Journal Article

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

Roué, Gaël, Rodriguez, Manuel S., Caminade, Anne-Marie, Armengol, Marc, Quinet, Grégoire, Guillermet-Guibert, Julie, Reybier, Karine, Alasseur, Quentin, Matthiesen, Rune, Profitós-Pelejà, Núria, Gonzalez-Santamarta, Maria, Freire, Raimundo, Sutherland, James D., Barrio, Rosa, Bouvier, Corentin, Rain, Jean Christophe, Xolalpa, Wendy, Ceccato, Laurie, Beck, Hans C., Carvalho, Ana Sofia

2025

Overview

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 (ZBR TRIM24 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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Springer Nature,Nature Publishing Group
• Subject: 631/45/474/2073 / 631/67/1990/291 / Apoptosis / Autophagy / Biochemistry / Biochemistry, Molecular Biology / Biomedical and Life Sciences / Bortezomib / Cell Biology / Cell Cycle Analysis / Cell proliferation / Chimeras / Gene deletion / Life Sciences / Localization / Lymphoma / Mantle cell lymphoma / p53 Protein / Proteasome inhibitors / Proteasomes / Proteolysis / Stem Cells / Tumor suppressor genes / Ubiquitin-protein ligase