2. Academic Validation
  3. Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma

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

  • Cell Death Discov. 2025 Mar 17;11(1):108. doi: 10.1038/s41420-025-02355-6.
Corentin Bouvier # 1,  Maria Gonzalez-Santamarta # 1,  Núria Profitós-Pelejà # 2,  Marc Armengol 2,  Grégoire Quinet 3 4,  Quentin Alasseur 5,  Laurie Ceccato 1,  Wendy Xolalpa 6,  Raimundo Freire 3 4 7,  Julie Guillermet-Guibert 8,  Karine Reybier 9,  Anne-Marie Caminade 1,  Hans C Beck 10,  Ana Sofia Carvalho 11,  Rune Matthiesen 11,  Jean Christophe Rain 12,  James D Sutherland 13,  Rosa Barrio 13,  Gaël Roué 14,  Manuel S Rodriguez 15 16 17
Affiliations

Affiliations

  • 1 Laboratoire de Chimie de Coordination (LCC) CNRS-UPR8241, Toulouse, 31077, France.
  • 2 Lymphoma Translational Group, UBIRed, Josep Carreras Leukaemia Research Institute, 08916, Badalona, Spain.
  • 3 Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Investigación Sanitaria de Canarias (IISC), La Laguna, La Laguna, Santa Cruz de Tenerife, Spain.
  • 4 Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, 38200, Santa Cruz de Tenerife, Spain.
  • 5 BMolecular, Centre Pierre Potier, Toulouse, 31100, France.
  • 6 Departamento de Ingeniería Celular y Biocatálisis, Instituto de Biotecnología, UNAM, 62210, Cuernavaca, Morelos, Mexico.
  • 7 Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
  • 8 Centre de Recherche en Cancerologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Toulouse, 31100, France.
  • 9 PharmaDev, UMR 152, Université de Toulouse, IRD, UT3, 31400, Toulouse, France.
  • 10 Department of Clinical Biochemistry, Odense University Hospital, Odense, Denmark.
  • 11 Computational and Experimental Biology Group, iNOVA4Health, Nova Medical School, Facultade de Ciências Médicas, Universidade Nova de Lisboa, 1150-082, Lisboa, Portugal.
  • 12 Hybrigenics Services, 1 rue Pierre Fontaine, 91000, Evry Genopole, France.
  • 13 Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain.
  • 14 Lymphoma Translational Group, UBIRed, Josep Carreras Leukaemia Research Institute, 08916, Badalona, Spain. groue@carrerasresearch.org.
  • 15 Laboratoire de Chimie de Coordination (LCC) CNRS-UPR8241, Toulouse, 31077, France. manuel.rodriguez@lcc-toulouse.fr.
  • 16 BMolecular, Centre Pierre Potier, Toulouse, 31100, France. manuel.rodriguez@lcc-toulouse.fr.
  • 17 PharmaDev, UMR 152, Université de Toulouse, IRD, UT3, 31400, Toulouse, France. manuel.rodriguez@lcc-toulouse.fr.
  • # Contributed equally.
PMID: 40097385 DOI: 10.1038/s41420-025-02355-6
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.

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