Transcytosis is the process by which various macromolecules are transported across the interior of a cell. Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ejected on the other side. Examples of macromolecules transported include IgA, transferrin, and insulin. While transcytosis is most commonly observed in cells of an epithelium, the process is also present elsewhere. Blood capillaries are a well-known site for transcytosis, though it occurs in other cells, including neurons, osteoclasts and M cells of the intestine.
The regulation of transcytosis varies greatly due to the many different tissues in which this process is observed. Various tissue specific mechanisms of transcytosis have been identified. Brefeldin A, a commonly used inhibitor of ER to Golgi apparatus transport, has been shown to inhibit transcytosis in dog kidney cells which provided the first clues as to the nature of transcytosis regulation. Transcytosis in dog kidney cells has also been shown be regulated at the apical membrane by Rab17, as well as Rab11a and Rab25. Further work on dog kidney cells has shown that a signaling cascade involving the phosphorylation of EGFR by Yes leading to the activation of Rab11FIP5 by MAPK1 upregulates transcytosis. Transcytosis has been shown to be inhibited by the combination of progesterone and estradiol followed by activation mediated by prolactin in the rabbit mammary gland during pregnancy. In the thyroid, follicular cell transcytosis is regulated positively by TSH. The phosphorylation of caveolin 1 induced by hydrogen peroxide has been shown to be critical to the activation of transcytosis in pulmonary vascular tissue. It can therefore be concluded that the regulation of transcytosis is a complex process that varies between tissues.
Role in pathogenesis
Due to the function of transcytosis as a process that transports macromolecules across cells, it can be a convenient mechanism by which pathogens can invade a tissue. Transcytosis has been shown to be critical to the entry of Cronobacter sakazakii across the intestinal epithelium as well as the blood–brain barrier. Listeria monocytogenes has been shown to enter the intestinal lumen via transcytosis across goblet cells. Shiga toxin secreted by enterohemorrhagic E. coli has been shown to be transcytosed into the intestinal lumen. From these examples, it can be said that transcytosis is vital to the process of pathogenesis for a variety of infectious agents.
Clinical Applications of Transcytosis
Pharmaceutical companies, such as Lundbeck, are currently exploring the use of transcytosis as a mechanism for transporting therapeutic drugs across the human blood–brain barrier (BBB). Exploiting the body’s own transport mechanism can help to overcome the high selectivity of the BBB which typically blocks the uptake of most therapeutic antibodies into the brain and Central Nervous System (CNS). The pharmaceutical company Genentech, after having synthesized a therapeutic antibody that effectively inhibited BACE1 enzymatic function, experienced problems transferring adequate, efficient levels of the antibody within the brain. BACE1 is the enzyme which processes amyloid precursor proteins into amyloid-β peptides, including the species that aggregate to form amyloid plaques associated with Alzheimer's disease. Researchers at Genentech proposed the creation of a bispecific antibody that could bind the BBB membrane, induce receptor-mediated transcytosis, and release itself on the other side into the brain and CNS. They utilized a mouse bispecific antibody with two active sites performing different functions. One arm had a low-affinity anti-transferrin receptor binding site that induces transcytosis. A high-affinity binding site would result in the antibody not being able to release from the BBB membrane after transcytosis. This way the amount of transported antibody is based on the concentration of antibody on either side of the barrier. The other arm had the previously developed high-affinity anti-BACE1 binding site that would inhibit BACE1 function and prevent amyloid plaque formation. Genentech was able to demonstrate in mouse models that the new bispecific antibody was able to reach therapeutic levels in the brain. Genentech’s method of disguising and transporting the therapeutic antibody by attaching it to a receptor-mediated transcytosis activator has been referred to as the “Trojan Horse” method.
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- Macromolecules Can Be Transferred Across Epithelial Cell Sheets by Transcytosis
- Transcytosis of IgA
- Transcytosis of bacteria