and UV-inactivated reovirus at m.o.i. equivalents of 1–100 p.f.u. per cell upregulated pIgR mRNA by 24 h post-infection and intracellular pIgR protein was increased at 48 h following exposure to UV-inactivated virus. Binding of virus to HT-29 cells was required, as pre-incubating virus with specific antiserum, but not non-immune serum, inhibited reovirus-mediated pIgR upregulation. Endosomal acidification leading to uncoating of virus is a required step for pIgR upregulation, as ammonium chloride or bafilomycin A1 pre-treatment inhibited virus-induced pIgR upregulation. Inhibition experiments using the calpain inhibitor N-acetyl-leucyl-leucyl-norleucinal suggested that calpains are involved in reovirus-mediated pIgR upregulation. Upregulation of pIgR following virus infection appears to be an innate immune response against invading pathogens that could help the host clear infection effectively. Signalling induced by microbes and their products may serve to augment pIgR-mediated transcytosis of IgA, linking the innate and acquired immune responses to viruses.

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Predescu, Sanda A., Dan N. Predescu, and Asrar B. Malik. "Molecular determinants of endothelial transcytosis and their role in endothelial permeability." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 4 (October 2007): L823—L842. http://dx.doi.org/10.1152/ajplung.00436.2006.

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Caveolae transcytosis with its diverse mechanisms–fluid phase, adsorptive, and receptor-mediated–plays an important role in the continuous exchange of molecules across the endothelium. We will discuss key features of endothelial transcytosis and caveolae that have been studied recently and have increased our understanding of caveolae function in transcytosis at the molecular level. During transcytosis, caveolae “pinch off” from the plasma membrane to form discrete vesicular carriers that shuttle to the opposite front of endothelial cells, fuse with the plasma membrane, and discharge their cargo into the perivascular space. Endothelial transcytosis exhibits distinct properties, the most important being rapid and efficient coupling of endocytosis to exocytosis on opposite plasma membrane. We address herein the membrane fusion-fission reactions that underlie transcytosis. Caveolae move across the endothelial cells with their cargo predominantly in the fluid phase through an active process that bypasses the lysosomes. Endothelial transcytosis is a constitutive process of vesicular transport. Recent studies show that transcytosis can be upregulated in response to pathological stimuli. Transcytosis via caveolae is an important route for the regulation of endothelial barrier function and may participate in different vascular diseases.

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Deng, Hua, Prashanta Dutta, and Jin Liu. "Stochastic modeling of nanoparticle internalization and expulsion through receptor-mediated transcytosis." Nanoscale 11, no. 23 (2019): 11227–35. http://dx.doi.org/10.1039/c9nr02710f.

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30

Wei, Hao, and Ji-Yang Wang. "Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis." International Journal of Molecular Sciences 22, no. 5 (February 25, 2021): 2284. http://dx.doi.org/10.3390/ijms22052284.

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Transcytosis of polymeric IgA and IgM from the basolateral surface to the apical side of the epithelium and subsequent secretion into mucosal fluids are mediated by the polymeric immunoglobulin receptor (pIgR). Secreted IgA and IgM have vital roles in mucosal immunity in response to pathogenic infections. Binding and recognition of polymeric IgA and IgM by pIgR require the joining chain (J chain), a small protein essential in the formation and stabilization of polymeric Ig structures. Recent studies have identified marginal zone B and B1 cell-specific protein (MZB1) as a novel regulator of polymeric IgA and IgM formation. MZB1 might facilitate IgA and IgM transcytosis by promoting the binding of J chain to Ig. In this review, we discuss the roles of pIgR in transcytosis of IgA and IgM, the roles of J chain in the formation of polymeric IgA and IgM and recognition by pIgR, and focus particularly on recent progress in understanding the roles of MZB1, a molecular chaperone protein.

