Regulation of the orphan G-protein–coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy

Megalencephalic leukoencephalopathy with subcortical cyst (MLC) is a rare leukodystrophy primarily caused by mutations in two genes: MLC1, encoding a membrane protein of unknown function, and GlialCAM, a cell adhesion molecule. Although MLC1 has been implicated in downregulating signaling pathways,...

ver descrição completa

Detalhes bibliográficos
Autores: Pont Espinós, Guillem, Pla Casillanis, Adrià, Ferigle, Laura, Alonso Gardón, Marta, González Subías, Marc, Elorza Vidal, Xabier, Gaitán-Peñas, Héctor, Errasti Murugarren, Ekaitz, Chevigné, Andy, López Hernández, Tania, Ciruela, Francisco, Estévez, Raúl
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2025
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:dnet:recercat____::51cd0cf4f9c787ffa04d8a1658a82186
Acesso em linha:https://hdl.handle.net/2445/228555
Access Level:Acceso aberto
Palavra-chave:Gliconeogènesi
Limfòcits
Immunoglobulina G
Gluconeogenesis
Lymphocytes
Immunoglobulin G
id ES_d64b7d6f6b91023ba7f177a1dbe6cda4
oai_identifier_str oai:dnet:recercat____::51cd0cf4f9c787ffa04d8a1658a82186
network_acronym_str ES
network_name_str España
repository_id_str
spelling Regulation of the orphan G-protein–coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathyPont Espinós, GuillemPla Casillanis, AdriàFerigle, LauraAlonso Gardón, MartaGonzález Subías, MarcElorza Vidal, XabierGaitán-Peñas, HéctorErrasti Murugarren, EkaitzChevigné, AndyLópez Hernández, TaniaCiruela, FranciscoEstévez, RaúlGliconeogènesiLimfòcitsImmunoglobulina GGluconeogenesisLymphocytesImmunoglobulin GMegalencephalic leukoencephalopathy with subcortical cyst (MLC) is a rare leukodystrophy primarily caused by mutations in two genes: MLC1, encoding a membrane protein of unknown function, and GlialCAM, a cell adhesion molecule. Although MLC1 has been implicated in downregulating signaling pathways, its molecular mechanisms remain elusive. Recently, the orphan G-protein-coupled receptor GPRC5B was identified as a novel interactor of both GlialCAM and MLC1, with dominant heterozygous mutations found in MLC patients, suggesting that GlialCAM and MLC1 may regulate cell signaling via GPRC5B. Here, we show that GPRC5B exhibits constitutive activity, which is inhibited by MLC1, likely through interference with GPRC5B oligomerization. Conversely, GlialCAM enhances beta-arrestin 2 recruitment, leading to its own mislocalization from cell-cell junctions. MLC-associated GPRC5B mutants show enhanced maturation and increased stability at the plasma membrane, retain normal constitutive activity and responsiveness to MLC1 and Glial-CAM but display increased affinity for GlialCAM and localize to cell-cell junctions in its presence. Notably, coexpression of GlialCAM with these mutants does not induce GlialCAM mislocalization. We propose a model in which finely tuned interactions among GPRC5B, GlialCAM, and MLC1 regulate receptor signaling. These findings provide the first biochemical evidence of GlialCAM and MLC1 modulating GPRC5B activity, suggesting a biochemical explanation for the gain-of-function phenotype observed in GPRC5B MLC mutants. Importantly, our work supports the potential of targeting GPRC5B as a therapeutic strategy in MLC.Elsevier BV2026202620252026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion16 p.application/pdfhttps://hdl.handle.net/2445/228555Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.jbc.2025.110987Journal of Biological Chemistry, 2026, vol. 302, num. 1, p. 110987https://doi.org/10.1016/j.jbc.2025.110987cc-by (c) Pont-Espinós, Guillem, et al., 2025https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:dnet:recercat____::51cd0cf4f9c787ffa04d8a1658a821862026-05-29T05:05:01Z
dc.title.none.fl_str_mv Regulation of the orphan G-protein–coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy
title Regulation of the orphan G-protein–coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy
spellingShingle Regulation of the orphan G-protein–coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy
