Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder

Sequence variants in the HERC2 gene are associated with a significant reduction in HERC2 protein levels and cause a neurodevelopmental disorder known as the HERC2-related disorder, which shares clinical features with Angelman syndrome, including global developmental delay, intellectual disability, a...

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Autores: Sala-Gastón, Joan, Pérez-Villegas, E., Armengol Butrón de Mújica, José Ángel, Rawlins, Lettie E., Baple, Emma L., Crosby, Andrew H., Ventura, Francesc, Rosa, Jose Luis
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universidad Pablo de Olavide (UPO)
Repositorio:RIO. Repositorio Institucional Olavide
Idioma:inglés
OAI Identifier:oai:rio.upo.es:10433/25767
Acceso en línea:https://hdl.handle.net/10433/25767
Access Level:acceso abierto
Palabra clave:HERC2
Autofagia
USP20
ULK1
Trastorno del neurodesarrollo
Síndrome de Angelman
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spelling Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorderDesregulación de la autofagia a través del eje USP20-ULK1 en el trastorno del neurodesarrollo relacionado con HERC2Sala-Gastón, JoanPérez-Villegas, E.Armengol Butrón de Mújica, José ÁngelRawlins, Lettie E.Baple, Emma L.Crosby, Andrew H.Ventura, FrancescRosa, Jose LuisHERC2AutofagiaUSP20ULK1Trastorno del neurodesarrolloSíndrome de AngelmanSequence variants in the HERC2 gene are associated with a significant reduction in HERC2 protein levels and cause a neurodevelopmental disorder known as the HERC2-related disorder, which shares clinical features with Angelman syndrome, including global developmental delay, intellectual disability, autism, and movement disorders. Remarkably, the HERC2 gene is commonly deleted in individuals with Angelman syndrome, suggesting a potential contribution of HERC2 to the pathophysiology of this disease. Given the known critical role of autophagy in brain development and its implication in neurodevelopmental diseases, we undertook different experimental approaches to monitor autophagy in fibroblasts derived from individuals affected by the HERC2-related disorder. Our findings reveal alterations in the levels of the autophagy-related protein LC3. Furthermore, experiments with lysosomal inhibitors provide confirmation of an upregulation of the autophagy pathway in these patient-derived cells. Mechanistically, we corroborate an interaction between HERC2 and the deubiquitylating enzyme USP20; and demonstrate that HERC2 deficiency leads to increased USP20 protein levels. Notably, USP20 upregulation correlates with enhanced stability of the autophagy initiating kinase ULK1, highlighting the role of HERC2 as an autophagy regulator factor through the USP20-ULK1 axis. Moreover, we show that p38 acts as a modulator of this pathway, since p38 activation disrupts HERC2-USP20 interaction, leading to increased USP20 and LC3-II protein levels. Together, these findings uncover a previously unknown role for HERC2 in autophagy regulation and provide insights into the pathomolecular mechanisms underlying the HERC2-related disorder and Angelman syndrome.Springer Nature (CDD Press).20262026-01-2220242024-04-0320242024-04-03journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10433/25767reponame:RIO. Repositorio Institucional Olavideinstname:Universidad Pablo de Olavide (UPO)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:rio.upo.es:10433/257672026-06-13T12:46:27Z
dc.title.none.fl_str_mv Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder
Desregulación de la autofagia a través del eje USP20-ULK1 en el trastorno del neurodesarrollo relacionado con HERC2
title Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder
spellingShingle Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder
Sala-Gastón, Joan
HERC2
Autofagia
USP20
ULK1
Trastorno del neurodesarrollo
Síndrome de Angelman
title_short Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder
title_full Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder
title_fullStr Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder
title_full_unstemmed Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder
title_sort Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder
dc.creator.none.fl_str_mv Sala-Gastón, Joan
Pérez-Villegas, E.
Armengol Butrón de Mújica, José Ángel
Rawlins, Lettie E.
Baple, Emma L.
Crosby, Andrew H.
Ventura, Francesc
Rosa, Jose Luis
author Sala-Gastón, Joan
author_facet Sala-Gastón, Joan
Pérez-Villegas, E.
Armengol Butrón de Mújica, José Ángel
Rawlins, Lettie E.
Baple, Emma L.
Crosby, Andrew H.
Ventura, Francesc
Rosa, Jose Luis
author_role author
author2 Pérez-Villegas, E.
Armengol Butrón de Mújica, José Ángel
Rawlins, Lettie E.
Baple, Emma L.
Crosby, Andrew H.
Ventura, Francesc
Rosa, Jose Luis
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv HERC2
Autofagia
USP20
ULK1
Trastorno del neurodesarrollo
Síndrome de Angelman
topic HERC2
Autofagia
USP20
ULK1
Trastorno del neurodesarrollo
Síndrome de Angelman
description Sequence variants in the HERC2 gene are associated with a significant reduction in HERC2 protein levels and cause a neurodevelopmental disorder known as the HERC2-related disorder, which shares clinical features with Angelman syndrome, including global developmental delay, intellectual disability, autism, and movement disorders. Remarkably, the HERC2 gene is commonly deleted in individuals with Angelman syndrome, suggesting a potential contribution of HERC2 to the pathophysiology of this disease. Given the known critical role of autophagy in brain development and its implication in neurodevelopmental diseases, we undertook different experimental approaches to monitor autophagy in fibroblasts derived from individuals affected by the HERC2-related disorder. Our findings reveal alterations in the levels of the autophagy-related protein LC3. Furthermore, experiments with lysosomal inhibitors provide confirmation of an upregulation of the autophagy pathway in these patient-derived cells. Mechanistically, we corroborate an interaction between HERC2 and the deubiquitylating enzyme USP20; and demonstrate that HERC2 deficiency leads to increased USP20 protein levels. Notably, USP20 upregulation correlates with enhanced stability of the autophagy initiating kinase ULK1, highlighting the role of HERC2 as an autophagy regulator factor through the USP20-ULK1 axis. Moreover, we show that p38 acts as a modulator of this pathway, since p38 activation disrupts HERC2-USP20 interaction, leading to increased USP20 and LC3-II protein levels. Together, these findings uncover a previously unknown role for HERC2 in autophagy regulation and provide insights into the pathomolecular mechanisms underlying the HERC2-related disorder and Angelman syndrome.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-04-03
2024
2024-04-03
2026
2026-01-22
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10433/25767
url https://hdl.handle.net/10433/25767
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature (CDD Press).
publisher.none.fl_str_mv Springer Nature (CDD Press).
dc.source.none.fl_str_mv reponame:RIO. Repositorio Institucional Olavide
instname:Universidad Pablo de Olavide (UPO)
instname_str Universidad Pablo de Olavide (UPO)
reponame_str RIO. Repositorio Institucional Olavide
collection RIO. Repositorio Institucional Olavide
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,198674

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