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Carpentier, Mathieu, Laurence Descamps, Fabrice Allain, Agnès Denys, Sandrine Durieux, Laurence Fenart, Claudine Kieda, Roméo Cecchelli, and Geneviève Spik. "Receptor-Mediated Transcytosis of Cyclophilin B Through the Blood-Brain Barrier." Journal of Neurochemistry 73, no. 1 (January 18, 2002): 260–70. http://dx.doi.org/10.1046/j.1471-4159.1999.0730260.x.

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Thuenauer, Roland, Stefan K. Müller, and Winfried Römer. "Pathways of protein and lipid receptor-mediated transcytosis in drug delivery." Expert Opinion on Drug Delivery 14, no. 3 (August 16, 2016): 341–51. http://dx.doi.org/10.1080/17425247.2016.1220364.

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Burgess, J. W., and K. K. Stanley. "Estrogens promote the clearance of desialylated LDL by receptor-mediated transcytosis." Atherosclerosis 109, no. 1-2 (September 1994): 188. http://dx.doi.org/10.1016/0021-9150(94)93754-0.

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34

Patel, Harish M., and Arthur E. Wild. "Fc receptor-mediated transcytosis of IgG-coated liposomes across epithelial barriers." FEBS Letters 234, no. 2 (July 18, 1988): 321–25. http://dx.doi.org/10.1016/0014-5793(88)80108-x.

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35

Roberts, R. L., R. E. Fine, and A. Sandra. "Receptor-mediated endocytosis of transferrin at the blood-brain barrier." Journal of Cell Science 104, no. 2 (February 1, 1993): 521–32. http://dx.doi.org/10.1242/jcs.104.2.521.

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Rat brains were perfuse with a transferrin-peroxidase conjugate (Tf-HRP) to characterize morphologically the endocytic pathway of transferrin in blood-brain barrier endothelial cells. Electron microscopic evaluation of rat brains perfused with Tf-HRP at 4 degrees C and subsequently warmed to 37 degrees C for brief periods of time (2 minutes) showed sequestration of Tf-HRP in clathrin coated pits and vesicles on the luminal membrane of the brain endothelium. After 5 minutes of warming, diaminobenzidine (DAB) reaction product was present in vesicular structures 250–500 nm in diameter and in associated tubules morphologically identified as large or sorting endosomes. Recycling endosomes were also heavily labelled at this time point. Almost no DAB reaction product remained in the cerebral endothelial cells when the warming period was longer than 15 minutes. Other rat brains were perfused with Tf-HRP at 30 degrees C for 15 minutes prior to fixation and DAB cytochemistry. In these studies, brain endothelial cells contained large amounts of DAB reaction product, mostly localized in 50–100 nm vesicles and tubules, often in the Golgi region of the cells. Coated pits and vesicles and large endosomes were also heavily labelled. Transcytosis of Tf-HRP was not identified in either perfusion protocol. Ultrastructural, indirect immunocytochemical localization of transferrin receptors showed that the transferrin receptor is highly polarized at the blood-brain barrier and is localized only on the apical membrane, in contrast to other polarized epithelial cells, like hepatocytes, in which the receptor is present on the basolateral membrane. The evidence supports an iron transport model in which iron-loaded transferrin is taken up by receptor-mediated endocytosis at the luminal membrane of brain capillaries. The iron then dissociates from transferrin in endosomal compartments and is transcytosed by unknown mechanisms, while the transferrin is retroendocytosed.

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Mao, Changchuin, Richard Near, Varuna Shibad, Xuemei Zhong, and Wenda Gao. "An IgA mimicry of IgG that binds polymeric immunoglobulin receptor for mucosa transcytosis." Antibody Therapeutics 3, no. 3 (July 2020): 157–62. http://dx.doi.org/10.1093/abt/tbaa014.

