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Transcytosis
Transcytosis (also known as cytopempsis) is a type of transcellular transport in 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 epithelial cells, 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 [citation needed]. 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.
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.
Transcytosis is also a suspected mechanism in atherosclerosis by which low density lipoprotein (LDL) macromolecules penetrate across endothelial cell monolayers of arterial walls, which is thought to occur via binding of LDL particles to scavenger receptor B1 and an eight amino-acid cytoplasmic domain on the receptor that recruits guanine nucleotide exchange factor dedicator of cytokinesis 4 (DOCK4). DOCK4 promotes the transport of LDL particles across the endothelial cell monolayers by activating RAC1, a small signalling GTPase whose activation results in the coupling of LDL particles to scavenger receptor B1, allowing internalization of this complex and therefore delivery of LDL carriers of cholesterol into the arterial intima.
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).[citation needed] 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.[citation needed]
Molecules are transported across an epithelial or endothelial barrier by one of two routes: 1) a transcellular route through the intracellular compartment of the cell, or 2) a paracellular route through the extracellular space between adjacent cells. The transcellular route is also called transcytosis. Transcytosis can be receptor-mediated and consists of three steps: 1) receptor-mediated endocytosis of the molecule on one side of the cell, e.g. the luminal side; 2) movement of the molecule through the intracellular compartment typically within the endosomal system; and 3) exocytosis of the molecule to the extracellular space on the other side of the cell, e.g. the abluminal side.
Transcytosis may be either unidirectional or bidirectional. Unidirectional transcytosis may occur selectively in the luminal to abluminal direction, or in the reverse direction, in the abluminal to luminal direction.
Transcytosis is prominent in brain microvascular peptide and protein transport, because the brain microvascular endothelium, which forms the blood-brain barrier (BBB) in vivo, expresses unique, epithelial-like, high-resistance tight junctions. The brain endothelial tight junctions virtually eliminate the paracellular pathway of solute transport across the microvascular endothelial wall in brain. In contrast, the endothelial barrier in peripheral organs does not express tight junctions, and solute movement through the paracellular pathway is prominent at the endothelial barrier in organs other than the brain or spinal cord.
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Transcytosis
Transcytosis (also known as cytopempsis) is a type of transcellular transport in 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 epithelial cells, 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 [citation needed]. 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.
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.
Transcytosis is also a suspected mechanism in atherosclerosis by which low density lipoprotein (LDL) macromolecules penetrate across endothelial cell monolayers of arterial walls, which is thought to occur via binding of LDL particles to scavenger receptor B1 and an eight amino-acid cytoplasmic domain on the receptor that recruits guanine nucleotide exchange factor dedicator of cytokinesis 4 (DOCK4). DOCK4 promotes the transport of LDL particles across the endothelial cell monolayers by activating RAC1, a small signalling GTPase whose activation results in the coupling of LDL particles to scavenger receptor B1, allowing internalization of this complex and therefore delivery of LDL carriers of cholesterol into the arterial intima.
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).[citation needed] 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.[citation needed]
Molecules are transported across an epithelial or endothelial barrier by one of two routes: 1) a transcellular route through the intracellular compartment of the cell, or 2) a paracellular route through the extracellular space between adjacent cells. The transcellular route is also called transcytosis. Transcytosis can be receptor-mediated and consists of three steps: 1) receptor-mediated endocytosis of the molecule on one side of the cell, e.g. the luminal side; 2) movement of the molecule through the intracellular compartment typically within the endosomal system; and 3) exocytosis of the molecule to the extracellular space on the other side of the cell, e.g. the abluminal side.
Transcytosis may be either unidirectional or bidirectional. Unidirectional transcytosis may occur selectively in the luminal to abluminal direction, or in the reverse direction, in the abluminal to luminal direction.
Transcytosis is prominent in brain microvascular peptide and protein transport, because the brain microvascular endothelium, which forms the blood-brain barrier (BBB) in vivo, expresses unique, epithelial-like, high-resistance tight junctions. The brain endothelial tight junctions virtually eliminate the paracellular pathway of solute transport across the microvascular endothelial wall in brain. In contrast, the endothelial barrier in peripheral organs does not express tight junctions, and solute movement through the paracellular pathway is prominent at the endothelial barrier in organs other than the brain or spinal cord.