Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma

Bibliographic Details
Main Author: Bouvier, Corentin
Publication Date: 2025
Other Authors: Gonzalez-Santamarta, Maria, Profitós-Pelejà, Núria, Armengol, Marc, Quinet, Grégoire, Alasseur, Quentin, Ceccato, Laurie, Xolalpa, Wendy, Freire, Raimundo, Guillermet-Guibert, Julie, Reybier, Karine, Caminade, Anne Marie, Beck, Hans C., Carvalho, Ana Sofia, Matthiesen, Rune, Rain, Jean Christophe, Sutherland, James D., Barrio, Rosa, Roué, Gaël, Rodriguez, Manuel S.
Format: Article
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: http://hdl.handle.net/10362/182104
Summary: Funding Information: GR received research funding from TG Therapeutics and Kancera, to support studies unrelated to the present work. MSR is scientific director of BMolecular and does not receive any economic compensation. Funding Information: This work was supported by the UbiCODE project funded by the EU\u2019s Horizon 2020 research and innovation program under the Marie Sk\u0142odowska-Curie grant agreement No 765445, the Telethon grant number 23115, the JANUS (ANR-23-CE13-0013), the ERMMIT (ANR-24-CE44) the CONACyT-SRE (Mexico) grant 0280365, the Fondation Toulouse Cancer Sant\u00E9 (PROTRIM project) and the REPERE and pr\u00E9maturation (ubipi\u00E8ges) programs of Occitanie. The authors also acknowledge the financial support from Fondo de Investigaci\u00F3n Sanitaria PI18/01383, European Regional Development Fund (ERDF) \u201CUna manera de hacer Europa\u201D (to GR). MA was a fellow of PROTEOblood (EFA360/19), a project co-financed by the ERDF through the Interreg V-A Spain-France-Andorra (POCTEFA) program. This work was carried out, in part, under the CERCA Program (Generalitat de Catalunya). CB received support from the ARC foundation (ARCDOC42023010005996) and La ligue contre le Cancer (TAJV22303). WX received support from Consejo Nacional de Ciencia y Tecnolog\u00EDa (CONACYT) grant CB-2017-2018-A1-S-22895. RB and JDS acknowledge MCIN/AEI/10.13039/501100011033 (PID2020-114178GB-I00, PID2023-147399NB-100 and CEX2021-001136-S Severo Ochoa Excellence Program). RF is supported by grant PID2022-139691OB-I00 funded by MCIN/AEI/10.13039/501100011033 and ERDF A way of making Europe (European Union). Funding Information: We do thank all members of UbiCARE and Rosas Barrio\u00B4s Laboratory and Olivier Coux for technical help and advice. We thank the COST Action CA20113 \u2018PROTEOCURE\u2018 supported by COST (European Cooperation in Science and Technology). Publisher Copyright: © The Author(s) 2025.
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spelling Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphomaImmunologyCellular and Molecular NeuroscienceCell BiologyCancer ResearchSDG 3 - Good Health and Well-beingFunding Information: GR received research funding from TG Therapeutics and Kancera, to support studies unrelated to the present work. MSR is scientific director of BMolecular and does not receive any economic compensation. Funding Information: This work was supported by the UbiCODE project funded by the EU\u2019s Horizon 2020 research and innovation program under the Marie Sk\u0142odowska-Curie grant agreement No 765445, the Telethon grant number 23115, the JANUS (ANR-23-CE13-0013), the ERMMIT (ANR-24-CE44) the CONACyT-SRE (Mexico) grant 0280365, the Fondation Toulouse Cancer Sant\u00E9 (PROTRIM project) and the REPERE and pr\u00E9maturation (ubipi\u00E8ges) programs of Occitanie. The authors also acknowledge the financial support from Fondo de Investigaci\u00F3n Sanitaria PI18/01383, European Regional Development Fund (ERDF) \u201CUna manera de hacer Europa\u201D (to GR). MA was a fellow of PROTEOblood (EFA360/19), a project co-financed by the ERDF through the Interreg V-A Spain-France-Andorra (POCTEFA) program. This work was carried out, in part, under the CERCA Program (Generalitat de Catalunya). CB received support from the ARC foundation (ARCDOC42023010005996) and La ligue contre le Cancer (TAJV22303). WX received support from Consejo Nacional de Ciencia y Tecnolog\u00EDa (CONACYT) grant CB-2017-2018-A1-S-22895. RB and JDS acknowledge