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Abstract Most pathogens establish infection through mucosa, where secretory immunoglobulin A (sIgA) plays an ‘immune exclusion’ role in humoral defense. Extravasation of intravenously (i.v.) administrated therapeutic immunoglobulin G (IgG) mainly relies on convection and/or neonatal Fc receptor-mediated transcytosis from circulation into interstitial space. Active transport of interstitial IgG further across epithelium into mucosa, like sIgA, is a much desired feature for the next generation of therapeutic antibodies, especially for anti-infection purposes. For the first time, we report the engineering of an IgA mimicry of IgG, with its Fc portion in fusion with the 18-aa tail piece (tp) of sIgA and the J chain, possessing sIgA’s full binding activity towards polymeric immunoglobulin receptor that mediates mucosa transcytosis. In a diphtheria toxin receptor (DTR) knockin mouse model, i.v. injected anti-diphtheria toxin (DT) IgG(tp)J protected DTR+ cells from deletion upon DT injection. The compact design of IgG(tp)J opens new revenues for more effective therapeutic IgG mimicking some of the important biological functions of IgA.

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Norouziyan, Fariba, Wei-Chiang Shen, and Sarah F. Hamm-Alvarez. "Tyrphostin A8 stimulates a novel trafficking pathway of apically endocytosed transferrin through Rab11-enriched compartments in Caco-2 cells." American Journal of Physiology-Cell Physiology 294, no. 1 (January 2008): C7—C21. http://dx.doi.org/10.1152/ajpcell.00372.2006.

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The potential application of transferrin receptors as delivery vehicles for transport of macromolecular drugs across intestinal epithelial cells is limited by several factors, including the low level of transferrin receptor-mediated transcytosis, particularly in the apical-to-basolateral direction. The GTPase inhibitor, AG10 (tyrphostin A8), has been shown previously to increase the apical-to-basolateral transcytosis of transferrin in Caco-2 cells. However, the mechanism of the increased transcytosis has not been established. In this report, the effect of AG10 on the trafficking of endocytosed transferrin among different endosomal compartments as well as the involvement of Rab11 in the intracellular trafficking of transferrin was investigated. Confocal microscopy studies showed a high level of colocalization of FITC-transferrin with Rab5 and Rab11 in Caco-2 cells pulsed at 16°C and 37°C, which indicated the presence of apically endocytosed FITC-transferrin in early endosomes and apical recycling endosomes at 16°C and 37°C, respectively. The effect of AG10 on the accumulation of transferrin within different endosomal compartment was studied, and an increase in the transcytosis and recycling of internalized 125I-labeled transferrin, as well as a decrease in cell-associated 125I-labeled transferrin, was observed in AG10-treated Caco-2 cells pulsed at 37°C for 30 min and chased for 30 min. Moreover, confocal microscopy showed that FITC-transferrin exhibited an increased level of colocalization with Rab11, but not with Rab5, in the presence of AG10. These results suggest an effect of AG10 on the later steps of transferrin receptor trafficking, which are involved in subsequent recycling, and possibly transcytosis, of endocytosed transferrin in Caco-2 cells.

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38

Praetor, A., I. Ellinger, and W. Hunziker. "Intracellular traffic of the MHC class I-like IgG Fc receptor, FcRn, expressed in epithelial MDCK cells." Journal of Cell Science 112, no. 14 (July 15, 1999): 2291–99. http://dx.doi.org/10.1242/jcs.112.14.2291.

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Transfer of passive immunity from mother to the fetus or newborn involves the transport of IgG across several epithelia. Depending on the species, IgG is transported prenatally across the placenta and yolk sac or is absorbed from colostrum and milk by the small intestine of the suckling newborn. In both cases apical to basolateral transepithelial transport of IgG is thought to be mediated by FcRn, an IgG Fc receptor with homology to MHC class I antigens. We have now expressed the human FcRn in polarized MDCK cells and analyzed the intracellular routing of the receptor. FcRn showed a predominant intracellular localization at steady state. Newly synthesized FcRn was delivered in a non-vectorial fashion to both the apical and basolateral surfaces of MDCK cell monolayers. Following internalization from the apical or basolateral domain, the receptor transcytosed to the opposite surface. These findings provide direct evidence for the transepithelial transport function of FcRn and indicate that the receptor undergoes multiple rounds of transcytosis.