Pont Espinós, Guillem
Gliconeogènesi
Limfòcits
Immunoglobulina G
Gluconeogenesis
Lymphocytes
Immunoglobulin G
title_short Regulation of the orphan G-protein–coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy
title_full Regulation of the orphan G-protein–coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy
title_fullStr Regulation of the orphan G-protein–coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy
title_full_unstemmed Regulation of the orphan G-protein–coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy
title_sort Regulation of the orphan G-protein–coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy
dc.creator.none.fl_str_mv Pont Espinós, Guillem
Pla Casillanis, Adrià
Ferigle, Laura
Alonso Gardón, Marta
González Subías, Marc
Elorza Vidal, Xabier
Gaitán-Peñas, Héctor
Errasti Murugarren, Ekaitz
Chevigné, Andy
López Hernández, Tania
Ciruela, Francisco
Estévez, Raúl
author Pont Espinós, Guillem
author_facet Pont Espinós, Guillem
Pla Casillanis, Adrià
Ferigle, Laura
Alonso Gardón, Marta
González Subías, Marc
Elorza Vidal, Xabier
Gaitán-Peñas, Héctor
Errasti Murugarren, Ekaitz
Chevigné, Andy
López Hernández, Tania
Ciruela, Francisco
Estévez, Raúl
author_role author
author2 Pla Casillanis, Adrià
Ferigle, Laura
Alonso Gardón, Marta
González Subías, Marc
Elorza Vidal, Xabier
Gaitán-Peñas, Héctor
Errasti Murugarren, Ekaitz
Chevigné, Andy
López Hernández, Tania
Ciruela, Francisco
Estévez, Raúl
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Gliconeogènesi
Limfòcits
Immunoglobulina G
Gluconeogenesis
Lymphocytes
Immunoglobulin G
topic Gliconeogènesi
Limfòcits
Immunoglobulina G
Gluconeogenesis
Lymphocytes
Immunoglobulin G
description Megalencephalic leukoencephalopathy with subcortical cyst (MLC) is a rare leukodystrophy primarily caused by mutations in two genes: MLC1, encoding a membrane protein of unknown function, and GlialCAM, a cell adhesion molecule. Although MLC1 has been implicated in downregulating signaling pathways, its molecular mechanisms remain elusive. Recently, the orphan G-protein-coupled receptor GPRC5B was identified as a novel interactor of both GlialCAM and MLC1, with dominant heterozygous mutations found in MLC patients, suggesting that GlialCAM and MLC1 may regulate cell signaling via GPRC5B. Here, we show that GPRC5B exhibits constitutive activity, which is inhibited by MLC1, likely through interference with GPRC5B oligomerization. Conversely, GlialCAM enhances beta-arrestin 2 recruitment, leading to its own mislocalization from cell-cell junctions. MLC-associated GPRC5B mutants show enhanced maturation and increased stability at the plasma membrane, retain normal constitutive activity and responsiveness to MLC1 and Glial-CAM but display increased affinity for GlialCAM and localize to cell-cell junctions in its presence. Notably, coexpression of GlialCAM with these mutants does not induce GlialCAM mislocalization. We propose a model in which finely tuned interactions among GPRC5B, GlialCAM, and MLC1 regulate receptor signaling. These findings provide the first biochemical evidence of GlialCAM and MLC1 modulating GPRC5B activity, suggesting a biochemical explanation for the gain-of-function phenotype observed in GPRC5B MLC mutants. Importantly, our work supports the potential of targeting GPRC5B as a therapeutic strategy in MLC.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
2026
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/2445/228555
url https://hdl.handle.net/2445/228555
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/10.1016/j.jbc.2025.110987
Journal of Biological Chemistry, 2026, vol. 302, num. 1, p. 110987
https://doi.org/10.1016/j.jbc.2025.110987
dc.rights.none.fl_str_mv cc-by (c) Pont-Espinós, Guillem, et al., 2025
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Pont-Espinós, Guillem, et al., 2025
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 16 p.
application/pdf
dc.publisher.none.fl_str_mv Elsevier BV
publisher.none.fl_str_mv Elsevier BV
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869420847218819072
score 15,81155

Registros relacionados