MCIN/AEI/10.13039/501100011033 (PID2020-114178GB-I00, PID2023-147399NB-100 and CEX2021-001136-S Severo Ochoa Excellence Program). RF is supported by grant PID2022-139691OB-I00 funded by MCIN/AEI/10.13039/501100011033 and ERDF A way of making Europe (European Union). Funding Information: We do thank all members of UbiCARE and Rosas Barrio\u00B4s Laboratory and Olivier Coux for technical help and advice. We thank the COST Action CA20113 \u2018PROTEOCURE\u2018 supported by COST (European Cooperation in Science and Technology). Publisher Copyright: © The Author(s) 2025.Resistance to bortezomib (BTZ) represents a major bottleneck to continue using this proteasome inhibitor in the treatment of mantle cell lymphoma (MCL). In this study, we investigated the mechanisms by which TRIM24 (tripartite motif-containing 24), a ubiquitin ligase enriched in the ubiquitome of BTZ-resistant MCL cells, modulates proteasome-autophagy crosstalk. The localization and stability of TRIM24 were differentially influenced by the inhibition of proteasome or autophagy in MCL cells with acquired BTZ resistance (ZBR). Moreover, genetic deletion of the TRIM24 gene in ZBR (ZBRTRIM24 KO) effectively impaired cell proliferation without impacting the degradation of the proteasome by proteaphagy that is typically observed in BTZ-resistant cells. Notably, pre-treatment of ZBR cells with a proteolysis-targeting chimera (PROTAC) targeting TRIM24 (dTRIM24) successfully restored BTZ susceptibility, underscoring the critical role of TRIM24 in mediating resistance to proteasome inhibition. Interestingly, the combined apoptogenic activity of dTRIM24 and BTZ was preserved in a second BTZ-resistant clone (JBR) that lacks functional p53, indicating that this tumor suppressor is not required for the observed effect. Furthermore, we demonstrated that reducing TRIM24 protein levels in BTZ-resistant cells via dTRIM24 treatment restored proteasome activity, facilitating efficient apoptosis induction in cells exposed to the dTRIM24/BTZ combination. Mechanistically, dTRIM24 treatment promoted the formation of K48-linked ubiquitin chains and their association with proteasome subunits, specifically in BTZ-resistant cells. Taken together, these findings reveal that TRIM24 plays a pivotal regulatory role in the crosstalk between the proteasome and autophagy in BTZ-resistant MCL cells by modulating ubiquitin chain abundance, thereby influencing the activation of one or the other proteolytic pathway. (Figure presented.)NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)iNOVA4Health - pólo NMSRUNBouvier, CorentinGonzalez-Santamarta, MariaProfitós-Pelejà, NúriaArmengol, MarcQuinet, GrégoireAlasseur, QuentinCeccato, LaurieXolalpa, WendyFreire, RaimundoGuillermet-Guibert, JulieReybier, KarineCaminade, Anne MarieBeck, Hans C.Carvalho, Ana SofiaMatthiesen, RuneRain, Jean ChristopheSutherland, James D.Barrio, RosaRoué, GaëlRodriguez, Manuel S.2025-04-10T16:03:16Z2025-032025-03-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/182104engPURE: 114641872https://doi.org/10.1038/s41420-025-02355-6info:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-05-12T01:45:21Zoai:run.unl.pt:10362/182104Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T06:26:02.850910Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma
title Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma
spellingShingle Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma
Bouvier, Corentin
Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research
SDG 3 - Good Health and Well-being
title_short Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma
title_full Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma
title_fullStr Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma
title_full_unstemmed Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma
title_sort Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma
author Bouvier, Corentin
author_facet Bouvier, Corentin
Gonzalez-Santamarta, Maria
Profitós-Pelejà, Núria
Armengol, Marc
Quinet, Grégoire
Alasseur, Quentin
Ceccato, Laurie
Xolalpa, Wendy
Freire, Raimundo
Guillermet-Guibert, Julie
Reybier, Karine
Caminade, Anne Marie
Beck, Hans C.