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MARINÓ, MICHELE, DAVID ANDREWS, DENNIS BROWN, and ROBERT T. McCLUSKEY. "Transcytosis of Retinol-Binding Protein across Renal Proximal Tubule Cells after Megalin (gp 330)-Mediated Endocytosis." Journal of the American Society of Nephrology 12, no. 4 (April 2001): 637–48. http://dx.doi.org/10.1681/asn.v124637.

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Abstract. Plasma retinol-binding protein (RBP) combined with vitamin A (retinol) is partially filtered through the glomerulus and then absorbed by proximal tubule cells, leading to recycling of retinol to the circulation. Recently, it was shown that reabsorption of RBP-retinol complexes by proximal tubule cells is mediated by megalin (gp 330), an apical endocytic receptor. It was proposed that RBP is transported by megalin to lysosomes, where it is degraded, thus liberating retinol, which then combines with newly synthesized RBP to be secreted into the bloodstream. This study shows that passage of RBP through immortalized rat renal proximal tubule (IRPT) cells occurs by transcytosis after megalin-mediated endocytosis, which provides an alternative pathway for recycling of retinol. IRPT cells cultured as polarized monolayers with tight junctions were used on permeable filters in the upper chamber of dual-chambered devices, with megalin expression exclusively on the upper surface. After addition of RBP to the upper chamber and incubation at 37°C, intact RBP was found in fluids that were collected from the lower chamber. In contrast, control substances (mannitol, lysozyme, albumin, and glutathione-S-transferase) were not appreciably transported across IRPT cells, indicating that passage of RBP was by transcytosis and not by paracellular leakage. Confocal microscopy analysis of IRPT cells after addition of RBP to the upper chamber revealed RBP-containing granules at the apical membrane, subapically, and also at basolateral membranes. When RBP was added to IRPT cells together with megalin competitors, the amount of transcytosed RBP was markedly reduced. We also found that some RBP was internalized and degraded by IRPT cells, but this process was not appreciably affected by megalin competitors, indicating that RBP endocytosed by megalin was not transported to lysosomes and degraded but rather transcytosed across IRPT cells.

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Wagner, Mark C., Jered Myslinski, Shiv Pratap, Brittany Flores, George Rhodes, Silvia B. Campos-Bilderback, Ruben M. Sandoval, et al. "Mechanism of increased clearance of glycated albumin by proximal tubule cells." American Journal of Physiology-Renal Physiology 310, no. 10 (May 15, 2016): F1089—F1102. http://dx.doi.org/10.1152/ajprenal.00605.2015.

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Serum albumin is the most abundant plasma protein and has a long half-life due to neonatal Fc receptor (FcRn)-mediated transcytosis by many cell types, including proximal tubule cells of the kidney. Albumin also interacts with, and is modified by, many small and large molecules. Therefore, the focus of the present study was to address the impact of specific known biological albumin modifications on albumin-FcRn binding and cellular handling. Binding at pH 6.0 and 7.4 was performed since FcRn binds albumin strongly at acidic pH and releases it after transcytosis at physiological pH. Equilibrium dissociation constants were measured using microscale thermophoresis. Since studies have shown that glycated albumin is excreted in the urine at a higher rate than unmodified albumin, we studied glucose and methylgloxal modified albumins (21 days). All had reduced affinity to FcRn at pH 6.0, suggesting these albumins would not be returned to the circulation via the transcytotic pathway. To address why modified albumin has reduced affinity, we analyzed the structure of the modified albumins using small-angle X-ray scattering. This analysis showed significant structural changes occurring to albumin with glycation, particularly in the FcRn-binding region, which could explain the reduced affinity to FcRn. These results offer an explanation for enhanced proximal tubule-mediated sorting and clearance of abnormal albumins.

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Hai, Mai Thu, Pierre Lescop, Hugues Loosfelt, and Nicolae Ghinea. "Receptor-mediated transcytosis of follicle-stimulating hormone through the rat testicular microvasculature." Biology of the Cell 96, no. 2 (March 2004): 133–44. http://dx.doi.org/10.1016/j.biolcel.2003.11.008.

