Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins

Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a type of vacuolating leukodystrophy, which is mainly caused by mutations in MLC1 or GLIALCAM. The two MLC-causing genes encode for membrane proteins of yet unknown function that have been linked to the regulation of different chlor...

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Autores: Alonso Gardón, Marta, Elorza Vidal, Xabier, Castellanos, Aida, La Sala, Gina, Armand-Ugón, Mercedes, Gilbert, Alice, Di Pietro, Chiara, Pla Casillanis, Adrià, Ciruela Alférez, Francisco, Gasull Casanova, Xavier, Nunes Martínez, Virginia, Martínez, Albert, Schulte, Uwe, Cohen Salmon, Martine, Marazziti, Daniela, Estévez Povedano, Raúl
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/180120
Acesso em linha:https://hdl.handle.net/2445/180120
Access Level:acceso abierto
Palavra-chave:Mielina
Immunoglobulines
Myelin sheath
Immunoglobulins
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spelling Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteinsAlonso Gardón, MartaElorza Vidal, XabierCastellanos, AidaLa Sala, GinaArmand-Ugón, MercedesGilbert, AliceDi Pietro, ChiaraPla Casillanis, AdriàCiruela Alférez, FranciscoGasull Casanova, XavierNunes Martínez, VirginiaMartínez, AlbertSchulte, UweCohen Salmon, MartineMarazziti, DanielaEstévez Povedano, RaúlMielinaImmunoglobulinesMyelin sheathImmunoglobulinsMegalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a type of vacuolating leukodystrophy, which is mainly caused by mutations in MLC1 or GLIALCAM. The two MLC-causing genes encode for membrane proteins of yet unknown function that have been linked to the regulation of different chloride channels such as the ClC-2 and VRAC. To gain insight into the role of MLC proteins, we have determined the brain GlialCAM interacting proteome. The proteome includes different transporters and ion channels known to be involved in the regulation of brain homeostasis, proteins related to adhesion or signaling as several G protein-coupled receptors (GPCRs), including the orphan GPRC5B and the proposed prosaposin receptor GPR37L1. Focusing on these two GPCRs, we could validate that they interact directly with MLC proteins. The inactivation of Gpr37l1 in mice upregulated MLC proteins without altering their localization. Conversely, a reduction of GPRC5B levels in primary astrocytes downregulated MLC proteins, leading to an impaired activation of ClC-2 and VRAC. The interaction between the GPCRs and MLC1 was dynamically regulated upon changes in the osmolarity or potassium concentration. We propose that GlialCAM and MLC1 associate with different integral membrane proteins modulating their functions and acting as a recruitment site for various signaling components as the GPCRs identified here. We hypothesized that the GlialCAM/MLC1 complex is working as an adhesion molecule coupled to a tetraspanin-like molecule performing regulatory effects through direct binding or influencing signal transduction events.Oxford University Press (OUP)2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/180120Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1093/hmg/ddab155Human Molecular Genetics, 2021, vol. 30, num. 17, p. 1649-1665https://doi.org/10.1093/hmg/ddab155info:eu-repo/grantAgreement/EC/H2020/730879cc-by-nc (c) Alonso Gardón, Marta, et al., 2021http://creativecommons.org/licenses/by-nc/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1801202026-05-27T06:46:51Z
dc.title.none.fl_str_mv Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins
title Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins
spellingShingle Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins
Alonso Gardón, Marta
Mielina
Immunoglobulines
Myelin sheath
Immunoglobulins
title_short Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins
title_full Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins
title_fullStr Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins
title_full_unstemmed Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins
title_sort Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins
dc.creator.none.fl_str_mv Alonso Gardón, Marta
Elorza Vidal, Xabier
Castellanos, Aida
La Sala, Gina
Armand-Ugón, Mercedes
Gilbert, Alice
Di Pietro, Chiara
Pla Casillanis, Adrià
Ciruela Alférez, Francisco
Gasull Casanova, Xavier
Nunes Martínez, Virginia
Martínez, Albert
Schulte, Uwe
Cohen Salmon, Martine
Marazziti, Daniela
Estévez Povedano, Raúl
author Alonso Gardón, Marta
author_facet Alonso Gardón, Marta
Elorza Vidal, Xabier
Castellanos, Aida
La Sala, Gina
Armand-Ugón, Mercedes
Gilbert, Alice
Di Pietro, Chiara
Pla Casillanis, Adrià
Ciruela Alférez, Francisco
Gasull Casanova, Xavier
Nunes Martínez, Virginia
Martínez, Albert
Schulte, Uwe
Cohen Salmon, Martine
Marazziti, Daniela
Estévez Povedano, Raúl
author_role author
author2 Elorza Vidal, Xabier
Castellanos, Aida
La Sala, Gina
Armand-Ugón, Mercedes
Gilbert, Alice
Di Pietro, Chiara
Pla Casillanis, Adrià
Ciruela Alférez, Francisco
Gasull Casanova, Xavier
Nunes Martínez, Virginia
Martínez, Albert
Schulte, Uwe
Cohen Salmon, Martine
Marazziti, Daniela
Estévez Povedano, Raúl
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Mielina
Immunoglobulines
Myelin sheath
Immunoglobulins
topic Mielina
Immunoglobulines
Myelin sheath
Immunoglobulins
description Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a type of vacuolating leukodystrophy, which is mainly caused by mutations in MLC1 or GLIALCAM. The two MLC-causing genes encode for membrane proteins of yet unknown function that have been linked to the regulation of different chloride channels such as the ClC-2 and VRAC. To gain insight into the role of MLC proteins, we have determined the brain GlialCAM interacting proteome. The proteome includes different transporters and ion channels known to be involved in the regulation of brain homeostasis, proteins related to adhesion or signaling as several G protein-coupled receptors (GPCRs), including the orphan GPRC5B and the proposed prosaposin receptor GPR37L1. Focusing on these two GPCRs, we could validate that they interact directly with MLC proteins. The inactivation of Gpr37l1 in mice upregulated MLC proteins without altering their localization. Conversely, a reduction of GPRC5B levels in primary astrocytes downregulated MLC proteins, leading to an impaired activation of ClC-2 and VRAC. The interaction between the GPCRs and MLC1 was dynamically regulated upon changes in the osmolarity or potassium concentration. We propose that GlialCAM and MLC1 associate with different integral membrane proteins modulating their functions and acting as a recruitment site for various signaling components as the GPCRs identified here. We hypothesized that the GlialCAM/MLC1 complex is working as an adhesion molecule coupled to a tetraspanin-like molecule performing regulatory effects through direct binding or influencing signal transduction events.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/180120
url https://hdl.handle.net/2445/180120
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1093/hmg/ddab155
Human Molecular Genetics, 2021, vol. 30, num. 17, p. 1649-1665
https://doi.org/10.1093/hmg/ddab155
info:eu-repo/grantAgreement/EC/H2020/730879
dc.rights.none.fl_str_mv cc-by-nc (c) Alonso Gardón, Marta, et al., 2021
http://creativecommons.org/licenses/by-nc/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc (c) Alonso Gardón, Marta, et al., 2021
http://creativecommons.org/licenses/by-nc/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Oxford University Press (OUP)
publisher.none.fl_str_mv Oxford University Press (OUP)
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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