SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation

p14ARF is a lysine-less tumor suppressor that enhances SUMOylation of its interactors. Although p14ARF is known to interact with the E2 SUMO conjugating enzyme UBC9, the link between ARF and SUMOylation is poorly understood and the potential impact of SUMOylation on p14ARF is unknown. Here we show t...

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Autores: El Motiam, Ahmed, Bouzaher, Yanis H, Chen, Haifen, Seoane, Rocío, Vidal, Santiago, Blanquer, María, Tolosa, Rocío M, Rodríguez-Lemus, Beatriz, Herrera-Gavilán, José A, Vidal, Anxo, Palmero, Ignacio, Rodríguez, Manuel S., Sutherland, James D, Barrio, Rosa, Xirodimas, Dimitris, Collado, Manuel, Bremner, Rod, Rivas, Carmen
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2025
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositório:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/415538
Acesso em linha:http://hdl.handle.net/10261/415538
https://api.elsevier.com/content/abstract/scopus_id/105010654198
Access Level:Acceso aberto
Palavra-chave:http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
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spelling SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradationEl Motiam, AhmedBouzaher, Yanis HChen, HaifenSeoane, RocíoVidal, SantiagoBlanquer, MaríaTolosa, Rocío MRodríguez-Lemus, BeatrizHerrera-Gavilán, José AVidal, AnxoPalmero, IgnacioRodríguez, Manuel S.Sutherland, James DBarrio, RosaXirodimas, DimitrisCollado, ManuelBremner, RodRivas, Carmenhttp://metadata.un.org/sdg/3Ensure healthy lives and promote well-being for all at all agesp14ARF is a lysine-less tumor suppressor that enhances SUMOylation of its interactors. Although p14ARF is known to interact with the E2 SUMO conjugating enzyme UBC9, the link between ARF and SUMOylation is poorly understood and the potential impact of SUMOylation on p14ARF is unknown. Here we show that SUMO2 conjugates to the N-terminus of p14ARF and stabilizes it. Either depleting UBC9 or pharmacologically inhibiting SUMOylation, induces p14ARF degradation. In contrast, blocking ubiquitination or NEDDylation, with TAK-243 or MLN4924/Pevonedistat respectively, increases p14ARF SUMOylation and restores p14ARF levels when SUMOylation is blocked. Treatment with MLN4924 also causes p14ARF-dependent mRNA upregulation of the SUMOylation components SUMO1, SUMO2, and UBC9, globally augmenting SUMOylation. Finally, p14ARF contributes to MLN4924-driven cytotoxicity of prostate cancer cells. Our results provide evidence that, despite lacking lysine, p14ARF is SUMOylated and this modification is critical to counter ubiquitin driven degradation and establishes a new link between inhibition of NEDDylation and SUMOylation.Funding at the laboratory of CR is provided by Ministry of Science, Innovation and Universities and FEDER (PID2021-126510NB-I00), and Xunta de Galicia/ FEDER “Una manera de hacer Europa” (ED431G 2023/10). MB is a predoctoral fellow funded by Banco Santander and University of Santiago de Compostela. RMT is a predoctoral fellow funded by Instituto de Investigación Sanitaria de Santiago de Compostela. BRL is a predoctoral fellow funded by Asociación Española Contra el Cáncer (AECC). JAHG is funded by FPU grant from Ministry of Science and Innovation (MCIN), Spain (FPU23/00271). CR, MSR, JDC, DX, and RB acknowledge COST Action ProteoCure CA20113. RB and JDS acknowledge MCIN/AEI/10.13039/501100011033 (projects PID2023-147399NB-I00 and PID2020-114178GB-I00). IP lab is funded by PID2021-122600OB-I0.Peer reviewedSpringer NatureMinisterio de Ciencia, Innovación y Universidades (España)Xunta de GaliciaBanco SantanderUniversidad de Santiago de CompostelaAsociación Española Contra el CáncerCollado, Manuel [0000-0002-0330-0880]Rivas, Carmen [0000-0002-0518-7199]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/415538https://api.elsevier.com/content/abstract/scopus_id/105010654198reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-126510NB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2023-147399NB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-114178GB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-122600OB-I00Cell death & diseaseapplication/pdfhttps://doi.org/10.1038/s41419-025-07854-zSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4155382026-05-22T06:33:51Z
dc.title.none.fl_str_mv SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation
title SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation
spellingShingle SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation
El Motiam, Ahmed
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
title_short SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation
title_full SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation
title_fullStr SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation
title_full_unstemmed SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation
title_sort SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation
dc.creator.none.fl_str_mv El Motiam, Ahmed
Bouzaher, Yanis H
Chen, Haifen
Seoane, Rocío
Vidal, Santiago
Blanquer, María
Tolosa, Rocío M
Rodríguez-Lemus, Beatriz
Herrera-Gavilán, José A
Vidal, Anxo
Palmero, Ignacio
Rodríguez, Manuel S.