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Tesar, Devin B., Evelyn J. Cheung, and Pamela J. Bjorkman. "The Chicken Yolk Sac IgY Receptor, a Mammalian Mannose Receptor Family Member, Transcytoses IgY across Polarized Epithelial Cells." Molecular Biology of the Cell 19, no. 4 (April 2008): 1587–93. http://dx.doi.org/10.1091/mbc.e07-09-0972.

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In mammals the transfer of passive immunity from mother to young is mediated by the MHC-related receptor FcRn, which transports maternal IgG across epithelial cell barriers. In birds, maternal IgY in egg yolk is transferred across the yolk sac to passively immunize chicks during gestation and early independent life. The chicken yolk sac IgY receptor (FcRY) is the ortholog of the mammalian phospholipase A2 receptor, a mannose receptor family member, rather than an FcRn or MHC homolog. FcRn and FcRY both exhibit ligand binding at the acidic pH of endosomes and ligand release at the slightly basic pH of blood. Here we show that FcRY expressed in polarized mammalian epithelial cells functioned in endocytosis, bidirectional transcytosis, and recycling of chicken FcY/IgY. Confocal immunofluorescence studies demonstrated that IgY binding and endocytosis occurred at acidic but not basic pH, mimicking pH-dependent uptake of IgG by FcRn. Colocalization studies showed FcRY-mediated internalization via clathrin-coated pits and transport involving early and recycling endosomes. Disruption of microtubules partially inhibited apical-to-basolateral and basolateral-to-apical transcytosis, but not recycling, suggesting the use of different trafficking machinery. Our results represent the first cell biological evidence of functional equivalence between FcRY and FcRn and provide an intriguing example of how evolution can give rise to systems in which similar biological requirements in different species are satisfied utilizing distinct protein folds.

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Osburg, B., C. Peiser, D. Dömling, L. Schomburg, Y. T. Ko, K. Voigt, and U. Bickel. "Effect of endotoxin on expression of TNF receptors and transport of TNF-α at the blood-brain barrier of the rat." American Journal of Physiology-Endocrinology and Metabolism 283, no. 5 (November 1, 2002): E899—E908. http://dx.doi.org/10.1152/ajpendo.00436.2001.

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The transport mechanism mediating brain uptake of tumor necrosis factor (TNF)-α has been studied. When 125I-labeled rat TNF-α was used in internal carotid artery perfusions in rats, the cytokine showed transcytosis through the blood-brain barrier in intact form (permeability-surface area product 0.34 ± 0.13 μl · min−1 · g−1). Uptake was inhibited by low nanomolar concentrations of unlabeled rat TNF-α. Human TNF-α, which does not interact with the p80 TNF receptor in rodents, showed no brain uptake. mRNA expression of both p60 and p80 receptors could be demonstrated in native brain microvessel preparations. These transcripts increased to 149% (p60) and 127% (p80) of control 4 h after a systemic immune stimulation (2 mg/kg bacterial endotoxin ip). Lipopolysaccharide treatment did not alter the rate of brain uptake of TNF-α measured between 4 and 24 h later. In conclusion, a receptor-mediated mechanism is responsible for the transcytosis of TNF-α. Saturable transport, requiring the p80 receptor, occurs at concentrations encountered under pathophysiological conditions and therefore constitutes a relevant mechanism of communication between the immune system and the brain.

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Ghitescu, L., A. Fixman, M. Simionescu, and N. Simionescu. "Specific binding sites for albumin restricted to plasmalemmal vesicles of continuous capillary endothelium: receptor-mediated transcytosis." Journal of Cell Biology 102, no. 4 (April 1, 1986): 1304–11. http://dx.doi.org/10.1083/jcb.102.4.1304.

