Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma
Abstract 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 ubiquit...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-03-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02355-6 |
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| author | Corentin Bouvier Maria Gonzalez-Santamarta Núria Profitós-Pelejà Marc Armengol Grégoire Quinet Quentin Alasseur Laurie Ceccato Wendy Xolalpa Raimundo Freire Julie Guillermet-Guibert Karine Reybier Anne-Marie Caminade Hans C. Beck Ana Sofia Carvalho Rune Matthiesen Jean Christophe Rain James D. Sutherland Rosa Barrio Gaël Roué Manuel S. Rodriguez |
| author_facet | Corentin Bouvier Maria Gonzalez-Santamarta Núria Profitós-Pelejà Marc Armengol Grégoire Quinet Quentin Alasseur Laurie Ceccato Wendy Xolalpa Raimundo Freire Julie Guillermet-Guibert Karine Reybier Anne-Marie Caminade Hans C. Beck Ana Sofia Carvalho Rune Matthiesen Jean Christophe Rain James D. Sutherland Rosa Barrio Gaël Roué Manuel S. Rodriguez |
| author_sort | Corentin Bouvier |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-6f4d106788c641999fb705fe87aedea1 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-6f4d106788c641999fb705fe87aedea12025-08-20T03:41:46ZengNature Publishing GroupCell Death Discovery2058-77162025-03-0111111310.1038/s41420-025-02355-6Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphomaCorentin Bouvier0Maria Gonzalez-Santamarta1Núria Profitós-Pelejà2Marc Armengol3Grégoire Quinet4Quentin Alasseur5Laurie Ceccato6Wendy Xolalpa7Raimundo Freire8Julie Guillermet-Guibert9Karine Reybier10Anne-Marie Caminade11Hans C. Beck12Ana Sofia Carvalho13Rune Matthiesen14Jean Christophe Rain15James D. Sutherland16Rosa Barrio17Gaël Roué18Manuel S. Rodriguez19Laboratoire de Chimie de Coordination (LCC) CNRS-UPR8241Laboratoire de Chimie de Coordination (LCC) CNRS-UPR8241Lymphoma Translational Group, UBIRed, Josep Carreras Leukaemia Research InstituteLymphoma Translational Group, UBIRed, Josep Carreras Leukaemia Research InstituteUnidad de Investigación, Hospital Universitario de Canarias, Instituto de Investigación Sanitaria de Canarias (IISC), La LagunaBMolecular, Centre Pierre PotierLaboratoire de Chimie de Coordination (LCC) CNRS-UPR8241Departamento de Ingeniería Celular y Biocatálisis, Instituto de Biotecnología, UNAMUnidad de Investigación, Hospital Universitario de Canarias, Instituto de Investigación Sanitaria de Canarias (IISC), La LagunaCentre de Recherche en Cancerologie de Toulouse (CRCT), Inserm, CNRS, Université de ToulousePharmaDev, UMR 152, Université de Toulouse, IRD, UT3Laboratoire de Chimie de Coordination (LCC) CNRS-UPR8241Department of Clinical Biochemistry, Odense University HospitalComputational and Experimental Biology Group, iNOVA4Health, Nova Medical School, Facultade de Ciências Médicas, Universidade Nova de LisboaComputational and Experimental Biology Group, iNOVA4Health, Nova Medical School, Facultade de Ciências Médicas, Universidade Nova de LisboaHybrigenics ServicesCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkLymphoma Translational Group, UBIRed, Josep Carreras Leukaemia Research InstituteLaboratoire de Chimie de Coordination (LCC) CNRS-UPR8241Abstract 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.https://doi.org/10.1038/s41420-025-02355-6 |
| spellingShingle | Corentin Bouvier Maria Gonzalez-Santamarta Núria Profitós-Pelejà Marc Armengol Grégoire Quinet Quentin Alasseur Laurie Ceccato Wendy Xolalpa Raimundo Freire Julie Guillermet-Guibert Karine Reybier Anne-Marie Caminade Hans C. Beck Ana Sofia Carvalho Rune Matthiesen Jean Christophe Rain James D. Sutherland Rosa Barrio Gaël Roué Manuel S. Rodriguez Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma Cell Death Discovery |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41420-025-02355-6 |
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