Sutherland, James D
Barrio, Rosa
Xirodimas, Dimitris
Collado, Manuel
Bremner, Rod
Rivas, Carmen
author El Motiam, Ahmed
author_facet El Motiam, Ahmed
Bouzaher, Yanis H
Chen, Haifen
Seoane, Rocío
Vidal, Santiago
Blanquer, María
Tolosa, Rocío M
Rodríguez-Lemus, Beatriz
Herrera-Gavilán, José A
Vidal, Anxo
Palmero, Ignacio
Rodríguez, Manuel S.
Sutherland, James D
Barrio, Rosa
Xirodimas, Dimitris
Collado, Manuel
Bremner, Rod
Rivas, Carmen
author_role author
author2 Bouzaher, Yanis H
Chen, Haifen
Seoane, Rocío
Vidal, Santiago
Blanquer, María
Tolosa, Rocío M
Rodríguez-Lemus, Beatriz
Herrera-Gavilán, José A
Vidal, Anxo
Palmero, Ignacio
Rodríguez, Manuel S.
Sutherland, James D
Barrio, Rosa
Xirodimas, Dimitris
Collado, Manuel
Bremner, Rod
Rivas, Carmen
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Xunta de Galicia
Banco Santander
Universidad de Santiago de Compostela
Asociación Española Contra el Cáncer
Collado, Manuel [0000-0002-0330-0880]
Rivas, Carmen [0000-0002-0518-7199]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
topic http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
description p14ARF is a lysine-less tumor suppressor that enhances SUMOylation of its interactors. Although p14ARF is known to interact with the E2 SUMO conjugating enzyme UBC9, the link between ARF and SUMOylation is poorly understood and the potential impact of SUMOylation on p14ARF is unknown. Here we show that SUMO2 conjugates to the N-terminus of p14ARF and stabilizes it. Either depleting UBC9 or pharmacologically inhibiting SUMOylation, induces p14ARF degradation. In contrast, blocking ubiquitination or NEDDylation, with TAK-243 or MLN4924/Pevonedistat respectively, increases p14ARF SUMOylation and restores p14ARF levels when SUMOylation is blocked. Treatment with MLN4924 also causes p14ARF-dependent mRNA upregulation of the SUMOylation components SUMO1, SUMO2, and UBC9, globally augmenting SUMOylation. Finally, p14ARF contributes to MLN4924-driven cytotoxicity of prostate cancer cells. Our results provide evidence that, despite lacking lysine, p14ARF is SUMOylated and this modification is critical to counter ubiquitin driven degradation and establishes a new link between inhibition of NEDDylation and SUMOylation.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
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/10261/415538
https://api.elsevier.com/content/abstract/scopus_id/105010654198
url http://hdl.handle.net/10261/415538
https://api.elsevier.com/content/abstract/scopus_id/105010654198
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-126510NB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2023-147399NB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-114178GB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-122600OB-I00
Cell death & disease
application/pdf
https://doi.org/10.1038/s41419-025-07854-z
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
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