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Function, Regulation, and Pathophysiological Relevance of the POT Superfamily, Specifically PepT1 in Inflammatory Bowel Disease

Emilie Viennois, Adani Pujada, Jane Zen, Didier Merlin

10.1002/cphy.c170032

Source: Volume 8, Issue 2, April 2018

Published online: March 2018

Full Article on Wiley Online Library



ABSTRACT

Mammalian members of the proton‐coupled oligopeptide transporter family are integral membrane proteins that mediate the cellular uptake of di/tripeptides and peptide‐like drugs and couple substrate translocation to the movement of H+, with the transmembrane electrochemical proton gradient providing the driving force. Peptide transporters are responsible for the (re)absorption of dietary and/or bacterial di‐ and tripeptides in the intestine and kidney and maintaining homeostasis of neuropeptides in the brain. These proteins additionally contribute to absorption of a number of pharmacologically important compounds. In this overview article, we have provided updated information on the structure, function, expression, localization, and activities of PepT1 (SLC15A1), PepT2 (SLC15A2), PhT1 (SLC15A4), and PhT2 (SLC15A3). Peptide transporters, in particular, PepT1 are discussed as drug‐delivery systems in addition to their implications in health and disease. Particular emphasis has been placed on the involvement of PepT1 in the physiopathology of the gastrointestinal tract, specifically, its role in inflammatory bowel diseases. © 2018 American Physiological Society. Compr Physiol 8:731‐760, 2018.

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Figure 1. Figure 1. Major events in the discovery of the members of the SLC15 family. Main discoveries that identified the different members of POT family, their expression and their function is displayed on the time line in a chronological manner.
Figure 2. Figure 2. Homology between human and mouse PepT1. Protein sequence alignment of Homo sapiens and Mus musculus PepT1 transporter. Identical residues are underlined with gray and show a 90% homology.
Figure 3. Figure 3. Homology between human PepT1 and PepT2. Sequence alignment of Homo sapiens PepT1 and PepT2 showing. Identical residues are underlined with green and show a 50% homology.
Figure 4. Figure 4. Schematic model of hPepT1 in the membrane and particularly the lipid raft. The structure of the transporter itself is presented within the lipid raft but is the same when localized in nonlipids raft membrane regions.
Figure 5. Figure 5. Model for PepT1 interaction with different peptides in the epithelial cell of the gut. The transporter activity of PepT1 is driven by the electrochemical proton gradient established by the apical Na+/H+ antiporter for the pH balance from the peptide‐transport‐induced intracellular acid load (center cell). This mechanism depends on the basolateral Na+/K+ ATPase (right cell). The uptake of di‐ and tripeptides will occur rapidly and they will be hydrolyzed in the cytosol, free amino acids will be released into the blood stream by different amino acid transporters located in the basolateral membrane. PepT1 transport of bacterial di‐ and tripeptides in the lumen, such as N‐formylmethionyl‐leucyl‐phenylalanine (fMLP), muramyl dipeptide (MDP), and L‐Ala‐γ‐D‐Glu‐meso‐diaminopimelic acid (tri‐DAP), into the intestinal epithelial cells (left cell). Due to the accumulation of bacterial di‐ and tripeptides, the NFkB pathway is stimulated leading to the activation of proinflammatory cytokines. Di‐ and tripeptides are common substrates cotransported with protons by PepT1.
Figure 6. Figure 6. Overview of the organs where members of the SCL15 family are expressed. Tissues expressing PepT1 are labeled in green, PepT2 in orange, PhT1 in purple, and PhT2 in light blue.
Figure 7. Figure 7. Model for PepT1 transport of bacterial peptide and downstream activation of proinflammatory pathway. PepT1 is upregulated during inflammatory bowel disease (IBD) causing the transport of bacterial di‐ and tripeptides in the lumen, such as N‐formylmethionyl‐leucyl‐phenylalanine (fMLP), muramyl dipeptide (MDP), and L‐Ala‐γ‐D‐Glu‐meso‐diaminopimelic acid (tri‐DAP), into the intestinal epithelial cells. Due to the accumulation of bacterial di‐ and tripeptides, the NFkB pathway is stimulated leading to the activation of proinflammatory cytokines. In addition, IBD can cause the disruption of barrier function leading the transport of bacterial di‐tripeptides (fMLP, MDP, tri‐DAP) via paracellular pathway. Once they are in the lamina propria, the di‐tripeptides can be taken by macrophages which also express PEPT1. The binding of PEPT1‐Di‐Tripeptide will signal the macrophage to upregulate major histocompatibility class I molecules. MCP, monocyte chemoattractant protein. Redrawn from (93).


Figure 1. Major events in the discovery of the members of the SLC15 family. Main discoveries that identified the different members of POT family, their expression and their function is displayed on the time line in a chronological manner.


Figure 2. Homology between human and mouse PepT1. Protein sequence alignment of Homo sapiens and Mus musculus PepT1 transporter. Identical residues are underlined with gray and show a 90% homology.


Figure 3. Homology between human PepT1 and PepT2. Sequence alignment of Homo sapiens PepT1 and PepT2 showing. Identical residues are underlined with green and show a 50% homology.


Figure 4. Schematic model of hPepT1 in the membrane and particularly the lipid raft. The structure of the transporter itself is presented within the lipid raft but is the same when localized in nonlipids raft membrane regions.


