RNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association

Developmental and epileptic encephalopathies (DEE) are rare and serious neurological disorders characterized by severe epilepsy with refractory seizures and a significant developmental delay. Recently, DEE73 was linked to genetic alterations of the RNF13 gene, which convert positions 311 or 312 in t...

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Autores principales:	Valérie C. Cabana, Antoine Y. Bouchard, Audrey M. Sénécal, Kim Ghilarducci, Saïd Kourrich, Laurent Cappadocia, Marc P. Lussier
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	RNF13 AP-3 complex endosomes lysosomes intracellular trafficking genetic mutations Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/19041a9cefa4484d8aa32a40fe48c868
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spelling	oai:doaj.org-article:19041a9cefa4484d8aa32a40fe48c8682021-11-25T17:11:01ZRNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association10.3390/cells101130632073-4409https://doaj.org/article/19041a9cefa4484d8aa32a40fe48c8682021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3063https://doaj.org/toc/2073-4409Developmental and epileptic encephalopathies (DEE) are rare and serious neurological disorders characterized by severe epilepsy with refractory seizures and a significant developmental delay. Recently, DEE73 was linked to genetic alterations of the RNF13 gene, which convert positions 311 or 312 in the RNF13 protein from leucine to serine or proline, respectively (L311S and L312P). Using a fluorescence microscopy approach to investigate the molecular and cellular mechanisms affected by RNF13 protein variants, the current study shows that wild-type RNF13 localizes extensively with endosomes and lysosomes, while L311S and L312P do not extensively colocalize with the lysosomal marker Lamp1. Our results show that RNF13 L311S and L312P proteins affect the size of endosomal vesicles along with the temporal and spatial progression of fluorescently labeled epidermal growth factor, but not transferrin, in the endolysosomal system. Furthermore, GST-pulldown and co-immunoprecipitation show that RNF13 variants disrupt association with AP-3 complex. Knockdown of AP-3 complex subunit AP3D1 alters the lysosomal localization of wild-type RNF13 and similarly affects the size of endosomal vesicles. Importantly, our study provides a first step toward understanding the cellular and molecular mechanism altered by DEE73-associated genetic variations of RNF13.Valérie C. CabanaAntoine Y. BouchardAudrey M. SénécalKim GhilarducciSaïd KourrichLaurent CappadociaMarc P. LussierMDPI AGarticleRNF13AP-3 complexendosomeslysosomesintracellular traffickinggenetic mutationsBiology (General)QH301-705.5ENCells, Vol 10, Iss 3063, p 3063 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	RNF13 AP-3 complex endosomes lysosomes intracellular trafficking genetic mutations Biology (General) QH301-705.5
spellingShingle	RNF13 AP-3 complex endosomes lysosomes intracellular trafficking genetic mutations Biology (General) QH301-705.5 Valérie C. Cabana Antoine Y. Bouchard Audrey M. Sénécal Kim Ghilarducci Saïd Kourrich Laurent Cappadocia Marc P. Lussier RNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association
description	Developmental and epileptic encephalopathies (DEE) are rare and serious neurological disorders characterized by severe epilepsy with refractory seizures and a significant developmental delay. Recently, DEE73 was linked to genetic alterations of the RNF13 gene, which convert positions 311 or 312 in the RNF13 protein from leucine to serine or proline, respectively (L311S and L312P). Using a fluorescence microscopy approach to investigate the molecular and cellular mechanisms affected by RNF13 protein variants, the current study shows that wild-type RNF13 localizes extensively with endosomes and lysosomes, while L311S and L312P do not extensively colocalize with the lysosomal marker Lamp1. Our results show that RNF13 L311S and L312P proteins affect the size of endosomal vesicles along with the temporal and spatial progression of fluorescently labeled epidermal growth factor, but not transferrin, in the endolysosomal system. Furthermore, GST-pulldown and co-immunoprecipitation show that RNF13 variants disrupt association with AP-3 complex. Knockdown of AP-3 complex subunit AP3D1 alters the lysosomal localization of wild-type RNF13 and similarly affects the size of endosomal vesicles. Importantly, our study provides a first step toward understanding the cellular and molecular mechanism altered by DEE73-associated genetic variations of RNF13.
format	article
author	Valérie C. Cabana Antoine Y. Bouchard Audrey M. Sénécal Kim Ghilarducci Saïd Kourrich Laurent Cappadocia Marc P. Lussier
author_facet	Valérie C. Cabana Antoine Y. Bouchard Audrey M. Sénécal Kim Ghilarducci Saïd Kourrich Laurent Cappadocia Marc P. Lussier
author_sort	Valérie C. Cabana
title	RNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association
title_short	RNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association
title_full	RNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association
title_fullStr	RNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association
title_full_unstemmed	RNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association
title_sort	rnf13 dileucine motif variants l311s and l312p interfere with endosomal localization and ap-3 complex association
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/19041a9cefa4484d8aa32a40fe48c868
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RNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association

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