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The interaction of homologous and heterologous albumin-gold complex (Alb-Au) with capillary endothelium was investigated in the mouse lung, heart, and diaphragm. Perfusion of the tracer in situ for from 3 to 35 min was followed by washing with phosphate-buffered saline, fixation by perfusion, and processing for electron microscopy. From the earliest time examined, one and sometimes two rows of densely packed particles bound to some restricted plasma membrane microdomains that appeared as uncoated pits, and to plasmalemmal vesicles open on the luminal front. Morphometric analysis, using various albumin-gold concentrations, showed that the binding is saturable at a very low concentration of the ligand and short exposure. After 5 min, tracer-carrying vesicles appeared on the abluminal front, discharging their content into the subendothelial space. As a function of tracer concentration 1-10% of plasmalemmal vesicles contained Alb-Au particles in fluid phase; from 5 min on, multivesicular bodies were labeled by the tracer. Plasma membrane, coated pits, and coated vesicles were not significantly marked at any time interval. Heparin or high ionic strength did not displace the bound Alb-Au from vesicle membrane. No binding was obtained when Alb-Au was competed in situ with albumin or was injected in vivo. Gold complexes with fibrinogen, fibronectin, glucose oxidase, or polyethyleneglycol did not give a labeling comparable to that of albumin. These results suggest that on the capillary endothelia examined, the Alb-Au is adsorbed on specific binding sites restricted to uncoated pits and plasmalemmal vesicles. The tracer is transported in transcytotic vesicles across endothelium by receptor-mediated transcytosis, and to a lesser extent is taken up by pinocytotic vesicles. The existence of albumin receptors on these continuous capillary endothelia may provide a specific mechanism for the transport of albumin and other molecules carried by this protein.

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Hunziker, Walter, and Peter J. Peters. "Rab17 Localizes to Recycling Endosomes and Regulates Receptor-mediated Transcytosis in Epithelial Cells." Journal of Biological Chemistry 273, no. 25 (June 19, 1998): 15734–41. http://dx.doi.org/10.1074/jbc.273.25.15734.

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Kobayashi, Noriyoshi, Yusuke Suzuki, Toshinao Tsuge, Ko Okumura, Chisei Ra, and Yasuhiko Tomino. "FcRn-mediated transcytosis of immunoglobulin G in human renal proximal tubular epithelial cells." American Journal of Physiology-Renal Physiology 282, no. 2 (February 1, 2002): F358—F365. http://dx.doi.org/10.1152/ajprenal.0164.2001.

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In the kidney, proteins filtered through glomeruli are reabsorbed by endocytosis along the proximal tubules to avoid renal loss of large amounts of proteins. Recently, neonatal Fc receptor (FcRn), which is involved in the transport of IgG across several epithelial and endothelial cells, was reported to be expressed in renal proximal tubular epithelial cells (RPTECs). However, there has been no direct evidence for receptor-mediated endocytosis of IgG in human RPTECs. To explore physiological roles of FcRn in the proximal tubules, we used the human RPTECs to examine IgG transport. FcRn was expressed in RPTECs and physically associated with β2-microglobulin, preserving the capacity of specific pH-dependent IgG binding. Human IgG was bound to the cell surface of RPTECs in a pH-dependent manner. The human IgG transport assay revealed that receptor-mediated transepithelial transport of intact IgG in RPTECs is bidirectional and that it requires the formation of acidified intracellular compartments. With the use of double immunofluorescence, the internalized human IgG was marked in cytoplasm of RPTECs and colocalized with FcRn. These data define the mechanisms of FcRn-associated IgG transport in RPTEC monolayers. It was suggested that the intact pathway for human IgG transepithelial transport may avoid lysosomal degradation of IgG.

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PERRONE, Lorena, Simona PALADINO, Marialuisa MAZZONE, Lucio NITSCH, Massimo GULISANO, and Chiara ZURZOLO. "Functional interaction between p75NTR and TrkA: the endocytic trafficking of p75NTR is driven by TrkA and regulates TrkA-mediated signalling." Biochemical Journal 385, no. 1 (December 14, 2004): 233–41. http://dx.doi.org/10.1042/bj20041155.

