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Tissue-Specific Amino Acid Transporter Partners ACE2 and Collectrin Differentially Interact With Hartnup Mutations
BACKGROUND & AIMS: Hartnup amino acid transporter B(0)AT1 (SLC6A19) is the major luminal sodium-dependent neutral amino acid transporter of small intestine and kidney proximal tubule. The expression of B(0)AT1 in kidney was recently shown to depend on its association with collectrin (Tmem27), a...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AGA Institute. Published by Elsevier Inc.
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094282/ https://www.ncbi.nlm.nih.gov/pubmed/19185582 http://dx.doi.org/10.1053/j.gastro.2008.10.055 |
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author | Camargo, Simone M.R. Singer, Dustin Makrides, Victoria Huggel, Katja Pos, Klaas M. Wagner, Carsten A. Kuba, Keiji Danilczyk, Ursula Skovby, Flemming Kleta, Robert Penninger, Josef M. Verrey, François |
author_facet | Camargo, Simone M.R. Singer, Dustin Makrides, Victoria Huggel, Katja Pos, Klaas M. Wagner, Carsten A. Kuba, Keiji Danilczyk, Ursula Skovby, Flemming Kleta, Robert Penninger, Josef M. Verrey, François |
author_sort | Camargo, Simone M.R. |
collection | PubMed |
description | BACKGROUND & AIMS: Hartnup amino acid transporter B(0)AT1 (SLC6A19) is the major luminal sodium-dependent neutral amino acid transporter of small intestine and kidney proximal tubule. The expression of B(0)AT1 in kidney was recently shown to depend on its association with collectrin (Tmem27), a protein homologous to the membrane-anchoring domain of angiotensin-converting enzyme (ACE) 2. METHODS: Because collectrin is almost absent from small intestine, we tested the hypothesis that it is ACE2 that interacts with B(0)AT1 in enterocytes. Furthermore, because B(0)AT1 expression depends on an associated protein, we tested the hypothesis that Hartnup-causing B(0)AT1 mutations differentially impact on B(0)AT1 interaction with intestinal and kidney accessory proteins. RESULTS: Immunofluorescence, coimmunoprecipitation, and functional experiments using wild-type and ace2-null mice showed that expression of B(0)AT1 in small intestine critically depends on ACE2. Coexpressing new and previously identified Hartnup disorder–causing missense mutations of B(0)AT1 with either collectrin or ACE2 in Xenopus laevis oocytes showed that the high-frequency D173N and the newly identified P265L mutant B(0)AT1 transporters can still be activated by ACE2 but not collectrin coexpression. In contrast, the human A69T and R240Q B(0)AT1 mutants cannot be activated by either of the associated proteins, although they function as wild-type B(0)AT1 when expressed alone. CONCLUSIONS: We thus show that ACE2 is necessary for the expression of the Hartnup transporter in intestine and suggest that the differential functional association of mutant B(0)AT1 transporters with ACE2 and collectrin in intestine and kidney, respectively, participates in the phenotypic heterogeneity of human Hartnup disorder. |
format | Online Article Text |
id | pubmed-7094282 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | AGA Institute. Published by Elsevier Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70942822020-03-25 Tissue-Specific Amino Acid Transporter Partners ACE2 and Collectrin Differentially Interact With Hartnup Mutations Camargo, Simone M.R. Singer, Dustin Makrides, Victoria Huggel, Katja Pos, Klaas M. Wagner, Carsten A. Kuba, Keiji Danilczyk, Ursula Skovby, Flemming Kleta, Robert Penninger, Josef M. Verrey, François Gastroenterology Basic—Alimentary Tract BACKGROUND & AIMS: Hartnup amino acid transporter B(0)AT1 (SLC6A19) is the major luminal sodium-dependent neutral amino acid transporter of small intestine and kidney proximal tubule. The expression of B(0)AT1 in kidney was recently shown to depend on its association with collectrin (Tmem27), a protein homologous to the membrane-anchoring domain of angiotensin-converting enzyme (ACE) 2. METHODS: Because collectrin is almost absent from small intestine, we tested the hypothesis that it is ACE2 that interacts with B(0)AT1 in enterocytes. Furthermore, because B(0)AT1 expression depends on an associated protein, we tested the hypothesis that Hartnup-causing B(0)AT1 mutations differentially impact on B(0)AT1 interaction with intestinal and kidney accessory proteins. RESULTS: Immunofluorescence, coimmunoprecipitation, and functional experiments using wild-type and ace2-null mice showed that expression of B(0)AT1 in small intestine critically depends on ACE2. Coexpressing new and previously identified Hartnup disorder–causing missense mutations of B(0)AT1 with either collectrin or ACE2 in Xenopus laevis oocytes showed that the high-frequency D173N and the newly identified P265L mutant B(0)AT1 transporters can still be activated by ACE2 but not collectrin coexpression. In contrast, the human A69T and R240Q B(0)AT1 mutants cannot be activated by either of the associated proteins, although they function as wild-type B(0)AT1 when expressed alone. CONCLUSIONS: We thus show that ACE2 is necessary for the expression of the Hartnup transporter in intestine and suggest that the differential functional association of mutant B(0)AT1 transporters with ACE2 and collectrin in intestine and kidney, respectively, participates in the phenotypic heterogeneity of human Hartnup disorder. AGA Institute. Published by Elsevier Inc. 2009-03 2008-10-29 /pmc/articles/PMC7094282/ /pubmed/19185582 http://dx.doi.org/10.1053/j.gastro.2008.10.055 Text en Copyright © 2009 AGA Institute. Published by Elsevier Inc. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Basic—Alimentary Tract Camargo, Simone M.R. Singer, Dustin Makrides, Victoria Huggel, Katja Pos, Klaas M. Wagner, Carsten A. Kuba, Keiji Danilczyk, Ursula Skovby, Flemming Kleta, Robert Penninger, Josef M. Verrey, François Tissue-Specific Amino Acid Transporter Partners ACE2 and Collectrin Differentially Interact With Hartnup Mutations |
title | Tissue-Specific Amino Acid Transporter Partners ACE2 and Collectrin Differentially Interact With Hartnup Mutations |
title_full | Tissue-Specific Amino Acid Transporter Partners ACE2 and Collectrin Differentially Interact With Hartnup Mutations |
title_fullStr | Tissue-Specific Amino Acid Transporter Partners ACE2 and Collectrin Differentially Interact With Hartnup Mutations |
title_full_unstemmed | Tissue-Specific Amino Acid Transporter Partners ACE2 and Collectrin Differentially Interact With Hartnup Mutations |
title_short | Tissue-Specific Amino Acid Transporter Partners ACE2 and Collectrin Differentially Interact With Hartnup Mutations |
title_sort | tissue-specific amino acid transporter partners ace2 and collectrin differentially interact with hartnup mutations |
topic | Basic—Alimentary Tract |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094282/ https://www.ncbi.nlm.nih.gov/pubmed/19185582 http://dx.doi.org/10.1053/j.gastro.2008.10.055 |
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