Carvalho, Ana Sofia
Matthiesen, Rune
Rain, Jean Christophe
Sutherland, James D.
Barrio, Rosa
Roué, Gaël
Rodriguez, Manuel S.
author_role author
author2 Gonzalez-Santamarta, Maria
Profitós-Pelejà, Núria
Armengol, Marc
Quinet, Grégoire
Alasseur, Quentin
Ceccato, Laurie
Xolalpa, Wendy
Freire, Raimundo
Guillermet-Guibert, Julie
Reybier, Karine
Caminade, Anne Marie
Beck, Hans C.
Carvalho, Ana Sofia
Matthiesen, Rune
Rain, Jean Christophe
Sutherland, James D.
Barrio, Rosa
Roué, Gaël
Rodriguez, Manuel S.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
iNOVA4Health - pólo NMS
RUN
dc.contributor.author.fl_str_mv Bouvier, Corentin
Gonzalez-Santamarta, Maria
Profitós-Pelejà, Núria
Armengol, Marc
Quinet, Grégoire
Alasseur, Quentin
Ceccato, Laurie
Xolalpa, Wendy
Freire, Raimundo
Guillermet-Guibert, Julie
Reybier, Karine
Caminade, Anne Marie
Beck, Hans C.
Carvalho, Ana Sofia
Matthiesen, Rune
Rain, Jean Christophe
Sutherland, James D.
Barrio, Rosa
Roué, Gaël
Rodriguez, Manuel S.
dc.subject.por.fl_str_mv Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research
SDG 3 - Good Health and Well-being
topic Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research
SDG 3 - Good Health and Well-being
description Funding Information: GR received research funding from TG Therapeutics and Kancera, to support studies unrelated to the present work. MSR is scientific director of BMolecular and does not receive any economic compensation. Funding Information: This work was supported by the UbiCODE project funded by the EU\u2019s Horizon 2020 research and innovation program under the Marie Sk\u0142odowska-Curie grant agreement No 765445, the Telethon grant number 23115, the JANUS (ANR-23-CE13-0013), the ERMMIT (ANR-24-CE44) the CONACyT-SRE (Mexico) grant 0280365, the Fondation Toulouse Cancer Sant\u00E9 (PROTRIM project) and the REPERE and pr\u00E9maturation (ubipi\u00E8ges) programs of Occitanie. The authors also acknowledge the financial support from Fondo de Investigaci\u00F3n Sanitaria PI18/01383, European Regional Development Fund (ERDF) \u201CUna manera de hacer Europa\u201D (to GR). MA was a fellow of PROTEOblood (EFA360/19), a project co-financed by the ERDF through the Interreg V-A Spain-France-Andorra (POCTEFA) program. This work was carried out, in part, under the CERCA Program (Generalitat de Catalunya). CB received support from the ARC foundation (ARCDOC42023010005996) and La ligue contre le Cancer (TAJV22303). WX received support from Consejo Nacional de Ciencia y Tecnolog\u00EDa (CONACYT) grant CB-2017-2018-A1-S-22895. RB and JDS acknowledge MCIN/AEI/10.13039/501100011033 (PID2020-114178GB-I00, PID2023-147399NB-100 and CEX2021-001136-S Severo Ochoa Excellence Program). RF is supported by grant PID2022-139691OB-I00 funded by MCIN/AEI/10.13039/501100011033 and ERDF A way of making Europe (European Union). Funding Information: We do thank all members of UbiCARE and Rosas Barrio\u00B4s Laboratory and Olivier Coux for technical help and advice. We thank the COST Action CA20113 \u2018PROTEOCURE\u2018 supported by COST (European Cooperation in Science and Technology). Publisher Copyright: © The Author(s) 2025.
publishDate 2025
dc.date.none.fl_str_mv 2025-04-10T16:03:16Z
2025-03
2025-03-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
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https://doi.org/10.1038/s41420-025-02355-6
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