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The topology and trafficking of receptors play a key role in their signalling capability. Indeed, receptor function is related to the microenvironment inside the cell, where specific signalling molecules are compartmentalized. The response to NGF (nerve growth factor) is strongly dependent on the trafficking of its receptor, TrkA. However, information is still scarce about the role of the cellular localization of the TrkA co-receptor, p75NTR (where NTR is neurotrophin receptor), following stimulation by NGF. It has been shown that these two receptors play a key role in epithelial tissue and in epithelial-derived tumours, where the microenvironment at the plasma membrane is defined by the presence of tight junctions. Indeed, in thyroid carcinomas, rearrangements of TrkA are frequently found, which produce TrkA mutants that are localized exclusively in the cytoplasm. We used a thyroid cellular model in which it was possible to dissect the trafficking of the two NGF receptors upon neurotrophin stimulation. In FRT (Fischer rat thyroid) cells, endogenous TrkA is localized exclusively on the basolateral surface, while transfected p75NTR is selectively distributed on the apical membrane. This cellular system enabled us to selectively stimulate either p75NTR or TrkA and to analyse the role of receptor trafficking in their signalling capability. We found that, after binding to NGF, p75NTR was co-immunoprecipitated with TrkA and was transcytosed at the basolateral membrane. We showed that the TrkA–p75NTR interaction is necessary for this relocation of p75NTR to the basolateral side. Interestingly, TrkA-specific stimulation by basolateral NGF loading also induced the TrkA–p75NTR interaction and subsequent p75NTR transcytosis at the basolateral surface. Moreover, specific stimulation of p75NTR by NGF activated TrkA and the MAPK (mitogen-activated protein kinase) pathway. Our data indicate that TrkA regulates the subcellular localization of p75NTR upon stimulation with neurotrophins, thus affecting the topology of the signal transduction molecules, driving the activation of a specific signal transduction pathway.

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48

Gonzalez-Hernandez, Mariam B., Thomas Liu, Luz P. Blanco, Heather Auble, Hilary C. Payne, and Christiane E. Wobus. "Murine Norovirus Transcytosis across anIn VitroPolarized Murine Intestinal Epithelial Monolayer Is Mediated by M-Like Cells." Journal of Virology 87, no. 23 (September 18, 2013): 12685–93. http://dx.doi.org/10.1128/jvi.02378-13.

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Noroviruses (NoVs) are the causative agent of the vast majority of nonbacterial gastroenteritis worldwide. Due to the inability to culture human NoVs and the inability to orally infect a small animal model, little is known about the initial steps of viral entry. One particular step that is not understood is how NoVs breach the intestinal epithelial barrier. Murine NoV (MNV) is the only NoV that can be propagatedin vitroby infecting murine macrophages and dendritic cells, making this virus an attractive model for studies of different aspects of NoV biology. Polarized murine intestinal epithelial mICcl2cells were used to investigate how MNV interacts with and crosses the intestinal epithelium. In thisin vitromodel of the follicle-associated epithelium (FAE), MNV is transported across the polarized cell monolayer in the absence of viral replication or disruption of tight junctions by a distinct epithelial cell with microfold (M) cell properties. In addition to transporting MNV, these M-like cells also transcytose microbeads and express an IgA receptor. Interestingly, B myeloma cells cultured in the basolateral compartment underlying the epithelial monolayer did not alter the number of M-like cells but increased their transcytotic activity. Our data demonstrate that MNV can cross an intact intestinal epithelial monolayerin vitroby hijacking the M-like cells' intrinsic transcytotic pathway and suggest a potential mechanism for MNV entry into the host.

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Cavaco, Marco, Diana Gaspar, Miguel ARB Castanho, and Vera Neves. "Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?" Pharmaceutics 12, no. 1 (January 13, 2020): 62. http://dx.doi.org/10.3390/pharmaceutics12010062.

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The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.

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Tesar, Devin B., Noreen E. Tiangco, and Pamela J. Bjorkman. "Ligand Valency Affects Transcytosis, Recycling and Intracellular Trafficking Mediated by the Neonatal Fc Receptor." Traffic 7, no. 9 (June 29, 2006): 1127–42. http://dx.doi.org/10.1111/j.1600-0854.2006.00457.x.

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Journal articles on the topic 'Receptor mediated transcytosis'

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