SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution

21 pags., 8 figs.

Detalhes bibliográficos
Autores: Maraschi, AnnaMaria, Gumina, Valentina, Dragotto, Jessica, Colombrita, Claudia, Mompeán, Miguel, Buratti, Emanuele, Silani, Vincenzo, Feligioni, Marco, Ratti, Antonia
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/253935
Acesso em linha:http://hdl.handle.net/10261/253935
Access Level:acceso abierto
Palavra-chave:TDP-43
SUMOylation
Amyotrophic lateral sclerosis
Nucleocytoplasmic transport
Splicing
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spelling SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic DistributionMaraschi, AnnaMariaGumina, ValentinaDragotto, JessicaColombrita, ClaudiaMompeán, MiguelBuratti, EmanueleSilani, VincenzoFeligioni, MarcoRatti, AntoniaTDP-43SUMOylationAmyotrophic lateral sclerosisNucleocytoplasmic transportSplicing21 pags., 8 figs.The nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106–110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.This study was financially supported by Fondazione Italiana di Ricerca per la SLA (AriSLA) (Grant SUMALS). M.M. is granted by La Caixa Foundation (Grant LCF/BQ/PR19/11700003).Peer reviewedSpringer NatureFondazione Italiana di Ricerca per la Sclerosi Laterale AmiotroficaFundación Caixa GaliciaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202120212021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/253935reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1007/s12035-021-02505-8Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2539352026-05-22T06:33:51Z
dc.title.none.fl_str_mv SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution
title SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution
spellingShingle SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution
Maraschi, AnnaMaria
TDP-43
SUMOylation
Amyotrophic lateral sclerosis
Nucleocytoplasmic transport
Splicing
title_short SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution
title_full SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution
title_fullStr SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution
title_full_unstemmed SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution
title_sort SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution
dc.creator.none.fl_str_mv Maraschi, AnnaMaria
Gumina, Valentina
Dragotto, Jessica
Colombrita, Claudia
Mompeán, Miguel
Buratti, Emanuele
Silani, Vincenzo
Feligioni, Marco
Ratti, Antonia
author Maraschi, AnnaMaria
author_facet Maraschi, AnnaMaria
Gumina, Valentina
Dragotto, Jessica
Colombrita, Claudia
Mompeán, Miguel
Buratti, Emanuele
Silani, Vincenzo
Feligioni, Marco
Ratti, Antonia
author_role author
author2 Gumina, Valentina
Dragotto, Jessica
Colombrita, Claudia
Mompeán, Miguel
Buratti, Emanuele
Silani, Vincenzo
Feligioni, Marco
Ratti, Antonia
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica
Fundación Caixa Galicia
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv TDP-43
SUMOylation
Amyotrophic lateral sclerosis
Nucleocytoplasmic transport
Splicing
topic TDP-43
SUMOylation
Amyotrophic lateral sclerosis
Nucleocytoplasmic transport
Splicing
description 21 pags., 8 figs.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/253935
url http://hdl.handle.net/10261/253935
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1007/s12035-021-02505-8
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869422979909156864
score 15,811543

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