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Megalin Orchestrates FcRn Endocytosis and Trafficking

The neonatal Fc receptor (FcRn) is highly expressed in the renal proximal tubule and is important for the reclamation of albumin by cellular transcytosis to prevent its loss in the urine. The initial event of this transcellular transport mechanism is the endocytosis of albumin by the apical scavenge...

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Autores principales: Dahlke, Eileen, Anan, Yaman, Klie, Lea Maximiliane, Hartkopf, Ariane Elisabeth, Theilig, Franziska
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818419/
https://www.ncbi.nlm.nih.gov/pubmed/36611847
http://dx.doi.org/10.3390/cells12010053
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author Dahlke, Eileen
Anan, Yaman
Klie, Lea Maximiliane
Hartkopf, Ariane Elisabeth
Theilig, Franziska
author_facet Dahlke, Eileen
Anan, Yaman
Klie, Lea Maximiliane
Hartkopf, Ariane Elisabeth
Theilig, Franziska
author_sort Dahlke, Eileen
collection PubMed
description The neonatal Fc receptor (FcRn) is highly expressed in the renal proximal tubule and is important for the reclamation of albumin by cellular transcytosis to prevent its loss in the urine. The initial event of this transcellular transport mechanism is the endocytosis of albumin by the apical scavenger receptors megalin and cubilin. An interaction of megalin and FcRn was postulated, however, evidence is still missing. Similarly, the intracellular trafficking of FcRn remains unknown and shall be identified in our study. Using a Venus-based bimolecular fluorescence complementation system, we detected an interaction between megalin and FcRn in the endosomal compartment, which significantly increased with the induction of endocytosis using albumin or lactoglobulin as a ligand. The interaction between megalin and FcRn occurred at a neutral and acidic pH between the extracellular domains of both proteins. Amnionless, another transmembrane acceptor of cubilin, revealed no interaction with FcRn. With the induction of endocytosis by albumin or lactoglobulin, super resolution microscopy demonstrated a redistribution of megalin and FcRn into clathrin vesicles and early endosomes. This trafficking into clathrin vesicles was impaired in megalin-deficient cells upon albumin-induced endocytosis, supporting the role of megalin in FcRn redistribution. Our results indicate that megalin and FcRn specifically bind and interact within their extracellular domains. The availability of megalin is necessary for the redistribution of FcRn. Megalin, therefore, orchestrates FcRn endocytosis and intracellular trafficking as an early event intranscytosis.
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spelling pubmed-98184192023-01-07 Megalin Orchestrates FcRn Endocytosis and Trafficking Dahlke, Eileen Anan, Yaman Klie, Lea Maximiliane Hartkopf, Ariane Elisabeth Theilig, Franziska Cells Article The neonatal Fc receptor (FcRn) is highly expressed in the renal proximal tubule and is important for the reclamation of albumin by cellular transcytosis to prevent its loss in the urine. The initial event of this transcellular transport mechanism is the endocytosis of albumin by the apical scavenger receptors megalin and cubilin. An interaction of megalin and FcRn was postulated, however, evidence is still missing. Similarly, the intracellular trafficking of FcRn remains unknown and shall be identified in our study. Using a Venus-based bimolecular fluorescence complementation system, we detected an interaction between megalin and FcRn in the endosomal compartment, which significantly increased with the induction of endocytosis using albumin or lactoglobulin as a ligand. The interaction between megalin and FcRn occurred at a neutral and acidic pH between the extracellular domains of both proteins. Amnionless, another transmembrane acceptor of cubilin, revealed no interaction with FcRn. With the induction of endocytosis by albumin or lactoglobulin, super resolution microscopy demonstrated a redistribution of megalin and FcRn into clathrin vesicles and early endosomes. This trafficking into clathrin vesicles was impaired in megalin-deficient cells upon albumin-induced endocytosis, supporting the role of megalin in FcRn redistribution. Our results indicate that megalin and FcRn specifically bind and interact within their extracellular domains. The availability of megalin is necessary for the redistribution of FcRn. Megalin, therefore, orchestrates FcRn endocytosis and intracellular trafficking as an early event intranscytosis. MDPI 2022-12-22 /pmc/articles/PMC9818419/ /pubmed/36611847 http://dx.doi.org/10.3390/cells12010053 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dahlke, Eileen
Anan, Yaman
Klie, Lea Maximiliane
Hartkopf, Ariane Elisabeth
Theilig, Franziska
Megalin Orchestrates FcRn Endocytosis and Trafficking
title Megalin Orchestrates FcRn Endocytosis and Trafficking
title_full Megalin Orchestrates FcRn Endocytosis and Trafficking
title_fullStr Megalin Orchestrates FcRn Endocytosis and Trafficking
title_full_unstemmed Megalin Orchestrates FcRn Endocytosis and Trafficking
title_short Megalin Orchestrates FcRn Endocytosis and Trafficking
title_sort megalin orchestrates fcrn endocytosis and trafficking
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818419/
https://www.ncbi.nlm.nih.gov/pubmed/36611847
http://dx.doi.org/10.3390/cells12010053
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