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Identification of Specific Trafficking Defects of Naturally Occurring Variants of the Human ABCG2 Transporter

Proper targeting of the urate and xenobiotic transporter ATP-binding transporter subfamily G member 2 (ABCG2) to the plasma membrane (PM) is essential for its normal function. The naturally occurring Q141K and M71V polymorphisms in ABCG2, associated with gout and hyperuricemia, affect the cellular r...

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Autores principales: Bartos, Zsuzsa, Homolya, László
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900420/
https://www.ncbi.nlm.nih.gov/pubmed/33634118
http://dx.doi.org/10.3389/fcell.2021.615729
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author Bartos, Zsuzsa
Homolya, László
author_facet Bartos, Zsuzsa
Homolya, László
author_sort Bartos, Zsuzsa
collection PubMed
description Proper targeting of the urate and xenobiotic transporter ATP-binding transporter subfamily G member 2 (ABCG2) to the plasma membrane (PM) is essential for its normal function. The naturally occurring Q141K and M71V polymorphisms in ABCG2, associated with gout and hyperuricemia, affect the cellular routing of the transporter, rather than its transport function. The cellular localization of ABCG2 variants was formerly studied by immunolabeling, which provides information only on the steady-state distribution of the protein, leaving the dynamics of its cellular routing unexplored. In the present study, we assessed in detail the trafficking of the wild-type, M71V-, and Q141K-ABCG2 variants from the endoplasmic reticulum (ER) to the cell surface using a dynamic approach, the so-called Retention Using Selective Hooks (RUSH) system. This method also allowed us to study the kinetics of glycosylation of these variants. We found that the fraction of Q141K- and M71V-ABCG2 that passes the ER quality control system is only partially targeted to the PM; a subfraction is immobile and retained in the ER. Surprisingly, the transit of these variants through the Golgi apparatus (either the appearance or the exit) was unaffected; however, their PM delivery beyond the Golgi was delayed. In addition to identifying the specific defects in the trafficking of these ABCG2 variants, our study provides a novel experimental tool for studying the effect of drugs that potentially promote the cell surface delivery of mutant or polymorphic ABCG2 variants with impaired trafficking.
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spelling pubmed-79004202021-02-24 Identification of Specific Trafficking Defects of Naturally Occurring Variants of the Human ABCG2 Transporter Bartos, Zsuzsa Homolya, László Front Cell Dev Biol Cell and Developmental Biology Proper targeting of the urate and xenobiotic transporter ATP-binding transporter subfamily G member 2 (ABCG2) to the plasma membrane (PM) is essential for its normal function. The naturally occurring Q141K and M71V polymorphisms in ABCG2, associated with gout and hyperuricemia, affect the cellular routing of the transporter, rather than its transport function. The cellular localization of ABCG2 variants was formerly studied by immunolabeling, which provides information only on the steady-state distribution of the protein, leaving the dynamics of its cellular routing unexplored. In the present study, we assessed in detail the trafficking of the wild-type, M71V-, and Q141K-ABCG2 variants from the endoplasmic reticulum (ER) to the cell surface using a dynamic approach, the so-called Retention Using Selective Hooks (RUSH) system. This method also allowed us to study the kinetics of glycosylation of these variants. We found that the fraction of Q141K- and M71V-ABCG2 that passes the ER quality control system is only partially targeted to the PM; a subfraction is immobile and retained in the ER. Surprisingly, the transit of these variants through the Golgi apparatus (either the appearance or the exit) was unaffected; however, their PM delivery beyond the Golgi was delayed. In addition to identifying the specific defects in the trafficking of these ABCG2 variants, our study provides a novel experimental tool for studying the effect of drugs that potentially promote the cell surface delivery of mutant or polymorphic ABCG2 variants with impaired trafficking. Frontiers Media S.A. 2021-02-09 /pmc/articles/PMC7900420/ /pubmed/33634118 http://dx.doi.org/10.3389/fcell.2021.615729 Text en Copyright © 2021 Bartos and Homolya. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Bartos, Zsuzsa
Homolya, László
Identification of Specific Trafficking Defects of Naturally Occurring Variants of the Human ABCG2 Transporter
title Identification of Specific Trafficking Defects of Naturally Occurring Variants of the Human ABCG2 Transporter
title_full Identification of Specific Trafficking Defects of Naturally Occurring Variants of the Human ABCG2 Transporter
title_fullStr Identification of Specific Trafficking Defects of Naturally Occurring Variants of the Human ABCG2 Transporter
title_full_unstemmed Identification of Specific Trafficking Defects of Naturally Occurring Variants of the Human ABCG2 Transporter
title_short Identification of Specific Trafficking Defects of Naturally Occurring Variants of the Human ABCG2 Transporter
title_sort identification of specific trafficking defects of naturally occurring variants of the human abcg2 transporter
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900420/
https://www.ncbi.nlm.nih.gov/pubmed/33634118
http://dx.doi.org/10.3389/fcell.2021.615729
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