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
Laboratoire de Chimie de Coordination (LCC) CNRS-UPR8241, Toulouse, 31077, France.
Lymphoma Translational Group, UBIRed, Josep Carreras Leukaemia Research Institute, 08916, Badalona, Spain.
Cell Death Discov. 2025 Mar 17;11(1):108. doi: 10.1038/s41420-025-02355-6.
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) 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.
对硼替佐米（BTZ）产生耐药性是在套细胞淋巴瘤（MCL）治疗中继续使用这种蛋白酶体抑制剂的主要瓶颈。在本研究中，我们调查了TRIM24（含三重基序的24），一种在对BTZ耐药的MCL细胞泛素组中富集的泛素连接酶，调节蛋白酶体-自噬串扰的机制。在获得性BTZ耐药的MCL细胞（ZBR）中，蛋白酶体或自噬的抑制对TRIM24的定位和稳定性有不同影响。此外，在ZBR细胞中基因缺失TRIM24基因有效地损害了细胞增殖，而不影响通常在BTZ耐药细胞中观察到的蛋白酶体通过蛋白酶体自噬的降解。值得注意的是，用靶向TRIM24的蛋白酶靶向嵌合体（PROTAC）（dTRIM24）预处理ZBR细胞成功恢复了BTZ敏感性，强调了TRIM24在介导对蛋白酶体抑制的耐药性中的关键作用。有趣的是，dTRIM24和BTZ的联合促凋亡活性在缺乏功能性p53的第二个BTZ耐药克隆（JBR）中得以保留，表明该肿瘤抑制因子对观察到的效应不是必需的。此外，我们证明通过dTRIM24处理降低BTZ耐药细胞中的TRIM24蛋白水平可恢复蛋白酶体活性，促进暴露于dTRIM24/BTZ组合的细胞中高效诱导凋亡。从机制上讲，dTRIM24处理促进了K48连接的泛素链的形成及其与蛋白酶体亚基的结合，特别是在BTZ耐药细胞中。综上所述，这些发现揭示了TRIM24通过调节泛素链丰度在BTZ耐药的MCL细胞的蛋白酶体和自噬之间的串扰中起关键调节作用，从而影响一种或另一种蛋白水解途径的激活。