Figure 5. Model for PepT1 interaction with different peptides in the epithelial cell of the gut. The transporter activity of PepT1 is driven by the electrochemical proton gradient established by the apical Na+/H+ antiporter for the pH balance from the peptide‐transport‐induced intracellular acid load (center cell). This mechanism depends on the basolateral Na+/K+ ATPase (right cell). The uptake of di‐ and tripeptides will occur rapidly and they will be hydrolyzed in the cytosol, free amino acids will be released into the blood stream by different amino acid transporters located in the basolateral membrane. PepT1 transport of bacterial di‐ and tripeptides in the lumen, such as N‐formylmethionyl‐leucyl‐phenylalanine (fMLP), muramyl dipeptide (MDP), and L‐Ala‐γ‐D‐Glu‐meso‐diaminopimelic acid (tri‐DAP), into the intestinal epithelial cells (left cell). Due to the accumulation of bacterial di‐ and tripeptides, the NFkB pathway is stimulated leading to the activation of proinflammatory cytokines. Di‐ and tripeptides are common substrates cotransported with protons by PepT1.


Figure 6. Overview of the organs where members of the SCL15 family are expressed. Tissues expressing PepT1 are labeled in green, PepT2 in orange, PhT1 in purple, and PhT2 in light blue.


Figure 7. Model for PepT1 transport of bacterial peptide and downstream activation of proinflammatory pathway. PepT1 is upregulated during inflammatory bowel disease (IBD) causing the transport of bacterial di‐ and tripeptides in the lumen, such as N‐formylmethionyl‐leucyl‐phenylalanine (fMLP), muramyl dipeptide (MDP), and L‐Ala‐γ‐D‐Glu‐meso‐diaminopimelic acid (tri‐DAP), into the intestinal epithelial cells. Due to the accumulation of bacterial di‐ and tripeptides, the NFkB pathway is stimulated leading to the activation of proinflammatory cytokines. In addition, IBD can cause the disruption of barrier function leading the transport of bacterial di‐tripeptides (fMLP, MDP, tri‐DAP) via paracellular pathway. Once they are in the lamina propria, the di‐tripeptides can be taken by macrophages which also express PEPT1. The binding of PEPT1‐Di‐Tripeptide will signal the macrophage to upregulate major histocompatibility class I molecules. MCP, monocyte chemoattractant protein. Redrawn from (93).
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Teaching Material

E. Viennois, A. Pujada, J. Zen, D. Merlin. Function, Regulation, and Pathophysiological Relevance of the POT Superfamily, Specifically PepT1 in Inflammatory Bowel Disease. Compr Physiol. 8: 2018, 731-760.

Didactic Synopsis

Major Teaching Points:

  • The proton-coupled oligopeptide transporter (POT) family comprises PepT1, PepT2, PhT2, and PhT1 encoded by SLC15A1, SLC15A2, SLC5A3, and SCL5A4 genes, respectively (belonging to the solute carrier gene group).
  • POT family transporters mediate the uptake of di- or tripeptides through the membrane using the transmembrane proton gradient as the driving force.
  • The primary sites of functional expression of PepT1 and PepT2 are the intestine and kidney, respectively. Other localization sites have additionally been identified.
  • Expression of PepT1 is regulated by a variety of parameters, including extracellular pH, circadian cycles, dietary supply, and inflammation.
  • PepT1 has significant physiopathological relevance in inflammatory bowel disease.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. This chronological axis shows the main discoveries that identified the different members of POT family, their site of expression and their function.

Figure 2. This figure illustrates the homology between the murine and human PepT1 transporters. Understanding the homology between species is crucial to predict functional similarities. In that case homology is of 90%.

Figure 3. This figure illustrates the homology between the human form of the two transporters PepT1 and PepT2. Understanding the homology between two different proteins is crucial to predict functional similarities. In that case homology is of 50%.

Figure 4. This figure represents the structure of the transporter and how it is incorporated into cell membrane.

Figure 5. This figure illustrates the different interactions between PepT1 and its different substrates in the gut and the downstream events occurring after substrate uptake. The transporter activity of PepT1 is driven by the electrochemical force caused by an intake of protons at the upper surface of the cell (center cell). This mechanism also depends on a pump at the basal surface (right cell). The substrate can be rapidly recovered in bloodstream. PepT1 can also transport di- and tripeptides produced by bacteria, such as N-formylmethionyl-leucyl-phenylalanine (fMLP), muramyl dipeptide (MDP), and L-Ala-γ-D-Glu-meso-diaminopimelic acid (tri-DAP), (left cell). Due to the accumulation of bacterial di- and tripeptides, inflammatory pathways are activated.

Figure 6. This figure illustrates, with a color code, the organs were PepT1 (green), PepT2 (orange), PhT1 (purple), and PhT2 (blue) are expressed. The knowledge of the site of localization/expression of these four transporters can help to predict their function and/or the diseases in which they might be involved.

Figure 7. This figure illustrates the role of PepT1 in the transport of bacterial products and its downstream effects. PepT1 is upregulated during inflammatory bowel disease (IBD). This condition is characterized by a chronic inflammation of the intestinal mucosa and a disruption of barrier function. In IBD, the presence of PepT1 in a larger quantity on the cell surface and the breach in the intestinal barrier can cause an increased uptake of bacterial products into and between the intestinal epithelial cells. Due to the accumulation of such products, inflammatory pathways are activated.


Related Articles:

Principles of Membrane Transport
Dietary Protein Processing: Intraluminal and Enterocyte Surface Events
Transport of Amino Acids in the Kidney
Tubular Transport of Amino Acids and Small Peptides

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Article Title: Function, Regulation, and Pathophysiological Relevance of the POT Superfamily, Specifically PepT1 in Inflammatory Bowel Disease
 

How to Cite

Emilie Viennois, Adani Pujada, Jane Zen, Didier Merlin. Function, Regulation, and Pathophysiological Relevance of the POT Superfamily, Specifically PepT1 in Inflammatory Bowel Disease. Compr Physiol 2018, 8: 731-760. doi: 10.1002/cphy.c170032