CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.

The survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels...

Descripción completa

Detalles Bibliográficos
Autores: Lafarga, Vanesa, Tapia, Olga, Sharma, Sahil, Bengoechea, Rocio, Stoecklin, Georg, Lafarga, Miguel, Berciano, Maria T
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26085
Acceso en línea:https://hdl.handle.net/20.500.12105/26085
Access Level:acceso abierto
Palabra clave:CBP
Cajal bodies
HDAC inhibitor
Nuclear speckles
Protein acetylation
SMA
SMN
SMN complex
SMN interactome
SnRNP
id ES_4ccfdf977d3d2110aecedf47726d6e03
oai_identifier_str oai:repisalud.isciii.es:20.500.12105/26085
network_acronym_str ES
network_name_str España
repository_id_str
spelling CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.Lafarga, VanesaTapia, OlgaSharma, SahilBengoechea, RocioStoecklin, GeorgLafarga, MiguelBerciano, Maria TCBPCajal bodiesHDAC inhibitorNuclear specklesProtein acetylationSMASMNSMN complexSMN interactomeSnRNPThe survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels in SMA lead to deficient snRNP biogenesis with consequent splicing pathology. Here, we demonstrate that SMN is a novel and specific target of the acetyltransferase CBP (CREB-binding protein). Furthermore, we identify lysine (K) 119 as the main acetylation site in SMN. Importantly, SMN acetylation enhances its cytoplasmic localization, causes depletion of CBs, and reduces the accumulation of snRNPs in nuclear speckles. In contrast, the acetylation-deficient SMNK119R mutant promotes formation of CBs and a novel category of promyelocytic leukemia (PML) bodies enriched in this protein. Acetylation increases the half-life of SMN protein, reduces its cytoplasmic diffusion rate and modifies its interactome. Hence, SMN acetylation leads to its dysfunction, which explains the ineffectiveness of HDAC (histone deacetylases) inhibitors in SMA therapy despite their potential to increase SMN levels.SpringuerEuropean Union (EU)FundAME (Spain)Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Spain20252025-01-2120182018-02-0120182018-02-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttps://hdl.handle.net/20.500.12105/26085reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)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:repisalud.isciii.es:20.500.12105/260852026-06-12T12:43:37Z
dc.title.none.fl_str_mv CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.
title CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.
spellingShingle CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.
Lafarga, Vanesa
CBP
Cajal bodies
HDAC inhibitor
Nuclear speckles
Protein acetylation
SMA
SMN
SMN complex
SMN interactome
SnRNP
title_short CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.
title_full CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.
title_fullStr CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.
title_full_unstemmed CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.
title_sort CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.
dc.creator.none.fl_str_mv Lafarga, Vanesa
Tapia, Olga
Sharma, Sahil
Bengoechea, Rocio
Stoecklin, Georg
Lafarga, Miguel
Berciano, Maria T
author Lafarga, Vanesa
author_facet Lafarga, Vanesa
Tapia, Olga
Sharma, Sahil
Bengoechea, Rocio
Stoecklin, Georg
Lafarga, Miguel
Berciano, Maria T
author_role author
author2 Tapia, Olga
Sharma, Sahil
Bengoechea, Rocio
Stoecklin, Georg
Lafarga, Miguel
Berciano, Maria T
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Union (EU)
FundAME (Spain)
Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Spain
dc.subject.none.fl_str_mv CBP
Cajal bodies
HDAC inhibitor
Nuclear speckles
Protein acetylation
SMA
SMN
SMN complex
SMN interactome
SnRNP
topic CBP
Cajal bodies
HDAC inhibitor
Nuclear speckles
Protein acetylation
SMA
SMN
SMN complex
SMN interactome
SnRNP
description The survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels in SMA lead to deficient snRNP biogenesis with consequent splicing pathology. Here, we demonstrate that SMN is a novel and specific target of the acetyltransferase CBP (CREB-binding protein). Furthermore, we identify lysine (K) 119 as the main acetylation site in SMN. Importantly, SMN acetylation enhances its cytoplasmic localization, causes depletion of CBs, and reduces the accumulation of snRNPs in nuclear speckles. In contrast, the acetylation-deficient SMNK119R mutant promotes formation of CBs and a novel category of promyelocytic leukemia (PML) bodies enriched in this protein. Acetylation increases the half-life of SMN protein, reduces its cytoplasmic diffusion rate and modifies its interactome. Hence, SMN acetylation leads to its dysfunction, which explains the ineffectiveness of HDAC (histone deacetylases) inhibitors in SMA therapy despite their potential to increase SMN levels.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018-02-01
2018
2018-02-01
2025
2025-01-21
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
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/20.500.12105/26085
url https://hdl.handle.net/20.500.12105/26085
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.publisher.none.fl_str_mv Springuer
publisher.none.fl_str_mv Springuer
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869407651184508928
score 15,808905

Similares en LA Referencia